Materiały źródłowe

• #1

  http://www.postdocjournal.com/archives/561/genes-and-signaling-pathways-affecting-the-pathogenesis-of-melanoma.htm

  Melanoma is probably the most aggressive cancer in humans and remains one of the leading causes of cancer deaths in developed countries. Melanoma represents a very small proportion of skin cancer incidences but is responsible for 80% skin cancer deaths. […] Ultraviolet radiation emitted from the sun is the main contributing factor towards the development of melanomas. […] In this review, the genes and signaling mechanisms that play an essential role in the development and progression of melanoma are described.

• #2 Apoptosis and Pathogenesis of Melanoma and Nonmelanoma Skin Cancer | SpringerLink

  https://link.springer.com/chapter/10.1007/978-0-387-77574-6_22

  Skin cancers, i.e., basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma, belong to the most frequent tumors. Their formation is based on constitutional and/or inherited factors usually combined with environmental factors, mainly UV-irradiation through long term sun exposure. […] UV-light can randomly induce DNA damage in keratinocytes, but it can also mutate genes essential for control and surveillance in the skin epidermis. Various repair and safety mechanisms exist to maintain the integrity of the skin epidermis. For example, UV-light damaged DNA is repaired and if this is not possible, the DNA damaged cells are eliminated by apoptosis (sunburn cells). This occurs under the control of the p53 suppressor gene. […] Mutation in the p53 gene is the starting point for the formation of SCC and some forms of BCC. Other BCCs originate through UV light mediated mutations of genes of the hedgehog signaling pathway which are essential for the maintainance of cell growth and differentiation. The transcription factor Gli2 plays a key role within this pathway, indeed, Gli2 is responsible for the marked apoptosis resistance of the BCCs. The formation of malignant melanoma is very complex. Melanocytes form nevi and from the nevi melanoma can develop through mutations in various genes.

• #3 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Malignant melanoma remains one of the fastest growing cancers worldwide. […] In view of high mortality rates due to metastatic melanoma, better understanding of the molecular pathogenesis of malignant melanoma is urgently needed. […] Such information is expected to prove very valuable in early detection of potential metastatic lesions and developing newer therapeutic approaches in order to better manage this malignancy. […] The extreme difficulties encountered in therapeutic management of melanoma patients have prompted large scale efforts to elucidate the molecular pathogenesis of malignant melanoma in hopes to finding more effective treatment options. […] Studies have shown that a major risk factor for melanoma development is exposure to Ultraviolet (UV) radiation exposure. […] This suggests that UV exposure plays an important role in melanoma tumorigenesis.

• #4 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  Melanomas have two growth phases: radial and vertical. During the radial growth phase, malignant cells grow in a radial fashion in the epidermis. With time, most melanomas progress to the vertical growth phase, in which the malignant cells invade the dermis and develop the ability to metastasize. This is usually indicated by a dermal nest larger than the largest junctional nest, a dermal nest with mitosis, or a dermal nest within reticular dermis. […] Melanomas originate from melanocytes, which arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis. […] Exposure to ultraviolet (UV) radiation is a critical factor in the development of most melanomas. Ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-320 nm, potentially are carcinogenic and actually may work in concert to induce a melanoma.

• #5 Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8232613/

  Melanoma develops from malignant transformations of the pigment-producing melanocytes. […] The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. […] Exposure to ultraviolet radiation is the leading risk factor for the development cM. […] The pro-oxidant action of the melanin results in an increase in the levels of intracellular oxygen radicals, which in turn causes damage to the DNA molecule of the melanocyte. […] The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. […] In 80% of the cases of melanoma or melanocytic nevi, mutations in NRAS or BRAF genes are observed, which confirms the crucial role of the MAPK pathway.

• #6 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma. […] The mitogen-activated protein kinase (MAPK) pathway, phosphoinositol-3-kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways. […] Melanocytes are neural crest-derived cells that can be found principally in the basal epidermis and in hair follicles, along mucosal surfaces, meninges and in the choroidal layer of the eye. […] In response to UV-induced DNA damage, skin keratinocytes produce the melanocyte stimulating hormone (MSH) that binds the melanocortin receptor 1 (MC1R) on the melanocytes that then produce and release melanin.

• #7 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  Melanomas have two growth phases: radial and vertical. During the radial growth phase, malignant cells grow in a radial fashion in the epidermis. With time, most melanomas progress to the vertical growth phase, in which the malignant cells invade the dermis and develop the ability to metastasize. This is usually indicated by a dermal nest larger than the largest junctional nest, a dermal nest with mitosis, or a dermal nest within reticular dermis. […] Melanomas originate from melanocytes, which arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis. […] Exposure to ultraviolet (UV) radiation is a critical factor in the development of most melanomas. Ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-320 nm, potentially are carcinogenic and actually may work in concert to induce a melanoma.

• #8 Melanoma Mechanism and Characteristics – Skin Cancer – Dermatology – Picmonic for Medicine

  https://www.picmonic.com/pathways/medicine/courses/standard/dermatology-10689/skin-cancer-39080/melanoma-mechanism-and-characteristics_1421

  The early stage of the disease is known as the radial growth phase when the tumor is less than 1 mm thick. Because the cancer cells have not yet reached the blood vessels lower in the skin, it is very unlikely that this early-stage cancer will spread to other parts of the body. If the melanoma is detected at this stage, it can usually be completely removed with resection. […] As the cancer cells have not yet reached the blood vessels lower in the skin, it is very unlikely that this early-stage cancer will metastasize to other parts of the body. […] The following step in the process is the invasive melanoma, the vertical growth phase. The tumor attains invasive potential, allowing it to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than 1 mm and involves the deeper parts of the dermis. […] During the vertical growth phase, the depth of tumor invasion correlates with the risk of metastasis.

• #9 Melanoma Mechanism and Characteristics – Skin Cancer – Dermatology – Picmonic for Medicine

  https://www.picmonic.com/pathways/medicine/courses/standard/dermatology-10689/skin-cancer-39080/melanoma-mechanism-and-characteristics_1421

  The early stage of the disease is known as the radial growth phase when the tumor is less than 1 mm thick. Because the cancer cells have not yet reached the blood vessels lower in the skin, it is very unlikely that this early-stage cancer will spread to other parts of the body. If the melanoma is detected at this stage, it can usually be completely removed with resection. […] As the cancer cells have not yet reached the blood vessels lower in the skin, it is very unlikely that this early-stage cancer will metastasize to other parts of the body. […] The following step in the process is the invasive melanoma, the vertical growth phase. The tumor attains invasive potential, allowing it to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than 1 mm and involves the deeper parts of the dermis. […] During the vertical growth phase, the depth of tumor invasion correlates with the risk of metastasis.

• #10 Melanoma Mechanism and Characteristics – Skin Cancer – Dermatology – Picmonic for Medicine

  https://www.picmonic.com/pathways/medicine/courses/standard/dermatology-10689/skin-cancer-39080/melanoma-mechanism-and-characteristics_1421

  The early stage of the disease is known as the radial growth phase when the tumor is less than 1 mm thick. Because the cancer cells have not yet reached the blood vessels lower in the skin, it is very unlikely that this early-stage cancer will spread to other parts of the body. If the melanoma is detected at this stage, it can usually be completely removed with resection. […] As the cancer cells have not yet reached the blood vessels lower in the skin, it is very unlikely that this early-stage cancer will metastasize to other parts of the body. […] The following step in the process is the invasive melanoma, the vertical growth phase. The tumor attains invasive potential, allowing it to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than 1 mm and involves the deeper parts of the dermis. […] During the vertical growth phase, the depth of tumor invasion correlates with the risk of metastasis.

• #11 Melanoma – Wikipedia

  https://en.wikipedia.org/wiki/Melanoma

  Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. […] The primary cause of melanoma is ultraviolet light (UV) exposure in those with low levels of the skin pigment melanin. […] A number of rare genetic conditions, such as xeroderma pigmentosum, also increase the risk. […] The earliest stage of melanoma starts when melanocytes begin out-of-control growth. […] The next step in the evolution is the invasive radial growth phase, in which individual cells start to acquire invasive potential. […] The vertical growth phase (VGP) following is invasive melanoma. […] About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the Raf to MAP kinase pathway.

• #12 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  Melanomas have two growth phases: radial and vertical. During the radial growth phase, malignant cells grow in a radial fashion in the epidermis. With time, most melanomas progress to the vertical growth phase, in which the malignant cells invade the dermis and develop the ability to metastasize. This is usually indicated by a dermal nest larger than the largest junctional nest, a dermal nest with mitosis, or a dermal nest within reticular dermis. […] Melanomas originate from melanocytes, which arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis. […] Exposure to ultraviolet (UV) radiation is a critical factor in the development of most melanomas. Ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-320 nm, potentially are carcinogenic and actually may work in concert to induce a melanoma.

• #13 Melanoma Mechanism and Characteristics – Skin Cancer – Dermatology – Picmonic for Medicine

  https://www.picmonic.com/pathways/medicine/courses/standard/dermatology-10689/skin-cancer-39080/melanoma-mechanism-and-characteristics_1421

  The early stage of the disease is known as the radial growth phase when the tumor is less than 1 mm thick. Because the cancer cells have not yet reached the blood vessels lower in the skin, it is very unlikely that this early-stage cancer will spread to other parts of the body. If the melanoma is detected at this stage, it can usually be completely removed with resection. […] As the cancer cells have not yet reached the blood vessels lower in the skin, it is very unlikely that this early-stage cancer will metastasize to other parts of the body. […] The following step in the process is the invasive melanoma, the vertical growth phase. The tumor attains invasive potential, allowing it to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than 1 mm and involves the deeper parts of the dermis. […] During the vertical growth phase, the depth of tumor invasion correlates with the risk of metastasis.

• #14 Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8232613/

  Melanoma develops from malignant transformations of the pigment-producing melanocytes. […] The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. […] Exposure to ultraviolet radiation is the leading risk factor for the development cM. […] The pro-oxidant action of the melanin results in an increase in the levels of intracellular oxygen radicals, which in turn causes damage to the DNA molecule of the melanocyte. […] The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. […] In 80% of the cases of melanoma or melanocytic nevi, mutations in NRAS or BRAF genes are observed, which confirms the crucial role of the MAPK pathway.

