Materiały źródłowe

• #1 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. […] 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.

• #2 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. […] In 2018, the WHO presented the latest version of the generalized classification of the pathways for the genesis of cutaneous, mucosal, and uveal melanomas based on the main aethiological factor (cumulative sun damage), clinical and pathological characteristics of the precursor lesions, and the genetic aberrations which accompany their development.

• #3 Melanoma: Molecular Pathogenesis and Therapeutic Management | Liu | Molecular and Cellular Pharmacology

  https://www.mcpharmacol.com/index.php/Journals/article/view/228

  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. […] This article reviews the available information on the molecular changes associated with malignant melanoma and discusses the potential of such information in facilitating the development of newer anti-melanoma therapeutics.

• #4 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  Studies have shown that a major risk factor for melanoma development is exposure to Ultraviolet (UV) radiation exposure. […] 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. […] After the melanoma spreads or metastasizes from its origin into other cutaneous or subcutaneous tissues, the response rate to treatment plummets to approximately 5-20%, and the 10-year survival rate becomes only about 10%. […] At the cellular level, cancer cells possess distinguishing molecular properties that allow for apoptosis evasion, limitless growth potential without the need for growth factors, angiogenesis, and metastasis.

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

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

  The risk factors of melanoma supported by strong epidemiologic evidence include UVR, multiple moles, family history (a family history/personal history of melanoma), and fair skin, eye, and hair. […] Intense UVR can induce genetic alterations like DNA damage and genetic mutation, reactive oxygen species (ROS) accumulation, and oxidative stress, as well as inflammatory responses involving macrophages and neutrophils infiltration, which are related to malignant switch of melanocytes. […] The therapeutic approaches of melanoma undergo a dramatic evolution in the past few decades due to the progress in the understanding of melanoma pathogenesis and thereby revolutionary advances of targeted therapies that specifically intervene mutant driver genes and immune checkpoints. […] Therefore, it is necessary to understand the molecular mechanisms underlying melanoma pathogenesis more comprehensively, which might lead to the innovations of more applicable therapeutic approaches and provide additional clinical options for melanoma therapy.

• #6 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.

• #7 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.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] The production of melanin by melanocytes is their unique feature. In turn, melanin has a complex of anti-oxidant and pro-oxidant properties. Its conversion from an antioxidant to a pro-oxidant agent under the influence of various etiological factors such as UV radiation, heavy metals, herbicides, etc., is the critical and earliest pathogenetic event that initiates carcinogenesis. 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 result of these mutations is excessive activation of various cell signalling pathways and results in the uncontrolled proliferation, dedifferentiation, and immortalization of specific cell types.

• #9 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. […] Molecular diagnostics for melanoma have made significant strides, largely due to advances in genomics, transcriptomics, and emerging techniques such as liquid biopsies. […] The increase in survival rates seen since the advent of BRAF-MEK inhibitors and immunotherapy signifies a major breakthrough in melanoma therapeutics.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  In 2018, the WHO presented the latest version of the generalized classification of the pathways for the genesis of cutaneous, mucosal, and uveal melanomas based on the main aethiological factor (cumulative sun damage), clinical and pathological characteristics of the precursor lesions, and the genetic aberrations which accompany their development. […] The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. This pathway is active under normal conditions, but in the cases of melanoma it is associated with excessive activation. […] 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.

• #11 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. […] 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.

• #12 Pathogenesis of Cutaneous Melanoma | Encyclopedia MDPI

  https://encyclopedia.pub/entry/12780

  Melanoma develops from malignant transformations of the pigment-producing melanocytes. […] Cutaneous melanoma (cM) develops from malignant transformations of pigment-producing melanocytes in the basal layer of the skin epidermis. […] The incidence and morbidity of cM are constantly increasing worldwide. […] The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. […] This pathway is active under normal conditions, but in the cases of melanoma it is associated with excessive activation. […] BRAF is a serine/threonine kinase that is activated directly by RAS and is strongly expressed in melanocytes, neural tissue, testes, and hematopoietic cells. […] The conversion of thymidine to adenine (T → A) is the most common mutation in the BRAF gene (~70%).

• #13 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  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. […] 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.

• #14 Pathogenesis of Cutaneous Melanoma | Encyclopedia MDPI

  https://encyclopedia.pub/entry/12780

  Mutations in the BRAF gene (V600E) are more common in melanoma that develops in parts of the body that are exposed to solar radiation. […] Activating RAS mutations were observed in only 10–20% of melanomas (mostly in amelanotic nodular subtypes), with NRAS mutations being the most common. […] The uncontrolled activation of the MAPK signalling pathway in melanomas may be caused by overexpression or hyperactivation of growth factor receptors such as c-Met, c-KIT, and epidermal growth factor receptor (EGFR). […] 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. […] Neurofibromatosis type 1 (NF1) tumour suppressor gene and the negative RAS regulator are other driving factors in the process.

