Materiały źródłowe

• #1 Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7916193/

  Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. […] cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. […] Extensive studies on cSCC pathogenic mechanisms identified several pharmaceutical targets. Indeed, the multistage process that leads to cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes.

• #1 Cutaneous Squamous Cell Carcinoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1965430-overview

  Malignant transformation of normal epidermal keratinocytes is the hallmark of cSCC. One critical pathogenic event is the development of apoptotic resistance through functional loss of TP53, a well-studied tumor suppressor gene. TP53 mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as in most precursor skin lesions, suggesting that loss of TP53 is an early event in the development of cSCC. […] UVR causes DNA damage through the creation of pyrimidine dimers, a process known to result in the genetic mutation of TP53. Upon subsequent UVR exposure, keratinocytes undergo clonal expansion, acquiring further genetic defects, ultimately leading to invasive cSCC. […] Many other genetic abnormalities are believed to contribute to the pathogenesis of cSCC, including mutations of BCL2 and RAS. Likewise, alterations in intracellular signal transduction pathways, including the epidermal growth factor receptor (EGFR) and cyclo-oxygenase (COX), have been shown to play a role in the development of cSCC. […] Given the central role that ultraviolet radiation (UVR) plays in the pathogenesis of cSCC, methods aimed at decreasing UVR exposure form the cornerstone of cSCC prevention. In addition, treatment of precancerous lesions and in situ SCC may prevent the future development of invasive lesions.

• #1 Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma

  https://www.mdpi.com/1422-0067/23/7/3478

  Both genetic and epigenetic alterations can increase the overall mutation rate, enhance proliferation, and decrease cell death. […] The primary carcinogen responsible for cSCC is cumulative lifetime exposure to ultraviolet radiation (UV). […] UV irradiation is capable of initiating and promoting the progression of all stages of squamous carcinogenesis. […] In cSCCs, reported rates of amplifications and activating mutations in Ras genes range widely from 3–30%. […] Mutations in the CDKN2A locus have been reported to occur in 24–45% of sporadic cSCCs. […] FAT1 encodes a tumor suppressor-related member of the FAT protocadherin family that is frequently mutated in numerous types of human cancers including cutaneous, head and neck, and oral SCCs. […] Aberrant DNA methylation in cSCC is associated with SCC, including CDKN2A (p14ARF and p16INK4A) promoter methylation, found in 40% of cSCC. […] Epigenetic alterations represent additional hallmarks in a cell’s transformation into cancer. […] The primary environmental risk factor for BCC, SCC, and melanoma is ultraviolet radiation, which, like arsenic, acts at the molecular level, in part, through epigenetic mechanisms.

• #1

  https://www.jci.org/articles/view/57415

  As with other cancers, cSCC exhibits impaired genomic maintenance that facilitates acquisition of new mutations. The mechanism leading to genomic instability in keratinocytes likely results from UVB-induced inactivation of p53, since approximately 58% of cSCCs harbor UVB signature mutations such as CCTT and CT transitions. The role of p53 in UVB-induced carcinogenesis has been confirmed in p53/mice which have an increased propensity for developing AK-like lesions and cSCCs secondary to UVB exposure. […] Aberrant activation of EGFR and Fyn, a Src-family tyrosine kinase (SFK), are seen in human cSCCs, and these kinases downregulate p53 mRNA and protein levels through a c-Jundependent mechanism, revealing another mechanism for controlling p53 function. […] Loss of heterozygosity has also been observed in cSCCs at chromosome 9p in 13 of 16 primary tumors. Loss of heterozygosity of p16, a cell cycle regulator that lies in this region, is hypothesized to be associated with progression from AKs to cSCCs, and loss of function of p16 is more frequent in cSCCs than in precancerous lesions.

• #1 Pathology Outlines – Squamous cell carcinoma

  https://pathologyoutlines.com/topic/skintumornonmelanocyticscc.Html

  Cutaneous squamous cell carcinoma appears to develop through a multistep process […] UV radiation, mutations involving genes (such as TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS / RAF / MEK / ERK and PI3K / AKT / mTOR) have been shown to play an important role in the pathogenesis.