• #15 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Malignant melanoma remains one of the fastest growing cancers worldwide. […] In view of high mortality rates due to metastatic melanoma, better understanding of the molecular pathogenesis of malignant melanoma is urgently needed. […] Such information is expected to prove very valuable in early detection of potential metastatic lesions and developing newer therapeutic approaches in order to better manage this malignancy. […] The extreme difficulties encountered in therapeutic management of melanoma patients have prompted large scale efforts to elucidate the molecular pathogenesis of malignant melanoma in hopes to finding more effective treatment options. […] Studies have shown that a major risk factor for melanoma development is exposure to Ultraviolet (UV) radiation exposure. […] This suggests that UV exposure plays an important role in melanoma tumorigenesis.

• #16 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  Melanomas have two growth phases: radial and vertical. During the radial growth phase, malignant cells grow in a radial fashion in the epidermis. With time, most melanomas progress to the vertical growth phase, in which the malignant cells invade the dermis and develop the ability to metastasize. This is usually indicated by a dermal nest larger than the largest junctional nest, a dermal nest with mitosis, or a dermal nest within reticular dermis. […] Melanomas originate from melanocytes, which arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis. […] Exposure to ultraviolet (UV) radiation is a critical factor in the development of most melanomas. Ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-320 nm, potentially are carcinogenic and actually may work in concert to induce a melanoma.

• #17 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  UV radiation appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA. […] Interestingly, melanoma does not have a direct relationship with the amount of sun exposure, because it is more common in white-collar workers than in those who work outdoors. […] Acute, intense, and intermittent blistering sunburns, especially on areas of the body that only occasionally receive sun exposure, are the greatest risk factor for the development of sun exposure-induced melanoma on the trunk and legs, whereas lentigo maligna is associated with chronic sun exposure. This sun-associated risk factor is different from that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

• #18 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Additional experiments have shown that UV radiation frequently leads to DNA mutations, such as the formation of pyrimidine dimers or deamination of cytosine into thymidine. […] Cutaneous melanoma samples demonstrate a high base mutation rate that exceeds that of almost every other form of solid cancer, which may be attributed to the potency of UV mutagenic effects. […] Identifying the specific molecular changes that allow melanoma cells to have a growth and survival advantage over others may allow for the development of more effective targeted therapies that can improve the prognosis of melanoma patients. […] Studies have shown that around 40-60% of all melanoma cases exhibit an activated BRAF mutation. […] The result is uncontrolled cell proliferation and that may play a role in tumor development and growth.

• #19 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Additional experiments have shown that UV radiation frequently leads to DNA mutations, such as the formation of pyrimidine dimers or deamination of cytosine into thymidine. […] Cutaneous melanoma samples demonstrate a high base mutation rate that exceeds that of almost every other form of solid cancer, which may be attributed to the potency of UV mutagenic effects. […] Identifying the specific molecular changes that allow melanoma cells to have a growth and survival advantage over others may allow for the development of more effective targeted therapies that can improve the prognosis of melanoma patients. […] Studies have shown that around 40-60% of all melanoma cases exhibit an activated BRAF mutation. […] The result is uncontrolled cell proliferation and that may play a role in tumor development and growth.

• #20 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  UV radiation appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA. […] Interestingly, melanoma does not have a direct relationship with the amount of sun exposure, because it is more common in white-collar workers than in those who work outdoors. […] Acute, intense, and intermittent blistering sunburns, especially on areas of the body that only occasionally receive sun exposure, are the greatest risk factor for the development of sun exposure-induced melanoma on the trunk and legs, whereas lentigo maligna is associated with chronic sun exposure. This sun-associated risk factor is different from that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

• #21 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  UV radiation appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA. […] Interestingly, melanoma does not have a direct relationship with the amount of sun exposure, because it is more common in white-collar workers than in those who work outdoors. […] Acute, intense, and intermittent blistering sunburns, especially on areas of the body that only occasionally receive sun exposure, are the greatest risk factor for the development of sun exposure-induced melanoma on the trunk and legs, whereas lentigo maligna is associated with chronic sun exposure. This sun-associated risk factor is different from that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

• #22 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  UV radiation appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA. […] Interestingly, melanoma does not have a direct relationship with the amount of sun exposure, because it is more common in white-collar workers than in those who work outdoors. […] Acute, intense, and intermittent blistering sunburns, especially on areas of the body that only occasionally receive sun exposure, are the greatest risk factor for the development of sun exposure-induced melanoma on the trunk and legs, whereas lentigo maligna is associated with chronic sun exposure. This sun-associated risk factor is different from that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

• #23 Malignant Melanoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/280245-overview

  UV radiation appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA. […] Interestingly, melanoma does not have a direct relationship with the amount of sun exposure, because it is more common in white-collar workers than in those who work outdoors. […] Acute, intense, and intermittent blistering sunburns, especially on areas of the body that only occasionally receive sun exposure, are the greatest risk factor for the development of sun exposure-induced melanoma on the trunk and legs, whereas lentigo maligna is associated with chronic sun exposure. This sun-associated risk factor is different from that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

• #24 Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8232613/

  Melanoma develops from malignant transformations of the pigment-producing melanocytes. […] The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. […] Exposure to ultraviolet radiation is the leading risk factor for the development cM. […] The pro-oxidant action of the melanin results in an increase in the levels of intracellular oxygen radicals, which in turn causes damage to the DNA molecule of the melanocyte. […] The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. […] In 80% of the cases of melanoma or melanocytic nevi, mutations in NRAS or BRAF genes are observed, which confirms the crucial role of the MAPK pathway.

• #25 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Additional experiments have shown that UV radiation frequently leads to DNA mutations, such as the formation of pyrimidine dimers or deamination of cytosine into thymidine. […] Cutaneous melanoma samples demonstrate a high base mutation rate that exceeds that of almost every other form of solid cancer, which may be attributed to the potency of UV mutagenic effects. […] Identifying the specific molecular changes that allow melanoma cells to have a growth and survival advantage over others may allow for the development of more effective targeted therapies that can improve the prognosis of melanoma patients. […] Studies have shown that around 40-60% of all melanoma cases exhibit an activated BRAF mutation. […] The result is uncontrolled cell proliferation and that may play a role in tumor development and growth.

• #26 Melanoma – Wikipedia

  https://en.wikipedia.org/wiki/Melanoma

  Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. […] The primary cause of melanoma is ultraviolet light (UV) exposure in those with low levels of the skin pigment melanin. […] A number of rare genetic conditions, such as xeroderma pigmentosum, also increase the risk. […] The earliest stage of melanoma starts when melanocytes begin out-of-control growth. […] The next step in the evolution is the invasive radial growth phase, in which individual cells start to acquire invasive potential. […] The vertical growth phase (VGP) following is invasive melanoma. […] About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the Raf to MAP kinase pathway.

• #27 What Causes Melanoma? | Causes of Melanoma Skin Cancer | American Cancer Society

  https://www.cancer.org/cancer/types/melanoma-skin-cancer/causes-risks-prevention/what-causes.html

  While there are many known risk factors for melanoma, it’s not always exactly clear how they might cause cancer. […] Researchers have found some gene changes inside mole cells that may cause them to become melanoma cells. […] Changes in genes that normally help cells grow, divide, or stay alive can lead to these genes being more active than they should be, causing them to become oncogenes. […] Genes that normally help keep cell division under control or cause cells to die at the right time are known as tumor suppressor genes. […] Changes that turn off these genes can result in cells growing out of control. […] Changes that turn off these DNA repair genes can result in the buildup of DNA changes within a cell, which might lead to them growing out of control. […] Most often, gene changes related to melanoma are acquired during a person’s lifetime and are not passed on to a person’s children (inherited).

• #28 What Causes Melanoma? | Causes of Melanoma Skin Cancer | American Cancer Society

  https://www.cancer.org/cancer/types/melanoma-skin-cancer/causes-risks-prevention/what-causes.html

  UV rays can damage the DNA in skin cells. […] The most common change in melanoma cells is a mutation in the BRAF oncogene, which is found in about half of all melanomas. […] Familial (inherited) melanomas most often have changes in tumor suppressor genes, such as CDKN2A (also known as p16), CDK4, or BAP1, that prevent these genes from doing their normal job of controlling cell growth. […] Some of the gene changes found in melanoma cells have proven to be good targets for drugs to help treat this disease.

• #29 What Causes Melanoma? | Causes of Melanoma Skin Cancer | American Cancer Society

  https://www.cancer.org/cancer/types/melanoma-skin-cancer/causes-risks-prevention/what-causes.html

  UV rays can damage the DNA in skin cells. […] The most common change in melanoma cells is a mutation in the BRAF oncogene, which is found in about half of all melanomas. […] Familial (inherited) melanomas most often have changes in tumor suppressor genes, such as CDKN2A (also known as p16), CDK4, or BAP1, that prevent these genes from doing their normal job of controlling cell growth. […] Some of the gene changes found in melanoma cells have proven to be good targets for drugs to help treat this disease.

• #30 What Causes Melanoma? | Causes of Melanoma Skin Cancer | American Cancer Society

  https://www.cancer.org/cancer/types/melanoma-skin-cancer/causes-risks-prevention/what-causes.html

  While there are many known risk factors for melanoma, it’s not always exactly clear how they might cause cancer. […] Researchers have found some gene changes inside mole cells that may cause them to become melanoma cells. […] Changes in genes that normally help cells grow, divide, or stay alive can lead to these genes being more active than they should be, causing them to become oncogenes. […] Genes that normally help keep cell division under control or cause cells to die at the right time are known as tumor suppressor genes. […] Changes that turn off these genes can result in cells growing out of control. […] Changes that turn off these DNA repair genes can result in the buildup of DNA changes within a cell, which might lead to them growing out of control. […] Most often, gene changes related to melanoma are acquired during a person’s lifetime and are not passed on to a person’s children (inherited).

• #31 Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8232613/

  Melanoma develops from malignant transformations of the pigment-producing melanocytes. […] The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. […] Exposure to ultraviolet radiation is the leading risk factor for the development cM. […] The pro-oxidant action of the melanin results in an increase in the levels of intracellular oxygen radicals, which in turn causes damage to the DNA molecule of the melanocyte. […] The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. […] In 80% of the cases of melanoma or melanocytic nevi, mutations in NRAS or BRAF genes are observed, which confirms the crucial role of the MAPK pathway.

• #32 Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8232613/

  Melanoma develops from malignant transformations of the pigment-producing melanocytes. […] The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. […] Exposure to ultraviolet radiation is the leading risk factor for the development cM. […] The pro-oxidant action of the melanin results in an increase in the levels of intracellular oxygen radicals, which in turn causes damage to the DNA molecule of the melanocyte. […] The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. […] In 80% of the cases of melanoma or melanocytic nevi, mutations in NRAS or BRAF genes are observed, which confirms the crucial role of the MAPK pathway.