• #15 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  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. […] 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.

• #16 Pathogenesis of Cutaneous Melanoma | Encyclopedia MDPI

  https://encyclopedia.pub/entry/12780

  Mutations in the BRAF gene (V600E) are more common in melanoma that develops in parts of the body that are exposed to solar radiation. […] Activating RAS mutations were observed in only 10–20% of melanomas (mostly in amelanotic nodular subtypes), with NRAS mutations being the most common. […] The uncontrolled activation of the MAPK signalling pathway in melanomas may be caused by overexpression or hyperactivation of growth factor receptors such as c-Met, c-KIT, and epidermal growth factor receptor (EGFR). […] 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. […] Neurofibromatosis type 1 (NF1) tumour suppressor gene and the negative RAS regulator are other driving factors in the process.

• #17 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  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. […] 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.

• #18 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. […] 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.

• #19 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  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. […] 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.

• #20 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  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. […] 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.

• #21 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. […] Molecular diagnostics for melanoma have made significant strides, largely due to advances in genomics, transcriptomics, and emerging techniques such as liquid biopsies. […] The increase in survival rates seen since the advent of BRAF-MEK inhibitors and immunotherapy signifies a major breakthrough in melanoma therapeutics.

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

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

  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. […] The activation of the AKT pathway is initiated by activated phosphoinositide 3-kinase (PI3K) after the stimulation by exogenous growth factors, followed by increased generation of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) that can promote the translocation of AKT to the plasma membrane for its subsequent phosphorylation and activation. […] The therapeutic approaches have gained revolutionary advances due to a deeper understanding of the molecular mechanisms underlying melanoma pathogenesis. […] The low response rate to immunotherapy and inevitable establishment of resistance to targeted therapy and immunotherapy significantly hinder the treatment efficacy.

• #23 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  The role of p53 in melanoma is disputed. […] Oncogene Cyclin-dependent kinase 4 (CDK4) and tumor suppressor gene CDKN2A, which encodes p16INK4a have been implicated in familial melanoma development. […] The proposed form of genetic inheritance of this predisposition is through autosomal dominant inheritance, with a 53% penetrance rate by the 8th decade. […] 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. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells.

• #24 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  The role of p53 in melanoma is disputed. […] Oncogene Cyclin-dependent kinase 4 (CDK4) and tumor suppressor gene CDKN2A, which encodes p16INK4a have been implicated in familial melanoma development. […] The proposed form of genetic inheritance of this predisposition is through autosomal dominant inheritance, with a 53% penetrance rate by the 8th decade. […] 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. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells.

• #25 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. […] 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.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] An essential factor for tumour development and progression is the environment itself. Human skin is generally hypoxic, which in turn favours melanogenesis. […] 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. […] The immune system also plays a significant role in the carcinogenesis of melanoma. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] An essential factor for tumour development and progression is the environment itself. Human skin is generally hypoxic, which in turn favours melanogenesis. […] 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. […] The immune system also plays a significant role in the carcinogenesis of melanoma. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

• #28 Pathogenesis of Cutaneous Melanoma | Encyclopedia MDPI

  https://encyclopedia.pub/entry/12780

  Mutations in the BRAF gene (V600E) are more common in melanoma that develops in parts of the body that are exposed to solar radiation. […] Activating RAS mutations were observed in only 10–20% of melanomas (mostly in amelanotic nodular subtypes), with NRAS mutations being the most common. […] The uncontrolled activation of the MAPK signalling pathway in melanomas may be caused by overexpression or hyperactivation of growth factor receptors such as c-Met, c-KIT, and epidermal growth factor receptor (EGFR). […] 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. […] Neurofibromatosis type 1 (NF1) tumour suppressor gene and the negative RAS regulator are other driving factors in the process.

• #29 Pathogenesis of Cutaneous Melanoma | Encyclopedia MDPI

  https://encyclopedia.pub/entry/12780

  PI3K-AKT is another critical signalling pathway in the cell. […] Microphthalmia-associated transcription factor (MITF) is a key regulator that is required for melanocyte differentiation, which may affect malignancy in some melanomas. […] p53 is the primary tumour suppressor gene, associated with apoptosis. […] An essential factor for tumour development and progression is the environment itself. […] The hypoxic response is primarily mediated by HIF. […] 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. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

• #30 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.