• #1 Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7916193/

  A complex network of deregulated signaling pathways plays an important role in the pathogenesis of cSCC. AK and cSCC lesions result from a multistage process, involving mutations in the genes implicated in epidermal homeostasis promoting the uncontrolled proliferation of atypical keratinocytes. […] cSCC is one of the cancers with the highest mutation rate. The commonest mutated genes belong to pathways involved in cell cycle regulation, apoptosis, senescence, differentiation, and mitogenic/survival signaling. […] The most frequently altered gene in cSCC is TP53, which encodes the tumor-suppressor protein p53. […] The mutation in TP53 sequence is an early event in cSCC pathogenesis, occurs in 54-95% of cases, and is responsible for the great genomic instability of these tumors. […] The CDKN2A locus gene encodes two alternatively spliced proteins, p16INK4a and p14ARF, which inhibit cell cycle progression and proliferation through the retinoblastoma (pRb) and p53 pathways, respectively.

• #1

  https://www.jci.org/articles/view/57415

  In a chemical carcinogenesis model of cSCC, 7,12-dimethyl-1,2-benzanthracene (DMBA) initiated epidermal tumor formation in mice treated with 5-fluorouracil (5-FU), a compound that kills actively cycling cells in the epidermis. […] Recent work has shown that PKC- mRNA is markedly downregulated in human cSCCs compared to epidermis suggesting that decreased PKC- levels are important for UVB-induced neoplasia. Fyn phosphorylates PKC-, and PKC- is an important regulator of UVB-induced apoptosis; it will be important to determine how Fyn and Srcasm regulate PKC- phosphorylation and protein/mRNA levels and correlate this UVB-induced apoptosis. […] Notch signaling has been implicated in both normal epidermal development and in the pathogenesis of cSCC. Notch signaling regulates many important cellular processes including stem cell maintenance, cell fate decisions, differentiation, proliferation, and apoptosis.

• #1

  https://www.jci.org/articles/view/57415

  Amplification and activating mutations of the Ras oncogene have been found in SCCs and AKs. Of the three Ras genes, Harvey rat sarcoma virus oncogene (Hras) is preferentially mutated in the general population. Ras molecules are a family of GTP-binding proteins that are among the most frequently mutated genes in humans cancers. Ras is an upstream activator of the Raf/Mek/Erk1/Erk2 kinase pathway, and activating mutations in Ras can promote cSCC formation. […] The interactions between tumor cells with their extracellular matrix and the basement membrane zone (BMZ) are important determinants of tumorigenesis and have been shown to play a role in cSCC. Laminin 332 (previously known as laminin 5) is a BMZ component involved in epithelial-mesenchymal cohesion in multiple tissues including the epidermis.

• #1 Squamous cell carcinoma of the skin pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Squamous_cell_carcinoma_of_the_skin_pathophysiology

  Aberrant activation of EGFR and Fyn, a Src-family tyrosine kinase (SFK), are seen in human cutaneous squamous cell carcinoma. […] Kinases downregulate p53 mRNA and protein levels through a c-Jun–dependent mechanism revealing another mechanism for controlling p53 function. […] Amplification and activating mutations of the Ras oncogene have been found in squamous cell carcinoma and actnic keratosis. […] Ras is an upstream activator of the Raf/Mek/Erk1/Erk2 kinase pathway, and activating mutations in Ras can promote cutaneous squamous cell carcinoma. […] Expression of β1-integrins and their ligands correlates with tumor progression in human skin. […] Ras family members of proto-oncogenes transduce cellular growth and proliferation signals downstream of cell membrane–bound receptor tyrosine kinases (RTKs). Ras can be activated by gene amplification, activating mutations, or overexpression of upstream RTKs. Aberrant Ras activation promotes several key tumorigenic phenotypes including mitogenesis, resistance to apoptosis, drug resistance.