• #33 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Additional experiments have shown that UV radiation frequently leads to DNA mutations, such as the formation of pyrimidine dimers or deamination of cytosine into thymidine. […] Cutaneous melanoma samples demonstrate a high base mutation rate that exceeds that of almost every other form of solid cancer, which may be attributed to the potency of UV mutagenic effects. […] Identifying the specific molecular changes that allow melanoma cells to have a growth and survival advantage over others may allow for the development of more effective targeted therapies that can improve the prognosis of melanoma patients. […] Studies have shown that around 40-60% of all melanoma cases exhibit an activated BRAF mutation. […] The result is uncontrolled cell proliferation and that may play a role in tumor development and growth.

• #34 What Causes Melanoma? | Causes of Melanoma Skin Cancer | American Cancer Society

  https://www.cancer.org/cancer/types/melanoma-skin-cancer/causes-risks-prevention/what-causes.html

  UV rays can damage the DNA in skin cells. […] The most common change in melanoma cells is a mutation in the BRAF oncogene, which is found in about half of all melanomas. […] Familial (inherited) melanomas most often have changes in tumor suppressor genes, such as CDKN2A (also known as p16), CDK4, or BAP1, that prevent these genes from doing their normal job of controlling cell growth. […] Some of the gene changes found in melanoma cells have proven to be good targets for drugs to help treat this disease.

• #35 Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8232613/

  BRAF is a serine/threonine kinase that is activated directly by RAS and is strongly expressed in melanocytes, neural tissue, testes, and hematopoietic cells. […] Mutations, leading to increased RAS activity in melanomas also increase cell proliferation, but this occurs significantly less frequently than in other solid tumours. […] c-KIT mutations cause insufficient pigmentation. […] Overexpression of another tyrosine kinase receptor c-MET and its ligand HGF (hepatocyte growth factor) correlates with melanoma progression. […] The hypoxic response is primarily mediated by HIF. […] The Notch signalling pathway has a substantial potential for the development and maintenance of tissue homeostasis. […] Telomerase reverse transcriptase (TERT) is a gene located on chromosome 5p15.33 and encodes the catalytic subunit of telomerase. […] Numerous cellular interactions, mediated by their cell adhesion molecules (cadherins and adherents) also play an important part in the pathogenesis of melanoma.

• #36 Melanoma Mechanism and Characteristics – Skin Cancer – Dermatology – Picmonic for Medicine

  https://www.picmonic.com/pathways/medicine/courses/standard/dermatology-10689/skin-cancer-39080/melanoma-mechanism-and-characteristics_1421

  Melanoma, in roughly 40% of patients, is driven by activating a mutation in B-RAF kinase. […] UV radiation from sunlight exposure and tanning beds is a carcinogen. The p16 pathway is favored at low doses of UV radiation and results in cell-cycle arrest. On the contrary, the p53 pathway is more responsive to higher doses and induces apoptosis depending on p53 mutation status. […] About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf kinase protein. […] Moles, or nevi, are often precursors to melanoma. Thus patients with many moles should monitor those that are irregular in color or shape and treat them as candidates for melanoma. […] The risk of melanoma is more than 10 times higher for whites than for African Americans. Whites with red or blond hair, blue or green eyes, or fair skin that freckles or burns easily are at increased risk.

• #37 Melanoma – Wikipedia

  https://en.wikipedia.org/wiki/Melanoma

  A cause common to most cancers is damage to DNA. […] If unrepaired, cyclobutane pyrimidine dimer (CPD) photoproducts can lead to mutations by inaccurate translesion synthesis during DNA replication or repair. […] The entire genomes of 25 melanomas were sequenced. […] On average, about 80,000 mutated bases (mostly C>T transitions) and about 100 structural rearrangements were found per melanoma genome. […] The most frequent mutation occurs in the 600th codon of BRAF (50% of cases). […] BRAF is normally involved in cell growth, and this specific mutation renders the protein constitutively active and independent of normal physiological regulation, thus fostering tumor growth. […] The likelihood that melanoma will reoccur or spread depends on its thickness, how fast the cells are dividing, and whether or not the overlying skin has broken down.

• #38 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  Up to 90% of melanomas exhibit an aberrant MAPK pathway activation and this is a central step in melanoma development, being responsible for cell cycle deregulation and apoptosis inhibition. […] Among the different mechanisms responsible for abnormal MAPK pathway signaling in melanoma, the most frequent genetic abnormalities are, by far, BRAF mutations. […] Indeed, 37 to 50% of melanomas carry a somatic mutation in the BRAF gene with the highest frequency in cutaneous melanomas derived from intermittent sun exposure damage. […] The catalytic domain is also responsible for maintaining the protein in its inactive conformation, through a hydrophobic interaction between the 'so-called’ glycine-rich loop and the activation segment, making it inaccessible for ATP binding. […] In the BRAFV600E mutation, hydrophobic valine is replaced by polar, hydrophilic glutamic acid, resulting in an abnormal flip of the catalytic domain that generates a constitutive active conformation with a kinase activity 500-fold higher than wild-type BRAF kinase.

• #39 Signal pathways of melanoma and targeted therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00827-6

  The presence of BRAF mutations has great potential in predicting an unfavorable prognosis in melanoma patients. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas.

• #40 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  The high prevalence of the BRAFV600E mutation in melanoma patients makes this a prime target for anti-melanoma therapeutics. […] Another source of molecular changes that may allow for melanoma initiation or propagation is found in the NRAS GTPase or neuroblastoma RAS oncogene. […] The patients with NRAS mutations possess thick vertical growth tumors that researchers attribute to the heightened cell proliferations rates induced by the NRAS mutation. […] The PI3K-AKT pathway is a separate mechanistic route that also plays a role in cell proliferation and survival. […] When this pathway is hyper-active or has lost its negative feedback regulation system, then chemotherapy and radiation therapy may lose their death inducing therapeutic potencies. […] The role of p53 in melanoma is disputed.

• #41 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  The high prevalence of the BRAFV600E mutation in melanoma patients makes this a prime target for anti-melanoma therapeutics. […] Another source of molecular changes that may allow for melanoma initiation or propagation is found in the NRAS GTPase or neuroblastoma RAS oncogene. […] The patients with NRAS mutations possess thick vertical growth tumors that researchers attribute to the heightened cell proliferations rates induced by the NRAS mutation. […] The PI3K-AKT pathway is a separate mechanistic route that also plays a role in cell proliferation and survival. […] When this pathway is hyper-active or has lost its negative feedback regulation system, then chemotherapy and radiation therapy may lose their death inducing therapeutic potencies. […] The role of p53 in melanoma is disputed.

• #42 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  The second most common cause of aberrant signaling through the MAPK pathway in cutaneous melanoma is represented by NRAS activating mutations. […] NRAS is mutated in 15-30% of melanomas and in the majority of cases, these mutations are missense mutations of codon 12, 13 or 61. […] Importantly, NRAS and BRAF mutations are considered mutually exclusive; however, co-mutations can rarely occur. […] NF1 is a tumor suppressor gene mutated in 10-15% of melanoma cases and is the third most frequently mutated gene in melanoma. […] The NF1 protein regulates the RAS family by converting the active RAS-guanosine triphosphate (RAS-GTP) to the inactive RAS-guanosine diphosphate (RAS-GDP), thereby inhibiting downstream RAS signaling. […] Therefore, NF1 loss-of-function determines the hyperactivation of NRAS protein and thus, increased MAPK and PI3K pathways signaling.

• #43 Signal pathways of melanoma and targeted therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00827-6

  The pro-tumorigenic effect of trauma and chronic inflammation might result from the increased cytokines and ROS that can induce genetic instability or activate oncogenic pathways in melanocytes. […] The activation of AKT and mTOR downstream effector 4E-BP1 is in strongly positive correlation with the aggressiveness of melanoma, and the poor prognosis of patients in two independent cohorts. […] The loss of NF1 or inactivating NF1 mutation are present in 46% of melanomas expressing wild-type BRAF and RAS, which leads to constitute activation of Ras by lessening its intrinsic GTPase activity and induces hyper-activation of MAPK pathway. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas. […] The presence of BRAF mutations has great potential in predicting an unfavorable prognosis in melanoma patients.

• #44 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  The high prevalence of the BRAFV600E mutation in melanoma patients makes this a prime target for anti-melanoma therapeutics. […] Another source of molecular changes that may allow for melanoma initiation or propagation is found in the NRAS GTPase or neuroblastoma RAS oncogene. […] The patients with NRAS mutations possess thick vertical growth tumors that researchers attribute to the heightened cell proliferations rates induced by the NRAS mutation. […] The PI3K-AKT pathway is a separate mechanistic route that also plays a role in cell proliferation and survival. […] When this pathway is hyper-active or has lost its negative feedback regulation system, then chemotherapy and radiation therapy may lose their death inducing therapeutic potencies. […] The role of p53 in melanoma is disputed.

• #45 Molecular Frontiers in Melanoma: Pathogenesis, Diagnosis, and Therapeutic Advances

  https://www.mdpi.com/1422-0067/25/5/2984

  NRAS mutations, which are found in 15–20% of melanoma cases, are significant drivers of the disease, affecting melanoma development through a distinct pathway. These mutations activate the MAPK pathway, albeit through a mechanism different from that of BRAF mutations. […] c-KIT mutations, while less common than BRAF and NRAS mutations, play a significant role in certain melanoma subtypes, particularly mucosal and acral melanomas. […] GNAQ/GNA11 mutations, commonly identified in uveal melanomas, represent a distinct genetic subgroup within melanoma. Despite the current limitations of available treatments, these mutations are under active study for targeted therapy options, reflecting a growing interest in developing specific treatments for these subtypes. […] The MAPK/ERK pathway is central to melanoma, with alterations in this pathway often driving tumorigenesis. This pathway, which includes RAS, RAF, ERK, and mitogen-activated extracellular signal-regulated kinase (MEK), is crucial for regulating cellular proliferation.