• #31 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.

• #32 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. […] About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf kinase protein. […] 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. […] 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.

• #33 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  The role of p53 in melanoma is disputed. […] Oncogene Cyclin-dependent kinase 4 (CDK4) and tumor suppressor gene CDKN2A, which encodes p16INK4a have been implicated in familial melanoma development. […] The proposed form of genetic inheritance of this predisposition is through autosomal dominant inheritance, with a 53% penetrance rate by the 8th decade. […] 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. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells.

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

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

  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. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

• #35 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  The role of p53 in melanoma is disputed. […] Oncogene Cyclin-dependent kinase 4 (CDK4) and tumor suppressor gene CDKN2A, which encodes p16INK4a have been implicated in familial melanoma development. […] The proposed form of genetic inheritance of this predisposition is through autosomal dominant inheritance, with a 53% penetrance rate by the 8th decade. […] 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. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells.

• #36 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  The role of p53 in melanoma is disputed. […] Oncogene Cyclin-dependent kinase 4 (CDK4) and tumor suppressor gene CDKN2A, which encodes p16INK4a have been implicated in familial melanoma development. […] The proposed form of genetic inheritance of this predisposition is through autosomal dominant inheritance, with a 53% penetrance rate by the 8th decade. […] 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. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] An essential factor for tumour development and progression is the environment itself. Human skin is generally hypoxic, which in turn favours melanogenesis. […] 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. […] The immune system also plays a significant role in the carcinogenesis of melanoma. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

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

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

  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. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

• #39 Unipd Research: discovering a mechanism that forms metastases in melanoma | Università di Padova

  https://www.unipd.it/news/unipd-research-discovering-mechanism-forms-metastases-melanoma

  A University of Padua Department of Biology research team, led by Prof Luigi Leanza, has shown that the protein Transglutaminase type 2 (TG2), known to be involved in celiac disease, also plays a key role in the regulation of melanogenesis and influencing the expression and MITF activities. […] Prof Leanza explains, Our team has proven that the expression of TG2 is associated with a lower ability of cells to form metastases. In particular, we observed that TG2 can interact with MITF, thus supporting its ability to activate genes involved in both differentiation and pigmentation through the production of melanin. The consequence is a lower ability to form metastases. In the absence of TG2, MITF is unable to function and this causes a reduction in both pigmentation and differentiation and an increase in the size of metastases. […] The numerous applications of the results of this study, which for the first time linked the action of TG2 to one of the most important signaling pathways of melanoma cells, are promising for the treatment of metastatic melanoma.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] An essential factor for tumour development and progression is the environment itself. Human skin is generally hypoxic, which in turn favours melanogenesis. […] 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. […] The immune system also plays a significant role in the carcinogenesis of melanoma. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

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

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

  The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. […] 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. […] An essential factor for tumour development and progression is the environment itself. […] The hypoxic response is primarily mediated by HIF.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] An essential factor for tumour development and progression is the environment itself. Human skin is generally hypoxic, which in turn favours melanogenesis. […] 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. […] The immune system also plays a significant role in the carcinogenesis of melanoma. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] An essential factor for tumour development and progression is the environment itself. Human skin is generally hypoxic, which in turn favours melanogenesis. […] 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. […] The immune system also plays a significant role in the carcinogenesis of melanoma. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

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

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

  The mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation, growth, and migration and is activated in almost all types of melanomas. […] 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. […] An essential factor for tumour development and progression is the environment itself. […] The hypoxic response is primarily mediated by HIF.

• #45 Nodular Melanoma: A Review of Pathogenesis, Presentation, Diagnosis, and Treatment

  https://www.dermatoljournal.com/articles/nodular-melanoma-a-review-of-pathogenesis-presentation-diagnosis-and-treatment.html

  Melanoma pathogenesis is also closely associated with the tumor microenvironment (TME) and immune system. The TME refers to the influential network of molecules, cells, and paracrine factors involved in the progression, proliferation, and differentiation of melanoma cells. […] Tumor cells have the potential to develop methods to evade any of these and other anti-tumor responses, e.g. by downregulating tumor-associated antigen production, downregulating MHC molecule expression, and increasing production of programmed death ligand-1 (PD-L1) to inhibit T-cell activation. […] Multiple mutations have been associated with the development of malignant melanoma. The mitogen-activated protein kinase (MAPK) pathway is involved in the regulation of cellular growth, proliferation, and apoptosis. Derangements in this pathway, such as its unintended activation, is involved in the pathogenesis of multiple cancer types including melanoma. Proto-oncogene B-raf (BRAF) gene mutations, typically missense mutations at valine 600, are the most common genetic abnormalities resulting in aberrant MAPK signaling. The phosphoinositol-3-kinase PI3K/AKT pathway, which plays a role in cellular homeostasis, is also implicated in melanoma pathogenesis. Activating mutations in the neuroblastoma RAS viral oncogene (NRAS) gene are also involved in melanoma pathogenesis via the aberrant activation of either MAPK or PI3K/AKT signaling.