• #1

  https://www.jci.org/articles/view/57415

  The role of STAT3 in UVB-induced cutaneous tumorigenesis was evaluated using transgenic and gene-deficient mouse models with constitutively active STAT3 expressed in the skin or skin-specific STAT3 deficiency. Following UVB exposure, the K5-Stat3C mice developed cSCCs at a greater frequency and with an increased multiplicity than control mice. Conversely, epidermal STAT3 deficiency protected mice from UVB tumorigenesis.

• #1 Skin cancer – Wikipedia

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

  A malignant epithelial tumor that primarily originates in the epidermis, in squamous mucosa or in areas of squamous metaplasia is referred to as a squamous-cell carcinoma. […] Macroscopically, the tumor is often elevated, fungating, or may be ulcerated with irregular borders. Microscopically, tumor cells destroy the basement membrane and form sheets or compact masses which invade the subjacent connective tissue (dermis). In well differentiated carcinomas, tumor cells are pleomorphic/atypical, but resembling normal keratinocytes from prickle layer (large, polygonal, with abundant eosinophilic (pink) cytoplasm and central nucleus). […] Their disposal tends to be similar to that of normal epidermis: immature/basal cells at the periphery, becoming more mature to the centre of the tumor masses. Tumor cells transform into keratinized squamous cells and form round nodules with concentric, laminated layers, called „cell nests” or „epithelial/keratinous pearls”. The surrounding stroma is reduced and contains inflammatory infiltrate (lymphocytes). Poorly differentiated squamous carcinomas contain more pleomorphic cells and no keratinization. […] A molecular factor involved in the disease process is mutation in gene PTCH1 that plays an important role in the Sonic hedgehog signaling pathway.

• #1 Update on the Molecular Pathology of Cutaneous Squamous Cell Carcinoma

  https://www.mdpi.com/1422-0067/24/7/6646

  The development of cSCC is a multistep process requiring the accumulation of multiple genetic and epigenetic alterations in keratinocytes. These alterations lead to an augmented mutation rate by increasing cellular proliferation and reducing cell death in mutated keratinocyte population. DNA mutations are caused by either exogenous factors, such as UV radiation, chemicals, and ionizing radiation, or endogenous factors, such as reactive oxygen species (ROS), genome editing, mitotic errors, or errors in DNA repair. […] Cumulative lifetime exposure to UV radiation is considered to be the most important carcinogen responsible for cSCC. UV exposure over-activates the DNA repair systems of keratinocytes, leading to ATP consumption. […] The risk of evolution from AK to SCC is very difficult to predict, with the numbers varying vastly between different studies (0.025–20%). Out of the cSCCs, only a small percentage can acquire additional genetic and epigenetic features that lead to metastatic disease.

• #1

  https://journals.lww.com/jdnaonline/fulltext/2010/01000/squamous_cell_carcinoma__a_review_of_etiology,.2.aspx

  The exact genetic alterations and numbers of mutations needed for malignant transformation are as yet unknown. The most readily accepted theory involves the transformation of the epidermal p53 gene clones by ultraviolet (UV) exposure to the precursors of squamous cell carcinoma. Early p53 mutations are believed to inhibit apoptosis of abnormal cells, allowing them to expand at the expense of normal presenting cells. Alterations of the p53 gene are the most common presenting malformation in all stages of squamous cell carcinoma, starting at the precancerous lesion and advancing to the invasive and potentially metastatic forms. Typically, this presents with one allele (DNA sequence) containing a missense point mutation with a UV signature, and the remaining allele is deleted. […] The pathogenesis of squamous cell carcinoma is multifactorial and includes many extrinsic and intrinsic factors. The most important extrinsic factor is generally recognized as UV sunlight exposure. As lifetime UV exposure increases, so does the incidence of squamous cell carcinoma. In fact, for every 8- to 10-degree decrease in latitude (e.g., Washington, DC to Tampa, FL), there is a doubling of the incidence of squamous cell carcinoma. Patients treated with psoralen with ultraviolet A are 30 times more likely to develop squamous cell carcinoma than the general population. The human papillomavirus type 16 is present in many of the genital and periungal forms of squamous cell, but human papillomavirus types 5, 8, 9, 18, 31, 33, 35, 39, 40, and 51-60, have all been isolated from squamous cell tumors. Other extrinsic factors that are related to the development of squamous cell carcinoma are industrial carcinogens, such as pitch, tar, crude paraffin oil, fuel oil, creosote, lubricating oils, arsenic, and nitrosoureas.