• #46 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  The second most common cause of aberrant signaling through the MAPK pathway in cutaneous melanoma is represented by NRAS activating mutations. […] NRAS is mutated in 15-30% of melanomas and in the majority of cases, these mutations are missense mutations of codon 12, 13 or 61. […] Importantly, NRAS and BRAF mutations are considered mutually exclusive; however, co-mutations can rarely occur. […] NF1 is a tumor suppressor gene mutated in 10-15% of melanoma cases and is the third most frequently mutated gene in melanoma. […] The NF1 protein regulates the RAS family by converting the active RAS-guanosine triphosphate (RAS-GTP) to the inactive RAS-guanosine diphosphate (RAS-GDP), thereby inhibiting downstream RAS signaling. […] Therefore, NF1 loss-of-function determines the hyperactivation of NRAS protein and thus, increased MAPK and PI3K pathways signaling.

• #47 Molecular Frontiers in Melanoma: Pathogenesis, Diagnosis, and Therapeutic Advances

  https://www.mdpi.com/1422-0067/25/5/2984

  The PI3K/AKT/mTOR pathway plays a central role in melanoma development, affecting cell survival, proliferation, and metastasis. Its activation, often driven by genetic mutations and signaling imbalances, underscores the need for targeted therapeutic interventions. […] Recent studies have highlighted the complex roles of melanin and melanogenesis in melanoma, revealing their protective effects against UV radiation and their potential to promote malignant transformation. […] Melanoma’s ability to influence both local and systemic physiological responses through the secretion of neuroendocrine factors, including proopiomelanocortin (POMC) peptides, corticotropin-releasing hormone (CRH), and glucocorticoids, underscores its complex role in the body’s regulatory systems.

• #48 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  The high prevalence of the BRAFV600E mutation in melanoma patients makes this a prime target for anti-melanoma therapeutics. […] Another source of molecular changes that may allow for melanoma initiation or propagation is found in the NRAS GTPase or neuroblastoma RAS oncogene. […] The patients with NRAS mutations possess thick vertical growth tumors that researchers attribute to the heightened cell proliferations rates induced by the NRAS mutation. […] The PI3K-AKT pathway is a separate mechanistic route that also plays a role in cell proliferation and survival. […] When this pathway is hyper-active or has lost its negative feedback regulation system, then chemotherapy and radiation therapy may lose their death inducing therapeutic potencies. […] The role of p53 in melanoma is disputed.

• #49 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  The high prevalence of the BRAFV600E mutation in melanoma patients makes this a prime target for anti-melanoma therapeutics. […] Another source of molecular changes that may allow for melanoma initiation or propagation is found in the NRAS GTPase or neuroblastoma RAS oncogene. […] The patients with NRAS mutations possess thick vertical growth tumors that researchers attribute to the heightened cell proliferations rates induced by the NRAS mutation. […] The PI3K-AKT pathway is a separate mechanistic route that also plays a role in cell proliferation and survival. […] When this pathway is hyper-active or has lost its negative feedback regulation system, then chemotherapy and radiation therapy may lose their death inducing therapeutic potencies. […] The role of p53 in melanoma is disputed.

• #50 Signal pathways of melanoma and targeted therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00827-6

  The pro-tumorigenic effect of trauma and chronic inflammation might result from the increased cytokines and ROS that can induce genetic instability or activate oncogenic pathways in melanocytes. […] The activation of AKT and mTOR downstream effector 4E-BP1 is in strongly positive correlation with the aggressiveness of melanoma, and the poor prognosis of patients in two independent cohorts. […] The loss of NF1 or inactivating NF1 mutation are present in 46% of melanomas expressing wild-type BRAF and RAS, which leads to constitute activation of Ras by lessening its intrinsic GTPase activity and induces hyper-activation of MAPK pathway. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas. […] The presence of BRAF mutations has great potential in predicting an unfavorable prognosis in melanoma patients.

• #51 Signal pathways of melanoma and targeted therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00827-6

  Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes. […] Therefore, it is necessary to understand the mechanisms underlying melanoma pathogenesis more comprehensively, which might lead to more substantial progress in therapeutic approaches and expand clinical options for melanoma therapy. […] In this review, we systemically summarized the signal pathways driving melanoma pathogenesis, including the main mutated driver genes and signals, key transcriptional factors and downstream molecular biology, epigenetic modification, metabolic reprogramming, crucial metastasis-related signals, and tumor-promoting inflammatory pathways and pro-angiogenic factors. […] The dysregulated activation of the AKT pathway occurs in around 70% of total melanomas, which is the result of AKT3 amplification and PTEN loss by epigenetic silencing or deletion as previously described.

• #52 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  The second most common cause of aberrant signaling through the MAPK pathway in cutaneous melanoma is represented by NRAS activating mutations. […] NRAS is mutated in 15-30% of melanomas and in the majority of cases, these mutations are missense mutations of codon 12, 13 or 61. […] Importantly, NRAS and BRAF mutations are considered mutually exclusive; however, co-mutations can rarely occur. […] NF1 is a tumor suppressor gene mutated in 10-15% of melanoma cases and is the third most frequently mutated gene in melanoma. […] The NF1 protein regulates the RAS family by converting the active RAS-guanosine triphosphate (RAS-GTP) to the inactive RAS-guanosine diphosphate (RAS-GDP), thereby inhibiting downstream RAS signaling. […] Therefore, NF1 loss-of-function determines the hyperactivation of NRAS protein and thus, increased MAPK and PI3K pathways signaling.

• #53 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  The second most common cause of aberrant signaling through the MAPK pathway in cutaneous melanoma is represented by NRAS activating mutations. […] NRAS is mutated in 15-30% of melanomas and in the majority of cases, these mutations are missense mutations of codon 12, 13 or 61. […] Importantly, NRAS and BRAF mutations are considered mutually exclusive; however, co-mutations can rarely occur. […] NF1 is a tumor suppressor gene mutated in 10-15% of melanoma cases and is the third most frequently mutated gene in melanoma. […] The NF1 protein regulates the RAS family by converting the active RAS-guanosine triphosphate (RAS-GTP) to the inactive RAS-guanosine diphosphate (RAS-GDP), thereby inhibiting downstream RAS signaling. […] Therefore, NF1 loss-of-function determines the hyperactivation of NRAS protein and thus, increased MAPK and PI3K pathways signaling.

• #54 Signal pathways of melanoma and targeted therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00827-6

  The pro-tumorigenic effect of trauma and chronic inflammation might result from the increased cytokines and ROS that can induce genetic instability or activate oncogenic pathways in melanocytes. […] The activation of AKT and mTOR downstream effector 4E-BP1 is in strongly positive correlation with the aggressiveness of melanoma, and the poor prognosis of patients in two independent cohorts. […] The loss of NF1 or inactivating NF1 mutation are present in 46% of melanomas expressing wild-type BRAF and RAS, which leads to constitute activation of Ras by lessening its intrinsic GTPase activity and induces hyper-activation of MAPK pathway. […] The mutations of NRAS usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of melanomas. […] The presence of BRAF mutations has great potential in predicting an unfavorable prognosis in melanoma patients.

• #55 Molecular Frontiers in Melanoma: Pathogenesis, Diagnosis, and Therapeutic Advances

  https://www.mdpi.com/1422-0067/25/5/2984

  NRAS mutations, which are found in 15–20% of melanoma cases, are significant drivers of the disease, affecting melanoma development through a distinct pathway. These mutations activate the MAPK pathway, albeit through a mechanism different from that of BRAF mutations. […] c-KIT mutations, while less common than BRAF and NRAS mutations, play a significant role in certain melanoma subtypes, particularly mucosal and acral melanomas. […] GNAQ/GNA11 mutations, commonly identified in uveal melanomas, represent a distinct genetic subgroup within melanoma. Despite the current limitations of available treatments, these mutations are under active study for targeted therapy options, reflecting a growing interest in developing specific treatments for these subtypes. […] The MAPK/ERK pathway is central to melanoma, with alterations in this pathway often driving tumorigenesis. This pathway, which includes RAS, RAF, ERK, and mitogen-activated extracellular signal-regulated kinase (MEK), is crucial for regulating cellular proliferation.

• #56 Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8232613/

  BRAF is a serine/threonine kinase that is activated directly by RAS and is strongly expressed in melanocytes, neural tissue, testes, and hematopoietic cells. […] Mutations, leading to increased RAS activity in melanomas also increase cell proliferation, but this occurs significantly less frequently than in other solid tumours. […] c-KIT mutations cause insufficient pigmentation. […] Overexpression of another tyrosine kinase receptor c-MET and its ligand HGF (hepatocyte growth factor) correlates with melanoma progression. […] The hypoxic response is primarily mediated by HIF. […] The Notch signalling pathway has a substantial potential for the development and maintenance of tissue homeostasis. […] Telomerase reverse transcriptase (TERT) is a gene located on chromosome 5p15.33 and encodes the catalytic subunit of telomerase. […] Numerous cellular interactions, mediated by their cell adhesion molecules (cadherins and adherents) also play an important part in the pathogenesis of melanoma.

• #57 Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8232613/

  BRAF is a serine/threonine kinase that is activated directly by RAS and is strongly expressed in melanocytes, neural tissue, testes, and hematopoietic cells. […] Mutations, leading to increased RAS activity in melanomas also increase cell proliferation, but this occurs significantly less frequently than in other solid tumours. […] c-KIT mutations cause insufficient pigmentation. […] Overexpression of another tyrosine kinase receptor c-MET and its ligand HGF (hepatocyte growth factor) correlates with melanoma progression. […] The hypoxic response is primarily mediated by HIF. […] The Notch signalling pathway has a substantial potential for the development and maintenance of tissue homeostasis. […] Telomerase reverse transcriptase (TERT) is a gene located on chromosome 5p15.33 and encodes the catalytic subunit of telomerase. […] Numerous cellular interactions, mediated by their cell adhesion molecules (cadherins and adherents) also play an important part in the pathogenesis of melanoma.

• #58 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  The high prevalence of the BRAFV600E mutation in melanoma patients makes this a prime target for anti-melanoma therapeutics. […] Another source of molecular changes that may allow for melanoma initiation or propagation is found in the NRAS GTPase or neuroblastoma RAS oncogene. […] The patients with NRAS mutations possess thick vertical growth tumors that researchers attribute to the heightened cell proliferations rates induced by the NRAS mutation. […] The PI3K-AKT pathway is a separate mechanistic route that also plays a role in cell proliferation and survival. […] When this pathway is hyper-active or has lost its negative feedback regulation system, then chemotherapy and radiation therapy may lose their death inducing therapeutic potencies. […] The role of p53 in melanoma is disputed.