• #46 Nodular Melanoma: A Review of Pathogenesis, Presentation, Diagnosis, and Treatment

  https://www.dermatoljournal.com/articles/nodular-melanoma-a-review-of-pathogenesis-presentation-diagnosis-and-treatment.html

  Melanoma pathogenesis is also closely associated with the tumor microenvironment (TME) and immune system. The TME refers to the influential network of molecules, cells, and paracrine factors involved in the progression, proliferation, and differentiation of melanoma cells. […] Tumor cells have the potential to develop methods to evade any of these and other anti-tumor responses, e.g. by downregulating tumor-associated antigen production, downregulating MHC molecule expression, and increasing production of programmed death ligand-1 (PD-L1) to inhibit T-cell activation. […] Multiple mutations have been associated with the development of malignant melanoma. The mitogen-activated protein kinase (MAPK) pathway is involved in the regulation of cellular growth, proliferation, and apoptosis. Derangements in this pathway, such as its unintended activation, is involved in the pathogenesis of multiple cancer types including melanoma. Proto-oncogene B-raf (BRAF) gene mutations, typically missense mutations at valine 600, are the most common genetic abnormalities resulting in aberrant MAPK signaling. The phosphoinositol-3-kinase PI3K/AKT pathway, which plays a role in cellular homeostasis, is also implicated in melanoma pathogenesis. Activating mutations in the neuroblastoma RAS viral oncogene (NRAS) gene are also involved in melanoma pathogenesis via the aberrant activation of either MAPK or PI3K/AKT signaling.

• #47 Inherited susceptibility to melanoma – UpToDate

  https://www.uptodate.com/contents/inherited-susceptibility-to-melanoma

  Inherited susceptibility to melanoma […] The etiology of all cancers depends upon the interplay between environmental and genetic factors. […] For melanoma, the most significant environmental risk factor is solar ultraviolet (UV) radiation exposure. […] However, this risk is greatly influenced by genetic factors. […] Significant progress has been made toward understanding the genes that contribute to inherited susceptibility for melanoma in some patients. […] Uncommon but high-risk alleles contribute to the hereditary cancer phenotype that includes multiple cases of the associated cancer or cancers on one side of the family, multiple primary cancers in a given individual, and early age of onset for a given cancer. […] With advances in genomic technologies and the conceptual framework to isolate more prevalent but lower risk alleles, the spectrum of genetic variants that contribute to melanoma risk has expanded. […] The hereditary risk factors for melanoma are discussed here, along with potential implications for genetic screening.

• #48 Inherited susceptibility to melanoma – UpToDate

  https://www.uptodate.com/contents/inherited-susceptibility-to-melanoma

  Inherited susceptibility to melanoma […] The etiology of all cancers depends upon the interplay between environmental and genetic factors. […] For melanoma, the most significant environmental risk factor is solar ultraviolet (UV) radiation exposure. […] However, this risk is greatly influenced by genetic factors. […] Significant progress has been made toward understanding the genes that contribute to inherited susceptibility for melanoma in some patients. […] Uncommon but high-risk alleles contribute to the hereditary cancer phenotype that includes multiple cases of the associated cancer or cancers on one side of the family, multiple primary cancers in a given individual, and early age of onset for a given cancer. […] With advances in genomic technologies and the conceptual framework to isolate more prevalent but lower risk alleles, the spectrum of genetic variants that contribute to melanoma risk has expanded. […] The hereditary risk factors for melanoma are discussed here, along with potential implications for genetic screening.

• #49 Inherited susceptibility to melanoma – UpToDate

  https://www.uptodate.com/contents/inherited-susceptibility-to-melanoma

  Inherited susceptibility to melanoma […] The etiology of all cancers depends upon the interplay between environmental and genetic factors. […] For melanoma, the most significant environmental risk factor is solar ultraviolet (UV) radiation exposure. […] However, this risk is greatly influenced by genetic factors. […] Significant progress has been made toward understanding the genes that contribute to inherited susceptibility for melanoma in some patients. […] Uncommon but high-risk alleles contribute to the hereditary cancer phenotype that includes multiple cases of the associated cancer or cancers on one side of the family, multiple primary cancers in a given individual, and early age of onset for a given cancer. […] With advances in genomic technologies and the conceptual framework to isolate more prevalent but lower risk alleles, the spectrum of genetic variants that contribute to melanoma risk has expanded. […] The hereditary risk factors for melanoma are discussed here, along with potential implications for genetic screening.