• #1

  https://www.jci.org/articles/view/57415

  Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with over 250,000 new cases annually in the US and is second in incidence only to basal cell carcinoma. cSCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. […] The classic multistep model of carcinogenesis is useful for understanding the progression from AK to cSCC. According to this model, mutations in one gene, often a tumor suppressor, may lead to the development of a precursor lesion with increased genetic instability or loss of cell cycle control. Additional mutations in other driver oncogenes permit the emergence of more neoplastic properties, leading to invasive carcinoma; the number of genetic changes required to transition from benign epithelium to metastatic carcinoma internal malignancies is thought to range from four to six. However, 3D models of human epidermis have shown that as few as two proto-oncogene mutations changes are sufficient to drive SCC.

• #1

  https://www.jci.org/articles/view/57415/

  Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with over 250,000 new cases annually in the US and is second in incidence only to basal cell carcinoma. cSCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. […] The classic multistep model of carcinogenesis is useful for understanding the progression from AK to cSCC. According to this model, mutations in one gene, often a tumor suppressor, may lead to the development of a precursor lesion with increased genetic instability or loss of cell cycle control. Additional mutations in other driver oncogenes permit the emergence of more neoplastic properties, leading to invasive carcinoma; the number of genetic changes required to transition from benign epithelium to metastatic carcinoma internal malignancies is thought to range from four to six. However, 3D models of human epidermis have shown that as few as two proto-oncogene mutations changes are sufficient to drive SCC.

• #1 Update on the Molecular Pathology of Cutaneous Squamous Cell Carcinoma

  https://www.mdpi.com/1422-0067/24/7/6646

  The epigenetic profile seems to represent an important tool for characterizing the aggressiveness and metastatic potential of this type of skin cancer. Moreover, multiple changes, such as CpG hypermethylation, seem to be involved in its occurrence. […] The hypermethylation of certain CpG areas (induced especially by the effect of ultraviolet radiation, -thereby increasing the expression of dimethyltransferase 1) leads to changes in some proteins with an important role in keratinocyte homeostasis, which is associated with aggressive behavior and metastasis. […] The understanding of cancer biology was revolutionized by the discovery of cancer stem cells (CSCs) by Bonnet and Dick, who described these cells in human acute myeloid leukemia. […] CSCs are considered to be the basis of any tumor development and responsible for intratumoral genetic and phenotypic heterogeneity.

• #1 Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7916193/

  The inactivation of the CDKN2A locus can be due to loss of heterozygosity, point mutations, and promoter hypermethylation and leads to unrestrained cell cycling and uncontrolled cell growth. […] HPV is a double-stranded DNA virus that infects squamous epithelia. […] The presence of beta-HPV DNA in cSCC samples and the detection of antibodies against HPV in patients with cSCC indicate that beta-HPV types can be involved in cSCC pathogenesis. […] The TME is important in the carcinogenesis of cSCC. cSCC emerges from the interplay of nascent neoplastic keratinocytes with other stromal cell types hosted in the local microenvironment.