• #59 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  The high prevalence of the BRAFV600E mutation in melanoma patients makes this a prime target for anti-melanoma therapeutics. […] Another source of molecular changes that may allow for melanoma initiation or propagation is found in the NRAS GTPase or neuroblastoma RAS oncogene. […] The patients with NRAS mutations possess thick vertical growth tumors that researchers attribute to the heightened cell proliferations rates induced by the NRAS mutation. […] The PI3K-AKT pathway is a separate mechanistic route that also plays a role in cell proliferation and survival. […] When this pathway is hyper-active or has lost its negative feedback regulation system, then chemotherapy and radiation therapy may lose their death inducing therapeutic potencies. […] The role of p53 in melanoma is disputed.

• #60 The Mechanics of Melanoma – HealthWell FoundationSearch Icon

  https://www.healthwellfoundation.org/realworldhealthcare/the-mechanics-of-melanoma/

  The gene most commonly mutated in familial melanoma is p53. […] Another gene, known as the BRAF gene, regulates cell growth and is mutated in inherited forms of melanoma. […] BRAF codes for a protein required for the transmission of a growth signal from a cell surface receptor to the cell nucleus (growth signal transduction). […] In BRAF-associated melanoma, the mutated BRAF is always turned on even when no growth factor is present. […] A few different checkpoint inhibitor therapies have been approved to treat metastatic melanoma. […] These drugs target inhibitory proteins on the surface of T-cells such us CTLA-4 and PD-1. […] A second type of immunotherapy that has been approved for melanoma is an oncolytic virus therapy. […] Last year, researchers at Tel Aviv University published a report describing how melanoma metastasizes.

• #61 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Despite the lack of p53 mutations, melanoma cells generally do not undergo apoptosis in response to gamma radiation or chemotoxic drugs, which suggests that perhaps p53 might not be functioning properly. […] A distinguishing feature of malignant neoplasms is the ability to metastasize to other organs and tissues throughout the body. […] This sequence of events are believed to allow the melanoma to spread out of its epidermal origin. […] The loss of E-cadherin prevents melanocyte regulation by keratinocytes. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells. […] Melanoma vasculogenic mimicry sheds light on the ability for melanoma tumors to gain access to blood supplies or their means of vascularization, which may lead to a major competitive growth advantage for the tumor.

• #62 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Despite the lack of p53 mutations, melanoma cells generally do not undergo apoptosis in response to gamma radiation or chemotoxic drugs, which suggests that perhaps p53 might not be functioning properly. […] A distinguishing feature of malignant neoplasms is the ability to metastasize to other organs and tissues throughout the body. […] This sequence of events are believed to allow the melanoma to spread out of its epidermal origin. […] The loss of E-cadherin prevents melanocyte regulation by keratinocytes. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells. […] Melanoma vasculogenic mimicry sheds light on the ability for melanoma tumors to gain access to blood supplies or their means of vascularization, which may lead to a major competitive growth advantage for the tumor.

• #63 Advances in Skin Cancer | IntechOpen

  https://www.intechopen.com/chapters/1177229

  The most frequent of these oncogenic targets is the v-Raf murine sarcoma viral oncogene (BRAF), which acts in the mitogen-activated protein kinase and extracellular signal-regulated kinase (MAP/ERK) pathway involved in the regulation of cell proliferation, cell growth, and migration. […] Further mutations in tumor suppressor genes such as PTEN and NRAS will contribute to melanocytes evading senescence, leading to the transformation of the nevus to melanoma confined to the epidermis where radial growth phase occurs (RGP) at early stages. […] Additionally, inactivation of the tumor suppressors CDKN2A and P53 aids in the progression and invasion of melanoma, causing the vertical growth phase (VGP) and ultimately metastasis. […] Melanocytes are normally connected to basal keratinocytes through the transmembrane glycoprotein E-cadherin.

• #64 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Despite the lack of p53 mutations, melanoma cells generally do not undergo apoptosis in response to gamma radiation or chemotoxic drugs, which suggests that perhaps p53 might not be functioning properly. […] A distinguishing feature of malignant neoplasms is the ability to metastasize to other organs and tissues throughout the body. […] This sequence of events are believed to allow the melanoma to spread out of its epidermal origin. […] The loss of E-cadherin prevents melanocyte regulation by keratinocytes. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells. […] Melanoma vasculogenic mimicry sheds light on the ability for melanoma tumors to gain access to blood supplies or their means of vascularization, which may lead to a major competitive growth advantage for the tumor.

• #65 Advances in Skin Cancer | IntechOpen

  https://www.intechopen.com/chapters/1177229

  When melanoma transitions to the metastatic stage, it undergoes epithelial to mesenchymal transition (EMT), which involves switching the E-cadherin to N-cadherin to be up regulated through the WNT signaling pathway. […] Subsequently, the newly increased N-cadherin facilitates melanoma migration into the dermis and its interaction with dermal fibroblasts and vascular endothelial cells allowing the spread of melanoma cancer.

• #66 Advances in Skin Cancer | IntechOpen

  https://www.intechopen.com/chapters/1177229

  When melanoma transitions to the metastatic stage, it undergoes epithelial to mesenchymal transition (EMT), which involves switching the E-cadherin to N-cadherin to be up regulated through the WNT signaling pathway. […] Subsequently, the newly increased N-cadherin facilitates melanoma migration into the dermis and its interaction with dermal fibroblasts and vascular endothelial cells allowing the spread of melanoma cancer.

• #67 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Despite the lack of p53 mutations, melanoma cells generally do not undergo apoptosis in response to gamma radiation or chemotoxic drugs, which suggests that perhaps p53 might not be functioning properly. […] A distinguishing feature of malignant neoplasms is the ability to metastasize to other organs and tissues throughout the body. […] This sequence of events are believed to allow the melanoma to spread out of its epidermal origin. […] The loss of E-cadherin prevents melanocyte regulation by keratinocytes. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells. […] Melanoma vasculogenic mimicry sheds light on the ability for melanoma tumors to gain access to blood supplies or their means of vascularization, which may lead to a major competitive growth advantage for the tumor.

• #68 Melanoma: Molecular Pathogenesis and Therapeutic Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4346328/

  Despite the lack of p53 mutations, melanoma cells generally do not undergo apoptosis in response to gamma radiation or chemotoxic drugs, which suggests that perhaps p53 might not be functioning properly. […] A distinguishing feature of malignant neoplasms is the ability to metastasize to other organs and tissues throughout the body. […] This sequence of events are believed to allow the melanoma to spread out of its epidermal origin. […] The loss of E-cadherin prevents melanocyte regulation by keratinocytes. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells. […] Melanoma vasculogenic mimicry sheds light on the ability for melanoma tumors to gain access to blood supplies or their means of vascularization, which may lead to a major competitive growth advantage for the tumor.

• #69

  https://journals.lww.com/oncology-times/fulltext/2016/09100/how_does_melanoma_spread_to_other_organs_in_the.7.aspx

  In a landmark discovery, researchers at Tel Aviv University (TAU) have unraveled the metastatic mechanism of melanoma, the most aggressive of all skin cancers. […] The scientists discovered that before spreading to other organs, a melanoma tumor sends out tiny vesicles containing molecules of microRNA. These induce morphological changes in the dermis in preparation for receiving and transporting the cancer cells. […] The threat of melanoma is not in the initial tumor that appears on the skin, but rather in its metastasis in the tumor cells sent off to colonize in vital organs like the brain, lungs, liver and bones, said research leader Carmit Levy, of the Department of Human Molecular Genetics and Biochemistry at TAU’s Sackler School of Medicine. […] We have discovered how the cancer spreads to distant organs and found ways to stop the process before the metastatic stage.

• #70

  https://journals.lww.com/oncology-times/fulltext/2016/09100/how_does_melanoma_spread_to_other_organs_in_the.7.aspx

  We found that even before the cancer itself invades the dermis, it sends out tiny vesicles containing molecules of microRNA, Levy said. These induce the morphological changes in the dermis in preparation for receiving and transporting the cancer cells. […] It then became clear to us that by blocking the vesicles, we might be able to stop the disease altogether. […] Having discovered the mechanism, the researchers proceeded to look for substances that could intervene and block the process in its earliest stages. […] They found two such chemicals: one (SB202190) inhibits the delivery of the vesicles from the melanoma tumor to the dermis; and the other (U0126) prevents the morphological changes in the dermis even after the arrival of the vesicles. […] Our study is an important step on the road to a full remedy for the deadliest skin cancer, said Levy.

• #71 The Mechanics of Melanoma – HealthWell FoundationSearch Icon

  https://www.healthwellfoundation.org/realworldhealthcare/the-mechanics-of-melanoma/

  Their work suggests that melanoma cells release tiny vesicles that contain microRNA, a type of regulatory RNA produced by all cells. […] The changes in the dermis induced by the small vesicles released from the melanoma cells makes the cancer cells able to access those blood vessels. […] Increased understanding of the molecular pathways that contribute to melanoma’s development and spread will provide physicians with additional tools to fight those cases of metastatic melanoma that inevitably will continue to arise.

• #72

  https://journals.lww.com/oncology-times/fulltext/2016/09100/how_does_melanoma_spread_to_other_organs_in_the.7.aspx

  We found that even before the cancer itself invades the dermis, it sends out tiny vesicles containing molecules of microRNA, Levy said. These induce the morphological changes in the dermis in preparation for receiving and transporting the cancer cells. […] It then became clear to us that by blocking the vesicles, we might be able to stop the disease altogether. […] Having discovered the mechanism, the researchers proceeded to look for substances that could intervene and block the process in its earliest stages. […] They found two such chemicals: one (SB202190) inhibits the delivery of the vesicles from the melanoma tumor to the dermis; and the other (U0126) prevents the morphological changes in the dermis even after the arrival of the vesicles. […] Our study is an important step on the road to a full remedy for the deadliest skin cancer, said Levy.

• #73 The Immune System and Pathogenesis of Melanoma and Non-melanoma Skin Cancer | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-030-46227-7_11

  Tumor development is the result of genetic derangement and the inability to prevent unfettered proliferation. Genetic derangements leading to tumorigenesis are variable, but the immune system plays a critical role in tumor development, prevention, and production. […] In this chapter, we will discuss the importance of the immune system as it relates to the development of skin cancerboth melanoma and non-melanoma skin cancers (NMSC).