• #50 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  The role of p53 in melanoma is disputed. […] Oncogene Cyclin-dependent kinase 4 (CDK4) and tumor suppressor gene CDKN2A, which encodes p16INK4a have been implicated in familial melanoma development. […] The proposed form of genetic inheritance of this predisposition is through autosomal dominant inheritance, with a 53% penetrance rate by the 8th decade. […] 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. […] Upreguated expression of VE-cadherin is another change that appears to promote the metastatic potential of melanoma cells.

• #51 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

  Mutations or other changes in any of these types of genes might lead to cells growing out of control. Changes in several different genes are usually needed for a cell to become a cancer cell. […] 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). […] For example, ultraviolet (UV) rays are a major cause of melanoma. […] 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.

• #52 Epigenetic mechanisms involved in melanoma pathogenesis and chemoresistance

  https://atm.amegroups.org/article/view/6964/8514

  The discovery of highly recurrent mutations in melanoma, such as BRAFV600E, completely changed the clinical management including therapy of melanoma patients. […] In addition to genetic biomarkers, epigenetic knowledge in melanoma has undergone a major step forward in recent years. In particular, epigenetics is unveiling new perspectives to fight this disease, providing an encouraging number of DNA methylation based biomarkers that will likely improve patient stratification for prognosis and treatment. […] Epigenetic inactivation of particular tumor suppressor genes has been extensively implicated in tumor initiation, promotion and progression. […] It was the first epigenetic alteration studied in melanoma occurring preferentially by the specific DNA methylation of promoter regions. […] Even though the first discoveries were made on disrupted genes by DNA hypermethylation, epigenome-wide DNA methylation landscape of melanoma revealed a global wave of hypomethylation throughout intergenic regions, gene bodies and locations away from CpG islands.

• #53 Epigenetic mechanisms involved in melanoma pathogenesis and chemoresistance

  https://atm.amegroups.org/article/view/6964/8514

  The discovery of highly recurrent mutations in melanoma, such as BRAFV600E, completely changed the clinical management including therapy of melanoma patients. […] In addition to genetic biomarkers, epigenetic knowledge in melanoma has undergone a major step forward in recent years. In particular, epigenetics is unveiling new perspectives to fight this disease, providing an encouraging number of DNA methylation based biomarkers that will likely improve patient stratification for prognosis and treatment. […] Epigenetic inactivation of particular tumor suppressor genes has been extensively implicated in tumor initiation, promotion and progression. […] It was the first epigenetic alteration studied in melanoma occurring preferentially by the specific DNA methylation of promoter regions. […] Even though the first discoveries were made on disrupted genes by DNA hypermethylation, epigenome-wide DNA methylation landscape of melanoma revealed a global wave of hypomethylation throughout intergenic regions, gene bodies and locations away from CpG islands.

• #54 Epigenetic mechanisms involved in melanoma pathogenesis and chemoresistance

  https://atm.amegroups.org/article/view/6964/8514

  The discovery of highly recurrent mutations in melanoma, such as BRAFV600E, completely changed the clinical management including therapy of melanoma patients. […] In addition to genetic biomarkers, epigenetic knowledge in melanoma has undergone a major step forward in recent years. In particular, epigenetics is unveiling new perspectives to fight this disease, providing an encouraging number of DNA methylation based biomarkers that will likely improve patient stratification for prognosis and treatment. […] Epigenetic inactivation of particular tumor suppressor genes has been extensively implicated in tumor initiation, promotion and progression. […] It was the first epigenetic alteration studied in melanoma occurring preferentially by the specific DNA methylation of promoter regions. […] Even though the first discoveries were made on disrupted genes by DNA hypermethylation, epigenome-wide DNA methylation landscape of melanoma revealed a global wave of hypomethylation throughout intergenic regions, gene bodies and locations away from CpG islands.