• #1 Cutaneous squamous cell carcinoma: Symptoms, Causes, and Treatment — DermNet

  https://dermnetnz.org/topics/cutaneous-squamous-cell-carcinoma

  Cutaneous squamous cell carcinoma (SCC) is a common type of keratinocyte cancer, or non-melanoma skin cancer. It is derived from cells within the epidermis that make keratin the horny protein that makes up skin, hair and nails. […] Cutaneous SCC is an invasive disease, referring to cancer cells that have grown beyond the epidermis. SCC can sometimes metastasise and may prove fatal. […] More than 90% of cases of SCC are associated with numerous DNA mutations in multiple somatic genes. Mutations in the p53 tumour suppressor gene are caused by exposure to ultraviolet radiation (UV), especially UVB (known as signature 7). Other signature mutations relate to cigarette smoking, ageing and immune suppression (eg, to drugs such as azathioprine). Mutations in signalling pathways affect the epidermal growth factor receptor, RAS, Fyn, and p16INK4a signalling. […] Beta-genus human papillomaviruses (wart virus) are thought to play a role in SCC arising in immune-suppressed populations. -HPV and HPV subtypes 5, 8, 17, 20, 24, and 38 have also been associated with an increased risk of cutaneous SCC in immunocompetent individuals.

• #1 Skin microbiome influences the progression of cutaneous squamous cell carcinoma through the immune system | World Journal of Surgical Oncology | Full Text

  https://wjso.biomedcentral.com/articles/10.1186/s12957-025-03791-5

  Two HPV oncoproteins, E6 and E7, play important roles in cancer development and HPV-induced carcinogenesis. […] Activin expression levels are upregulated in mouse and human skin wounds, as well as in cSCC. Its overexpression reduces the number of tumor suppressive T cells and increases the number of protumorigenic regulatory T cells in the ear skin of HPV8 transgenic mice, which promotes the occurrence of skin tumors. […] Inflammation is an important mechanistic contributor to carcinogenesis. It has been suggested that Staphylococcus aureus can lead to tumor formation by producing chronic inflammation, inducing various cytokines, including TNF-, and activating NF-B signaling. […] The colonization of certain Staphylococcus aureus strains may promote the development of a tumor-supportive microenvironment in the skin more than other strains.

• #1 Skin microbiome influences the progression of cutaneous squamous cell carcinoma through the immune system | World Journal of Surgical Oncology | Full Text

  https://wjso.biomedcentral.com/articles/10.1186/s12957-025-03791-5

  Recent evidence based on observational and microbiome sequencing studies suggests that dysregulation of the skin microbiome is related to cSCC pathogenesis. […] Different types of skin microorganisms have varied regulatory effects on the host immune system during skin cancer development and progression. Therefore, investigating the interactions between skin microbes and the immune system and their involvement in cSCC pathogenesis and progression is worthy of further exploration. […] HPV is a DNA virus that parasitizes humans, with HPV infections significantly contributing to the development of a variety of forms of SCC. HPV is categorized into five genera using the L1 nucleotide sequences (alpha, beta, gamma, mu, and nu). Both -HPV and -HPV are closely related to cSCC, with nearly half of patients presenting as high-risk -HPV positive.

• #1 Skin microbiome influences the progression of cutaneous squamous cell carcinoma through the immune system | World Journal of Surgical Oncology | Full Text

  https://wjso.biomedcentral.com/articles/10.1186/s12957-025-03791-5

  Some Staphylococcus aureus strains can secrete compounds similar to UV radiation, which can promote SCC progression through the expression of SCC biomarkers. They can also impair the DNA repair and skin barrier functions, leading to further oxidative stress and DNA damage in the skin. […] These findings suggest that S. epidermidis may be useful as a probiotic for treating cSCC.