• #74 Melanoma: Review of Pathogenesis and Treatment Options

  https://www.uspharmacist.com/article/melanoma-review-of-pathogenesis-and-treatment-options

  Targeted therapies have been a focal point in melanoma research. Studies of several antiangiogenesis agents and tyrosine kinase inhibitors have shown promise in preclinical and early-phase clinical trials. Sorafenib is a multikinase inhibitor, targeting CRAF, vascular endothelial growth factor receptor 2, platelet-derived growth factor beta, p39, flt-3, and c-kit. While sorafenib is currently approved for use in RCC and hepatocellular carcinoma, several phase I and II studies in melanoma have been performed, most of which have demonstrated stable disease. […] Immunologic therapy continues to be explored as a possible treatment for melanoma. Research efforts have focused on vaccines derived from tumor cells, DNA, peptides, and dendritic cells, as well as on different emulsions for adjuvants to potentiate immune responses. Numerous early-phase clinical trials have shown that vaccines are able to stimulate the immune system in patients with metastatic disease. However, these trials involved a limited number of patients; larger trials are needed to make further conclusions about efficacy in metastatic and adjuvant settings.

• #75

  https://journals.lww.com/melanomaresearch/fulltext/2010/06001/the_pathogenesis_of_skin_cancer_in_the.50.aspx

  Current evidence, however, suggests that inflammation may be a double-edged sword. […] Especially at a low grade, inflammation may simultaneously initiate and promote cancer formation. […] Nevertheless, the findings from several current and pre-publication studies are relevant to SCC, suggesting that a chronic smouldering inflammation may well contribute to tumour formation in SCC. […] If research bears out the suspicion that low-grade inflammation may drive carcinogenesis, then anti-inflammatory agents may prove helpful in preventing SCC development.

• #76 Apoptosis and Pathogenesis of Melanoma and Nonmelanoma Skin Cancer | SpringerLink

  https://link.springer.com/chapter/10.1007/978-0-387-77574-6_22

  Once the keratinocytes or melanocytes have been transformed they re-express FasL which may allow the expanding tumor to evade the attack of immune effector cells. FasL which is involved in immune evasion or genes which govern the apoptosis resistance, e.g., Gli2 could therefore be prime targets to prevent tumor formation and growth. […] Thus, siRNAs and/or shRNAs may become a novel and promising approach to treat skin cancers at an early stage.

• #77 Immune system turning on itself may trigger melanoma growth | Yale News

  https://news.yale.edu/2012/03/28/immune-system-turning-itself-may-trigger-melanoma-growth

  A new study by researchers from Yale and Johns Hopkins reveals the molecular pathway by which the bodys inflammatory immune response may trigger its own inhibition, protecting tumor cells from destruction and allowing the growth of melanoma the deadliest form of skin cancer. […] The researchers focused on a specific immune-inhibiting molecule in melanoma tumors known as B7-H1. They found that in patients whose tumors expressed B7-H1, suppression of the inflammatory immune response promoted the growth and aggressiveness of their melanoma tumors. […] Further, they uncovered the mechanism by which this happens: Tumor cells somehow utilize an active component of the immune response itself, interferon gamma, to turn on B7-H1 and protect themselves by suppressing the immune system. […] Chen said that this mechanism may be responsible for immune suppression, and therefore tumor growth, in up to 40 percent of melanoma patients. The researchers suggest that therapies that block this anti-immune pathway may benefit patients.

• #78 Immune system turning on itself may trigger melanoma growth | Yale News

  https://news.yale.edu/2012/03/28/immune-system-turning-itself-may-trigger-melanoma-growth

  A new study by researchers from Yale and Johns Hopkins reveals the molecular pathway by which the bodys inflammatory immune response may trigger its own inhibition, protecting tumor cells from destruction and allowing the growth of melanoma the deadliest form of skin cancer. […] The researchers focused on a specific immune-inhibiting molecule in melanoma tumors known as B7-H1. They found that in patients whose tumors expressed B7-H1, suppression of the inflammatory immune response promoted the growth and aggressiveness of their melanoma tumors. […] Further, they uncovered the mechanism by which this happens: Tumor cells somehow utilize an active component of the immune response itself, interferon gamma, to turn on B7-H1 and protect themselves by suppressing the immune system. […] Chen said that this mechanism may be responsible for immune suppression, and therefore tumor growth, in up to 40 percent of melanoma patients. The researchers suggest that therapies that block this anti-immune pathway may benefit patients.

• #79 Immune system turning on itself may trigger melanoma growth | Yale News

  https://news.yale.edu/2012/03/28/immune-system-turning-itself-may-trigger-melanoma-growth

  A new study by researchers from Yale and Johns Hopkins reveals the molecular pathway by which the bodys inflammatory immune response may trigger its own inhibition, protecting tumor cells from destruction and allowing the growth of melanoma the deadliest form of skin cancer. […] The researchers focused on a specific immune-inhibiting molecule in melanoma tumors known as B7-H1. They found that in patients whose tumors expressed B7-H1, suppression of the inflammatory immune response promoted the growth and aggressiveness of their melanoma tumors. […] Further, they uncovered the mechanism by which this happens: Tumor cells somehow utilize an active component of the immune response itself, interferon gamma, to turn on B7-H1 and protect themselves by suppressing the immune system. […] Chen said that this mechanism may be responsible for immune suppression, and therefore tumor growth, in up to 40 percent of melanoma patients. The researchers suggest that therapies that block this anti-immune pathway may benefit patients.

• #80 Researchers discover control mechanism for melanoma skin cancer | Doherty Website

  https://www.doherty.edu.au/news-events/news/researchers-discover-control-mechanism-for-melanoma-skin-cancer

  Australian scientists have discovered how the immune system can control melanoma, a mechanism which could be used to enhance cancer treatments. […] TRM cells were able to control the tumour in the mice for the life of the animal, which is likely to equate to decades of protection in humans. […] I was able to see through moving images that these TRM cells are important for maintaining the control of the tumour cells; if you remove the TRM cells you have a break in that control and the cancer can start to grow back again, Ms Park said. […] If you could make more of these TRM cells through immunotherapies, or enhance the activity of those that are already there in some way, you could boost anti-tumour immunity. […] Senior author on the paper, University of Melbourne Associate Professor Thomas Gebhardt, Laboratory Head at the Doherty Institute, said an increase of TRM cells has already been associated with better outcomes in cancer patients, but the way they work to suppress tumours has remained unknown.

• #81 Researchers discover control mechanism for melanoma skin cancer | Doherty Website

  https://www.doherty.edu.au/news-events/news/researchers-discover-control-mechanism-for-melanoma-skin-cancer

  Australian scientists have discovered how the immune system can control melanoma, a mechanism which could be used to enhance cancer treatments. […] TRM cells were able to control the tumour in the mice for the life of the animal, which is likely to equate to decades of protection in humans. […] I was able to see through moving images that these TRM cells are important for maintaining the control of the tumour cells; if you remove the TRM cells you have a break in that control and the cancer can start to grow back again, Ms Park said. […] If you could make more of these TRM cells through immunotherapies, or enhance the activity of those that are already there in some way, you could boost anti-tumour immunity. […] Senior author on the paper, University of Melbourne Associate Professor Thomas Gebhardt, Laboratory Head at the Doherty Institute, said an increase of TRM cells has already been associated with better outcomes in cancer patients, but the way they work to suppress tumours has remained unknown.

• #82 Researchers discover control mechanism for melanoma skin cancer | Doherty Website

  https://www.doherty.edu.au/news-events/news/researchers-discover-control-mechanism-for-melanoma-skin-cancer

  The principal of cutting-edge immunotherapies currently in clinical practise is that they generate a T-cell response. But if we can hone in on one type of T-cell – the TRM cells specifically, we could have an even bigger impact on stopping cancers from coming back, Associate Professor Gebhardt said. […] We now have a much better understanding of which T-cells are important in controlling skin cancers and how those cells are working but there is still much more work to do to make these cells work even better, Associate Professor Gebhardt said.

• #83 Molecular Frontiers in Melanoma: Pathogenesis, Diagnosis, and Therapeutic Advances

  https://www.mdpi.com/1422-0067/25/5/2984

  The progression from benign melanocytic nevi to malignant melanoma and metastasis involves an interplay of genetic factors and UV-induced damage. Melanocytic nevi, typically benign, can evolve into melanoma through mutations, primarily BRAFV600E in common nevi and various mutations in MAPK signaling, the TERT promoter, and CDKN2A in dysplastic nevi. The progression is marked by additional mutations, such as in NRAS, and is influenced by the activation of the WNT signaling pathway, which is important for metastasis. […] BRAF mutations are found in approximately 50% of melanomas and play a crucial role in the disease’s pathogenesis. These mutations are predominantly observed in cutaneous melanomas and are frequently associated with UV radiation exposure. This link is evidenced by the high levels of UV radiation signatures, especially C > T substitutions, found in these tumors.

• #84 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  Over the past years, a deeper understanding of melanoma development and biology has been reached. […] It has become clear that the development of fully-evolved melanoma from pre-neoplastic lesions is not represented by a single evolutionary pattern. […] Each melanoma subtype can evolve from different precursor lesions, and can involve different gene mutations and stage of transformation. […] An interesting finding is that BRAF is mutated in up to 80% of benign nevi, resulting in limited melanocyte proliferation through the oncogene-mediated activation of cell senescence. […] Therefore, oncogenic BRAF alone is not sufficient for melanoma development and rarely benign nevi further progress to melanoma. […] When this usually occurs, it is associated with the acquisition of subsequent mutations in key genes, such as TERT or CDKN2A.

• #85 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  Over the past years, a deeper understanding of melanoma development and biology has been reached. […] It has become clear that the development of fully-evolved melanoma from pre-neoplastic lesions is not represented by a single evolutionary pattern. […] Each melanoma subtype can evolve from different precursor lesions, and can involve different gene mutations and stage of transformation. […] An interesting finding is that BRAF is mutated in up to 80% of benign nevi, resulting in limited melanocyte proliferation through the oncogene-mediated activation of cell senescence. […] Therefore, oncogenic BRAF alone is not sufficient for melanoma development and rarely benign nevi further progress to melanoma. […] When this usually occurs, it is associated with the acquisition of subsequent mutations in key genes, such as TERT or CDKN2A.