• #55 Epigenetic mechanisms involved in melanoma pathogenesis and chemoresistance

  https://atm.amegroups.org/article/view/6964/8514

  Interestingly, the authors related this particular mutation (BRAFV600E) with an event of global hypomethylation and a decrease in DNMT3A expression, one of de novo DNA methyltransferases in cells. […] Systematic characterization of epigenetically disrupted genes in melanoma has provided new insights regarding to the progression of the malignancy or the acquisition of resistance in melanoma patients. […] At this respect, the most valuable DNA methylation-associated biomarkers would be those intimately related to the metastatic stage but being also present in low grade primary melanomas with bad prognosis. […] Hence, melanoma could be molecularly stratified and personalized treatments could be applied improving the melanoma patients survival. […] Resistance to cancer therapy is a multifactorial process related not only to the kind of neoplasia and the tumor genotype and heterogeneity but also to own patients features.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] An essential factor for tumour development and progression is the environment itself. Human skin is generally hypoxic, which in turn favours melanogenesis. […] 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. […] The immune system also plays a significant role in the carcinogenesis of melanoma. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

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

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

  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. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

• #58 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  Studies have shown that a major risk factor for melanoma development is exposure to Ultraviolet (UV) radiation exposure. […] 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. […] After the melanoma spreads or metastasizes from its origin into other cutaneous or subcutaneous tissues, the response rate to treatment plummets to approximately 5-20%, and the 10-year survival rate becomes only about 10%. […] At the cellular level, cancer cells possess distinguishing molecular properties that allow for apoptosis evasion, limitless growth potential without the need for growth factors, angiogenesis, and metastasis.

• #59 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

  Mutations or other changes in any of these types of genes might lead to cells growing out of control. Changes in several different genes are usually needed for a cell to become a cancer cell. […] 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). […] For example, ultraviolet (UV) rays are a major cause of melanoma. […] 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.

• #60 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. […] 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.

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

  https://www.mdpi.com/1422-0067/22/12/6395

  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. […] An essential factor for tumour development and progression is the environment itself. Human skin is generally hypoxic, which in turn favours melanogenesis. […] 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. […] The immune system also plays a significant role in the carcinogenesis of melanoma. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

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

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

  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. […] A distinctive feature of the malignant neoplasms is their ability to disseminate and metastasize.

• #63 Melanoma: Molecular Pathogenesis and Therapeutic Management

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

  Studies have shown that a major risk factor for melanoma development is exposure to Ultraviolet (UV) radiation exposure. […] 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. […] After the melanoma spreads or metastasizes from its origin into other cutaneous or subcutaneous tissues, the response rate to treatment plummets to approximately 5-20%, and the 10-year survival rate becomes only about 10%. […] At the cellular level, cancer cells possess distinguishing molecular properties that allow for apoptosis evasion, limitless growth potential without the need for growth factors, angiogenesis, and metastasis.

• #64 Key Mechanism Behind Melanoma’s Early Resistance to BRAF Inhibitors Identified | Inside Precision Medicine

  https://www.insideprecisionmedicine.com/topics/oncology/key-mechanism-behind-melanomas-early-resistance-to-braf-inhibitors-identified/

  New research from scientists at the Institute for Systems Biology (ISB) and MIT has identified a critical survival mechanism that allows melanoma cells to quickly evade BRAF inhibitor treatments. The study, published in Cell Systems, identified a reversible adaption that can occur within hours of the first treatment and does not rely on reactivating the BRAF-ERK pathway, the most common mechanism of resistance. […] The finding is an important piece to gain a better understanding of why BRAF inhibitor drugs like vemurafenib, which initially halt tumor growth, often fail after a short time. […] Melanoma tumors are often driven by mutations in the BRAF gene. BRAF inhibitors work by blocking this gene’s activity, but their effectiveness is often short-lived. The new study uncovers the role of the SFK signaling pathway that enables melanoma cells to evade treatment before genetic resistance occurs.

• #65 Key Mechanism Behind Melanoma’s Early Resistance to BRAF Inhibitors Identified | Inside Precision Medicine

  https://www.insideprecisionmedicine.com/topics/oncology/key-mechanism-behind-melanomas-early-resistance-to-braf-inhibitors-identified/

  Their findings showed that as melanoma cells are exposed to BRAF inhibitors, they accumulate reactive oxygen species (ROS), which then trigger the SFK pathway. This adaptation allows the cells to survive, but it is reversible. […] Recognizing this vulnerability, the team tested a combination therapy, pairing the BRAF inhibitor with the SFK inhibitor dasatinib, and found that it effectively blocked the survival pathway, reducing cell survival and stabilizing tumors in animal models. […] These new findings build off earlier studies of cellular behavior to targeted cancer therapies, which have shown that cancer cells can adapt to therapeutic pressure by activating alternative signaling pathways. This study now offers a more detailed picture of the early stages of adaptation—information that can be used to develop new therapeutic approaches to treat melanoma. […] Building on this finding, the researchers will conduct additional preclinical studies to explore the role of ROS and SFK in the adaptive survival of melanoma cells and to test the combination therapy in additional melanoma models.

• #66 Melanoma Drug Resistance Mechanism and Biomarker Identified

  https://www.insideprecisionmedicine.com/news-and-features/melanoma-drug-resistance-mechanism-and-biomarker-identified/

  Researchers at the Mount Sinai School of Medicine and The University of Sydney, Australia have discovered a previously unknown mechanism of drug resistance in a subtype of melanoma patients. […] They identified a novel epigenetic mechanism that causes resistance to the standard treatment in those melanoma patients that harbor a specific mutation in the BRAF gene known as BRAF V600E. […] This particular mutation, which results in a constitutively activated BRAF, has been implicated in different mechanisms underlying melanomagenesis, most of which are due to the deregulated activation of the downstream MEK/ERK effectors. […] One of the challenges is the development of resistance to the standard therapy. […] The researchers sought to investigate the epigenetic and, more specifically, chromatin-mediated mechanisms involved in melanoma resistance to MAPKi.

• #67 Melanoma Drug Resistance Mechanism and Biomarker Identified

  https://www.insideprecisionmedicine.com/news-and-features/melanoma-drug-resistance-mechanism-and-biomarker-identified/

  Researchers at the Mount Sinai School of Medicine and The University of Sydney, Australia have discovered a previously unknown mechanism of drug resistance in a subtype of melanoma patients. […] They identified a novel epigenetic mechanism that causes resistance to the standard treatment in those melanoma patients that harbor a specific mutation in the BRAF gene known as BRAF V600E. […] This particular mutation, which results in a constitutively activated BRAF, has been implicated in different mechanisms underlying melanomagenesis, most of which are due to the deregulated activation of the downstream MEK/ERK effectors. […] One of the challenges is the development of resistance to the standard therapy. […] The researchers sought to investigate the epigenetic and, more specifically, chromatin-mediated mechanisms involved in melanoma resistance to MAPKi.

• #68 NKI researchers unravel drug resistance mechanism of melanoma | Netherlands Cancer Institute

  https://www.nki.nl/news-events/news/nki-researchers-unravel-drug-resistance-mechanism-of-melanoma/

  Patients with melanoma, an aggressive form of skin cancer, can benefit greatly from novel drugs like BRAF and MEK inhibitors. […] Judith Mller from the research team of Daniel Peeper at the Netherlands Cancer Institute (NKI) has unraveled a mechanism causing melanomas to display broad drug resistance, and also found how this type of resistance might be countered. […] It turns out that melanoma cells can escape from BRAF inhibitors by shutting down the production of a protein called MITF. This leads to a number of changes in the cancer cells, which eventually causes them to lose their dependency on the BRAF-route to survive. Thus, BRAF-inhibitors become obsolete. Downregulation of their MITF production causes melanoma cells to develop resistance against different types of personalized medicines, including MEK inhibitors.

• #69 NKI researchers unravel drug resistance mechanism of melanoma | Netherlands Cancer Institute

  https://www.nki.nl/news-events/news/nki-researchers-unravel-drug-resistance-mechanism-of-melanoma/

  Patients with melanoma, an aggressive form of skin cancer, can benefit greatly from novel drugs like BRAF and MEK inhibitors. […] Judith Mller from the research team of Daniel Peeper at the Netherlands Cancer Institute (NKI) has unraveled a mechanism causing melanomas to display broad drug resistance, and also found how this type of resistance might be countered. […] It turns out that melanoma cells can escape from BRAF inhibitors by shutting down the production of a protein called MITF. This leads to a number of changes in the cancer cells, which eventually causes them to lose their dependency on the BRAF-route to survive. Thus, BRAF-inhibitors become obsolete. Downregulation of their MITF production causes melanoma cells to develop resistance against different types of personalized medicines, including MEK inhibitors.

• #70 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240627/Study-identifies-mechanism-that-impedes-the-effectiveness-of-melanoma-therapies.aspx

  In many cases of malignant melanoma, the effect of targeted treatment is lost over time. A research team from UZH and USZ has now discovered that a factor secreted by tumor cells is responsible for the resistance. These findings could pave the way for more effective therapies. […] A study under his lead has now identified a mechanism that impedes the effectiveness of therapies. The result provides new ideas for treatments to suppress the development of resistance. […] One of the most relevant findings concerned the POSTN gene: it codes for a secreted factor that plays an important role in resistant tumors. In fact, the tumors of patients with rapidly progressing disease despite treatment showed increased POSTN levels. […] Through a series of further experiments both with human cancer cells and with mice the research team was able to show how the interaction of increased POSTN levels and this type of macrophage triggers resistance: the POSTN factor binds to receptors on the surface of the macrophages and polarizes them to protect melanoma cells from cell death. „This is why the targeted therapy no longer works,” says Sommer. […] „The study highlights the potential of targeting specific types of macrophages within the tumor microenvironment to overcome resistance,” says Sommer. „In combination with already known therapies, this could significantly improve the success of treatment for patients with malignant melanoma.”