• #86 Cutaneous melanoma: From pathogenesis to therapy (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2018.4287

  On the other hand, melanomas associated with chronic sun-exposed skin usually do not arise from pre-existing nevi, but from melanomas in situ or dysplastic lesions and carry a different set of mutations. […] The increasing understanding of the biological determinants of melanoma evolution and their potential integration in the management of melanoma patients may lead to an improved diagnosis and the earlier recognition of lesions at an increased risk of progression, thus improving patient risk stratification. […] Several studies have demonstrated that melanoma spreading is the result of genetic mutations and tumor microenvironmental alterations, characterized by the overexpression of proteins able to favor tumor invasion and surrounding infiltration. […] In particular, a key role is played by the overexpression of matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-2, that induces the degradation of the components of the extracellular matrix, thus favoring tumor cell infiltration and spreading through the bloodstream.

• #87 Melanoma with drug resistance: Cause identified – ecancer

  https://ecancer.org/en/news/25477-melanoma-with-drug-resistance-cause-identified

  Melanoma is a type of cancer that originates from melanocytes, the cells responsible for producing skin pigment, and is known as the most lethal form of skin cancer due to its high rates of metastasis and recurrence. […] However, drug resistance to BRAF inhibitors develops quickly, limiting the effectiveness of these treatments. […] A research team led by Dr. Tackhoon Kim at the Center for Medicinal Materials Research at the Korea Institute of Science and Technology (KIST, President Sang-Rok Oh) has identified a new key mechanism behind the resistance of melanoma to BRAF inhibitors and has proposed a strategy to develop new anticancer therapies to overcome this resistance. […] The research team used melanoma cell line models resistant to BRAF inhibitors and discovered that the activation of the AMD1 gene plays a crucial role in the development of drug resistance.

• #88 Melanoma with drug resistance: Cause identified – ecancer

  https://ecancer.org/en/news/25477-melanoma-with-drug-resistance-cause-identified

  Melanoma is a type of cancer that originates from melanocytes, the cells responsible for producing skin pigment, and is known as the most lethal form of skin cancer due to its high rates of metastasis and recurrence. […] However, drug resistance to BRAF inhibitors develops quickly, limiting the effectiveness of these treatments. […] A research team led by Dr. Tackhoon Kim at the Center for Medicinal Materials Research at the Korea Institute of Science and Technology (KIST, President Sang-Rok Oh) has identified a new key mechanism behind the resistance of melanoma to BRAF inhibitors and has proposed a strategy to develop new anticancer therapies to overcome this resistance. […] The research team used melanoma cell line models resistant to BRAF inhibitors and discovered that the activation of the AMD1 gene plays a crucial role in the development of drug resistance.

• #89 Melanoma with drug resistance: Cause identified – ecancer

  https://ecancer.org/en/news/25477-melanoma-with-drug-resistance-cause-identified

  It was found that polyamine levels are generally higher in BRAF inhibitor resistant cancer cells. […] Through experiments, the team confirmed that inhibiting polyamine biosynthesis lowers resistance to BRAF inhibitors, leading to melanoma cell death. […] Furthermore, the study revealed that the oncogene c-Myc triggers the increase of polyamine biosynthesis in BRAF-resistant melanoma. […] The researchers identified this process as the core mechanism driving BRAF inhibitor resistance in melanoma. […] This is the first study in the world to pinpoint polyamine biosynthesis as a cause of BRAF inhibitor resistance. […] The KIST team also suggested an anticancer drug development strategy to block each stage of the resistance mechanism. […] This research opens the door to developing new anticancer therapies based on regulating polyamine metabolism, which could be used to treat melanoma, a cancer that has been difficult to cure due to frequent drug resistance. […] Dr. Kim of KIST stated, „We have identified the key mechanism behind drug resistance in melanoma, the deadliest form of skin cancer.”

• #90 Melanoma with drug resistance: Cause identified – ecancer

  https://ecancer.org/en/news/25477-melanoma-with-drug-resistance-cause-identified

  It was found that polyamine levels are generally higher in BRAF inhibitor resistant cancer cells. […] Through experiments, the team confirmed that inhibiting polyamine biosynthesis lowers resistance to BRAF inhibitors, leading to melanoma cell death. […] Furthermore, the study revealed that the oncogene c-Myc triggers the increase of polyamine biosynthesis in BRAF-resistant melanoma. […] The researchers identified this process as the core mechanism driving BRAF inhibitor resistance in melanoma. […] This is the first study in the world to pinpoint polyamine biosynthesis as a cause of BRAF inhibitor resistance. […] The KIST team also suggested an anticancer drug development strategy to block each stage of the resistance mechanism. […] This research opens the door to developing new anticancer therapies based on regulating polyamine metabolism, which could be used to treat melanoma, a cancer that has been difficult to cure due to frequent drug resistance. […] Dr. Kim of KIST stated, „We have identified the key mechanism behind drug resistance in melanoma, the deadliest form of skin cancer.”

• #91 Blocking Nitrosylation Boosts MEK Inhibitors in Aggressive Melanoma

  https://www.targetedonc.com/view/blocking-nitrosylation-boosts-mek-inhibitors-in-aggressive-melanoma

  NRAS mutations, present in 15% to 25% of melanomas, drive aggressive cancer growth that resists current treatments. […] These melanomas often have overactive nitric oxide synthases (NOS), linked to worse outcomes. A study co-led by Srivastava explored how nitrosylation, a modification caused by nitric oxide, affects the cancer-promoting MEK/ERK pathway and a process called immunogenic cell death (ICD) in NRAS-mutant melanomas. […] Blocking nitrosylation made the melanoma cells more sensitive to MEK inhibitors. […] Investigators found a strong link between reduced nitrosylation of MEK/ERK pathway proteins and similar changes in danger signals (DAMPs) that trigger ICD. […] Interestingly, melanoma cells that became resistant to MEK inhibitors showed increased nitrosylation and activation of cancer-promoting proteins, which was reversed by blocking NOS.

• #92 Blocking Nitrosylation Boosts MEK Inhibitors in Aggressive Melanoma

  https://www.targetedonc.com/view/blocking-nitrosylation-boosts-mek-inhibitors-in-aggressive-melanoma

  NRAS mutations, present in 15% to 25% of melanomas, drive aggressive cancer growth that resists current treatments. […] These melanomas often have overactive nitric oxide synthases (NOS), linked to worse outcomes. A study co-led by Srivastava explored how nitrosylation, a modification caused by nitric oxide, affects the cancer-promoting MEK/ERK pathway and a process called immunogenic cell death (ICD) in NRAS-mutant melanomas. […] Blocking nitrosylation made the melanoma cells more sensitive to MEK inhibitors. […] Investigators found a strong link between reduced nitrosylation of MEK/ERK pathway proteins and similar changes in danger signals (DAMPs) that trigger ICD. […] Interestingly, melanoma cells that became resistant to MEK inhibitors showed increased nitrosylation and activation of cancer-promoting proteins, which was reversed by blocking NOS.

• #93 Blocking Nitrosylation Boosts MEK Inhibitors in Aggressive Melanoma

  https://www.targetedonc.com/view/blocking-nitrosylation-boosts-mek-inhibitors-in-aggressive-melanoma

  NRAS mutations, present in 15% to 25% of melanomas, drive aggressive cancer growth that resists current treatments. […] These melanomas often have overactive nitric oxide synthases (NOS), linked to worse outcomes. A study co-led by Srivastava explored how nitrosylation, a modification caused by nitric oxide, affects the cancer-promoting MEK/ERK pathway and a process called immunogenic cell death (ICD) in NRAS-mutant melanomas. […] Blocking nitrosylation made the melanoma cells more sensitive to MEK inhibitors. […] Investigators found a strong link between reduced nitrosylation of MEK/ERK pathway proteins and similar changes in danger signals (DAMPs) that trigger ICD. […] Interestingly, melanoma cells that became resistant to MEK inhibitors showed increased nitrosylation and activation of cancer-promoting proteins, which was reversed by blocking NOS.

• #94 Blocking Nitrosylation Boosts MEK Inhibitors in Aggressive Melanoma

  https://www.targetedonc.com/view/blocking-nitrosylation-boosts-mek-inhibitors-in-aggressive-melanoma

  NRAS mutations, present in 15% to 25% of melanomas, drive aggressive cancer growth that resists current treatments. […] These melanomas often have overactive nitric oxide synthases (NOS), linked to worse outcomes. A study co-led by Srivastava explored how nitrosylation, a modification caused by nitric oxide, affects the cancer-promoting MEK/ERK pathway and a process called immunogenic cell death (ICD) in NRAS-mutant melanomas. […] Blocking nitrosylation made the melanoma cells more sensitive to MEK inhibitors. […] Investigators found a strong link between reduced nitrosylation of MEK/ERK pathway proteins and similar changes in danger signals (DAMPs) that trigger ICD. […] Interestingly, melanoma cells that became resistant to MEK inhibitors showed increased nitrosylation and activation of cancer-promoting proteins, which was reversed by blocking NOS.

• #95 Blocking Nitrosylation Boosts MEK Inhibitors in Aggressive Melanoma

  https://www.targetedonc.com/view/blocking-nitrosylation-boosts-mek-inhibitors-in-aggressive-melanoma

  In mice with NRAS-mutant melanoma, inhibiting both nitrosylation and MEK significantly slowed tumor growth. […] Blocking nitrosylation not only improves how well MEK inhibitors work but also triggers ICD. Further research into the detailed mechanisms will reveal new treatment targets for this currently difficult-to-treat NRAS-mutant melanoma.

• #96 Melanoma biology and treatment: a review of novel regulated cell death-based approaches | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-024-03220-9

  The WHO classification of melanoma not only reflects the pathway concept of melanoma pathogenesis but also reveals distinct molecular signatures associated with different anatomical locations and levels of patient sun exposure. […] In addition to these driver mutations, a combination of genetic alterations leads to cancer development. […] The application of immunotherapy and targeted therapy has ushered in a new era of melanoma treatment. […] As evasion from RCD is a key feature of tumorigenesis, targeting various nonapoptotic RCDs with pharmacological small-molecule compounds is a promising therapeutic avenue. […] The second part of this review focuses on summarizing five nonapoptotic RCDs in melanoma: autophagy-dependent cell death, pyroptosis, necroptosis, ferroptosis, and cuproptosis. […] Overall, a comprehensive understanding of the molecular mechanisms underlying melanoma development, combined with the exploration of novel therapeutic strategies targeting RCD pathways, shows the potential to further enhance treatment outcomes and address existing challenges in melanoma management.

• #97 Melanoma Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq

  Genomic subtypes may suggest drug targets and clinical trial design, as well as guide clinical decision-making for targeted therapies. […] Targeted therapies have demonstrated efficacy and received U.S. Food and Drug Administration approval for the BRAF-altered subtype of melanoma. […] Combination therapies with a BRAF plus a MEK inhibitor have shown improvement in outcomes over a single-agent inhibitor alone. […] However, virtually all patients acquire resistance to this therapy and experience disease relapse. […] Therefore, clinical trials remain an important option for patients with melanoma and a BRAF pathogenic variant and other genomic subtypes of melanoma. […] A variety of immunotherapies have been approved for the treatment of melanoma regardless of genetic subtype. […] The benefit of immunotherapy has not been associated with a specific pathogenic variant or molecular subtype.

• #98 Melanoma Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq

  Genomic subtypes may suggest drug targets and clinical trial design, as well as guide clinical decision-making for targeted therapies. […] Targeted therapies have demonstrated efficacy and received U.S. Food and Drug Administration approval for the BRAF-altered subtype of melanoma. […] Combination therapies with a BRAF plus a MEK inhibitor have shown improvement in outcomes over a single-agent inhibitor alone. […] However, virtually all patients acquire resistance to this therapy and experience disease relapse. […] Therefore, clinical trials remain an important option for patients with melanoma and a BRAF pathogenic variant and other genomic subtypes of melanoma. […] A variety of immunotherapies have been approved for the treatment of melanoma regardless of genetic subtype. […] The benefit of immunotherapy has not been associated with a specific pathogenic variant or molecular subtype.

• #99 Melanoma Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq

  Genomic subtypes may suggest drug targets and clinical trial design, as well as guide clinical decision-making for targeted therapies. […] Targeted therapies have demonstrated efficacy and received U.S. Food and Drug Administration approval for the BRAF-altered subtype of melanoma. […] Combination therapies with a BRAF plus a MEK inhibitor have shown improvement in outcomes over a single-agent inhibitor alone. […] However, virtually all patients acquire resistance to this therapy and experience disease relapse. […] Therefore, clinical trials remain an important option for patients with melanoma and a BRAF pathogenic variant and other genomic subtypes of melanoma. […] A variety of immunotherapies have been approved for the treatment of melanoma regardless of genetic subtype. […] The benefit of immunotherapy has not been associated with a specific pathogenic variant or molecular subtype.

• #100 Melanoma Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq

  Genomic subtypes may suggest drug targets and clinical trial design, as well as guide clinical decision-making for targeted therapies. […] Targeted therapies have demonstrated efficacy and received U.S. Food and Drug Administration approval for the BRAF-altered subtype of melanoma. […] Combination therapies with a BRAF plus a MEK inhibitor have shown improvement in outcomes over a single-agent inhibitor alone. […] However, virtually all patients acquire resistance to this therapy and experience disease relapse. […] Therefore, clinical trials remain an important option for patients with melanoma and a BRAF pathogenic variant and other genomic subtypes of melanoma. […] A variety of immunotherapies have been approved for the treatment of melanoma regardless of genetic subtype. […] The benefit of immunotherapy has not been associated with a specific pathogenic variant or molecular subtype.

• #101 The Mechanics of Melanoma – HealthWell FoundationSearch Icon

  https://www.healthwellfoundation.org/realworldhealthcare/the-mechanics-of-melanoma/

  The gene most commonly mutated in familial melanoma is p53. […] Another gene, known as the BRAF gene, regulates cell growth and is mutated in inherited forms of melanoma. […] BRAF codes for a protein required for the transmission of a growth signal from a cell surface receptor to the cell nucleus (growth signal transduction). […] In BRAF-associated melanoma, the mutated BRAF is always turned on even when no growth factor is present. […] A few different checkpoint inhibitor therapies have been approved to treat metastatic melanoma. […] These drugs target inhibitory proteins on the surface of T-cells such us CTLA-4 and PD-1. […] A second type of immunotherapy that has been approved for melanoma is an oncolytic virus therapy. […] Last year, researchers at Tel Aviv University published a report describing how melanoma metastasizes.

• #102 The Mechanics of Melanoma – HealthWell FoundationSearch Icon

  https://www.healthwellfoundation.org/realworldhealthcare/the-mechanics-of-melanoma/

  The gene most commonly mutated in familial melanoma is p53. […] Another gene, known as the BRAF gene, regulates cell growth and is mutated in inherited forms of melanoma. […] BRAF codes for a protein required for the transmission of a growth signal from a cell surface receptor to the cell nucleus (growth signal transduction). […] In BRAF-associated melanoma, the mutated BRAF is always turned on even when no growth factor is present. […] A few different checkpoint inhibitor therapies have been approved to treat metastatic melanoma. […] These drugs target inhibitory proteins on the surface of T-cells such us CTLA-4 and PD-1. […] A second type of immunotherapy that has been approved for melanoma is an oncolytic virus therapy. […] Last year, researchers at Tel Aviv University published a report describing how melanoma metastasizes.

• #103 Melanoma Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq

  Genomic subtypes may suggest drug targets and clinical trial design, as well as guide clinical decision-making for targeted therapies. […] Targeted therapies have demonstrated efficacy and received U.S. Food and Drug Administration approval for the BRAF-altered subtype of melanoma. […] Combination therapies with a BRAF plus a MEK inhibitor have shown improvement in outcomes over a single-agent inhibitor alone. […] However, virtually all patients acquire resistance to this therapy and experience disease relapse. […] Therefore, clinical trials remain an important option for patients with melanoma and a BRAF pathogenic variant and other genomic subtypes of melanoma. […] A variety of immunotherapies have been approved for the treatment of melanoma regardless of genetic subtype. […] The benefit of immunotherapy has not been associated with a specific pathogenic variant or molecular subtype.

• #104 Melanoma biology and treatment: a review of novel regulated cell death-based approaches | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-024-03220-9

  The WHO classification of melanoma not only reflects the pathway concept of melanoma pathogenesis but also reveals distinct molecular signatures associated with different anatomical locations and levels of patient sun exposure. […] In addition to these driver mutations, a combination of genetic alterations leads to cancer development. […] The application of immunotherapy and targeted therapy has ushered in a new era of melanoma treatment. […] As evasion from RCD is a key feature of tumorigenesis, targeting various nonapoptotic RCDs with pharmacological small-molecule compounds is a promising therapeutic avenue. […] The second part of this review focuses on summarizing five nonapoptotic RCDs in melanoma: autophagy-dependent cell death, pyroptosis, necroptosis, ferroptosis, and cuproptosis. […] Overall, a comprehensive understanding of the molecular mechanisms underlying melanoma development, combined with the exploration of novel therapeutic strategies targeting RCD pathways, shows the potential to further enhance treatment outcomes and address existing challenges in melanoma management.

• #105 Melanoma biology and treatment: a review of novel regulated cell death-based approaches | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-024-03220-9

  The incidence of melanoma, the most lethal form of skin cancer, has increased due to ultraviolet exposure. […] This review provides an introduction to the molecular-level pathogenesis of melanoma and offers an overview of current treatment options and their limitations. […] Understanding the underlying pathogenesis is crucial for overcoming treatment obstacles in unresponsive metastatic melanomas. […] In the second part of the article, the relationship between regulated cell death (RCD), namely, autophagy-dependent cell death, pyroptosis, necroptosis, ferroptosis and cuproptosis, and melanoma is discussed. […] All these RCDs differ from apoptosis and have been studied in the melanoma context, either in vitro or in vivo, showing a promising role in inducing the death of melanoma cells.

• #106 Anti-cancer effects of lucidadiol against malignant melanoma cells | Applied Biological Chemistry | Full Text

  https://applbiolchem.springeropen.com/articles/10.1186/s13765-021-00647-w

  Melanoma is one of the most aggressive and lethal skin cancers. […] However, the anti-cancer effects and mechanism of action of lucidadiol in malignant melanoma are unknown. In this study, lucidadiol significantly reduced B16 melanoma cell viability in a dose- and time-dependent manner. In addition, lucidadiol induced apoptosis and suppressed cell mobility in B16 melanoma cells. Moreover, our findings revealed that lucidadiol remarkably downregulated phospho-Akt/ERK/JNK, but not p38. Taken together, our results suggest that lucidadiol could exerts its anti-cancer effects by inducing apoptosis via modulation of the Akt/MAPK pathway. Therefore, lucidadiol may be a potential cancer therapeutic agent for malignant melanoma. […] Recent studies have found that melanoma has the highest mutation frequency among cancers analyzed to determine genetic factors of malignancies. In particular, the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are among the most important signaling pathways which might play a role in the pathogenesis of melanoma. The PI3K/Akt pathway is one of the most critical signaling networks in cancer development and is frequently activated in melanomas, with an N-RAS mutation being exhibited by 20% of cases. In addition, the MAPK signaling pathways include ERK, c-Jun NH2-terminal kinase (JNK), and p38 MAPK. MAPK pathways modulate various cellular functions such as proliferation, survival, and invasion in melanoma.

• #107 Recent advancements in skin cancer treatment: a critical review

  https://www.explorationpub.com/Journals/em/Article/1001178

  In both sporadic and hereditary types of BCC, the hedgehog signalizing passageway is inappropriately stimulated. […] Life-span-threat of BCC is somewhat higher for those who are constantly immune-compromised, such as those who have had an organ or stem cell transplant or those who are living with HIV/AIDS. […] The majority of skin cancers are associated with UV radiation exposure, which is a significant risk factor for melanoma. […] The hedgehog signaling mechanism in cancer therapy is illustrated in Figure 1. […] The hedgehog transcription causes the production of an extra-cellular protein that binds to the receptor network on the cell membrane, triggering a series of events that culminates in cell division.

• #108 Melanoma biology and treatment: a review of novel regulated cell death-based approaches | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-024-03220-9

  The WHO classification of melanoma not only reflects the pathway concept of melanoma pathogenesis but also reveals distinct molecular signatures associated with different anatomical locations and levels of patient sun exposure. […] In addition to these driver mutations, a combination of genetic alterations leads to cancer development. […] The application of immunotherapy and targeted therapy has ushered in a new era of melanoma treatment. […] As evasion from RCD is a key feature of tumorigenesis, targeting various nonapoptotic RCDs with pharmacological small-molecule compounds is a promising therapeutic avenue. […] The second part of this review focuses on summarizing five nonapoptotic RCDs in melanoma: autophagy-dependent cell death, pyroptosis, necroptosis, ferroptosis, and cuproptosis. […] Overall, a comprehensive understanding of the molecular mechanisms underlying melanoma development, combined with the exploration of novel therapeutic strategies targeting RCD pathways, shows the potential to further enhance treatment outcomes and address existing challenges in melanoma management.

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