• #71 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240627/Study-identifies-mechanism-that-impedes-the-effectiveness-of-melanoma-therapies.aspx

  In many cases of malignant melanoma, the effect of targeted treatment is lost over time. A research team from UZH and USZ has now discovered that a factor secreted by tumor cells is responsible for the resistance. These findings could pave the way for more effective therapies. […] A study under his lead has now identified a mechanism that impedes the effectiveness of therapies. The result provides new ideas for treatments to suppress the development of resistance. […] One of the most relevant findings concerned the POSTN gene: it codes for a secreted factor that plays an important role in resistant tumors. In fact, the tumors of patients with rapidly progressing disease despite treatment showed increased POSTN levels. […] Through a series of further experiments both with human cancer cells and with mice the research team was able to show how the interaction of increased POSTN levels and this type of macrophage triggers resistance: the POSTN factor binds to receptors on the surface of the macrophages and polarizes them to protect melanoma cells from cell death. „This is why the targeted therapy no longer works,” says Sommer. […] „The study highlights the potential of targeting specific types of macrophages within the tumor microenvironment to overcome resistance,” says Sommer. „In combination with already known therapies, this could significantly improve the success of treatment for patients with malignant melanoma.”

• #72 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240627/Study-identifies-mechanism-that-impedes-the-effectiveness-of-melanoma-therapies.aspx

  In many cases of malignant melanoma, the effect of targeted treatment is lost over time. A research team from UZH and USZ has now discovered that a factor secreted by tumor cells is responsible for the resistance. These findings could pave the way for more effective therapies. […] A study under his lead has now identified a mechanism that impedes the effectiveness of therapies. The result provides new ideas for treatments to suppress the development of resistance. […] One of the most relevant findings concerned the POSTN gene: it codes for a secreted factor that plays an important role in resistant tumors. In fact, the tumors of patients with rapidly progressing disease despite treatment showed increased POSTN levels. […] Through a series of further experiments both with human cancer cells and with mice the research team was able to show how the interaction of increased POSTN levels and this type of macrophage triggers resistance: the POSTN factor binds to receptors on the surface of the macrophages and polarizes them to protect melanoma cells from cell death. „This is why the targeted therapy no longer works,” says Sommer. […] „The study highlights the potential of targeting specific types of macrophages within the tumor microenvironment to overcome resistance,” says Sommer. „In combination with already known therapies, this could significantly improve the success of treatment for patients with malignant melanoma.”

• #73 Researchers discover a new mechanism involved in early melanoma metastasis

  https://medicalxpress.com/news/2021-11-mechanism-involved-early-melanoma-metastasis.html

  Researchers discover a new mechanism involved in early melanoma metastasis. Research led by CNIO scientist Héctor Peinado shows that the NGFR molecule drives the entire process of early metastasis in melanoma and that blocking it drastically reduces metastasis in animal models. […] Peinado is the head of the CNIO’s Microenvironment & Metastasis Group, which studies the mechanisms involved in metastatic progression, including how nanoparticles called exosomes, which are released by tumors, manipulate the tumor microenvironment to favor metastasis. […] The scientists also propose NGFR as a new biomarker of early melanoma metastasis to define risk groups and predict metastasis. […] Unlike other skin cancers, melanoma is one of the most aggressive tumors; it can metastasise when the primary lesion is still very small.

• #74 Researchers discover a new mechanism involved in early melanoma metastasis

  https://medicalxpress.com/news/2021-11-mechanism-involved-early-melanoma-metastasis.html

  Researchers discover a new mechanism involved in early melanoma metastasis. Research led by CNIO scientist Héctor Peinado shows that the NGFR molecule drives the entire process of early metastasis in melanoma and that blocking it drastically reduces metastasis in animal models. […] Peinado is the head of the CNIO’s Microenvironment & Metastasis Group, which studies the mechanisms involved in metastatic progression, including how nanoparticles called exosomes, which are released by tumors, manipulate the tumor microenvironment to favor metastasis. […] The scientists also propose NGFR as a new biomarker of early melanoma metastasis to define risk groups and predict metastasis. […] Unlike other skin cancers, melanoma is one of the most aggressive tumors; it can metastasise when the primary lesion is still very small.

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