• #1 Skin microbiome influences the progression of cutaneous squamous cell carcinoma through the immune system | World Journal of Surgical Oncology | Full Text

  https://wjso.biomedcentral.com/articles/10.1186/s12957-025-03791-5

  Cutaneous squamous cell carcinoma (cSCC) is a type of skin tumor that develops in the epithelial cells. This disease has the second highest incidence of human skin cancers, with a high metastatic rate. While ultraviolet radiation significantly contributes to the genomic changes that support cSCC development, the dysbiosis of the skin microbiome and influence of the immune system also play important roles in this process. […] Overall, skin microbes play an important role in cSCC pathogenesis and progression. Here, we review the interactions between cSCC-related skin microbes and skin immunity, then discuss the prospect of applying skin symbiotic microorganisms for treating cSCC in the future. […] The immune system plays a key role in cSCC pathogenesis and progression. Clinical observational studies have found that the risk of cSCC in patients with organ transplantation and long-term immunosuppressive treatment is 100 times higher than that of the general population. In addition, immunosuppression may also cause cSCC to be more aggressive.

• #1

  https://www.jci.org/articles/view/57415/

  In a chemical carcinogenesis model of cSCC, 7,12-dimethyl-1,2-benzanthracene (DMBA) initiated epidermal tumor formation in mice treated with 5-fluorouracil (5-FU), a compound that kills actively cycling cells in the epidermis. These data suggest that the tumors arose from the quiescent, 5-FUinsensitive epidermal stem cells rather than the rapidly proliferating epidermal cells. […] The role of STAT3 in UVB-induced cutaneous tumorigenesis was evaluated using transgenic and gene-deficient mouse models with constitutively active STAT3 expressed in the skin or skin-specific STAT3 deficiency. Following UVB exposure, the K5-Stat3C mice developed cSCCs at a greater frequency and with an increased multiplicity than control mice. Conversely, epidermal STAT3 deficiency protected mice from UVB tumorigenesis.

• #1 Role of Voriconazole in Cutaneous Squamous Cell Carcinoma Development – The ASCO Post

  https://ascopost.com/news/november-2019/role-of-voriconazole-in-cutaneous-squamous-cell-carcinoma-development/

  For the last decade, medical experts have known that voriconazole, an antifungal medication used to prevent infections in patients with compromised immune systems, is linked to the development of particularly aggressive squamous cell carcinoma in skin exposed to ultraviolet (UV) rays. However, the mechanism of how voriconazole causes cutaneous squamous cell carcinoma was unclear. […] Now a team has shown that voriconazole increases levels of oxidative stress in skin cells called keratinocytes, and that a common antioxidant, N-acetylcysteine, can mitigate voriconazole’s cancer-inducing side effect in keratinocytes. […] Inhibition of catalase would then induce higher levels of oxidative stress in skin cells, promoting the formation of cutaneous squamous cell carcinoma. […] The team found that the antioxidant reduced two markers of oxidative stress in mouse skin tissue exposed to UV radiation. […] This finding sets the stage for trials pairing voriconazole with an antioxidant to see if the combination decreases rates of cutaneous squamous cell carcinoma and if it could serve as an effective treatment for those who have to take the antifungal drug.

• #1 Understanding Squamous Cell Carcinoma

  https://skintel.co.nz/articles/squamous-cell-carcinoma/

  SCCs develop from a complex interaction of genes and environmental influences, in particular UV-induced DNA damage. The exact mechanism of SCC development has not been identified, however, several genetic mutations have been identified, mostly related to UV-mediated DNA damage of tumour suppressor genes. The main genes involved include p53 (66%), NOTCH1/2 (40%), FAT1 (30%) and CDKN2A (35%). P53 mutations are involved in 50% of all cancers. […] Mutations in these genes within squamous cells of the epidermis allow uncontrolled replication and growth of affected cells resulting in the development of SCC.

• #1 Cutaneous Squamous Cell Carcinoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441939/

  Squamous cell carcinoma is the second most common skin malignancy in the United States, and its incidence steadily rises each year, posing a significant public health concern. […] This activity covers the etiology, epidemiology, pathophysiology, histopathological subtypes, clinical features, and management options for cutaneous squamous cell carcinoma. This activity emphasizes the critical role of photoprotection in reducing the risk of developing cutaneous squamous cell carcinoma due to its strong association with UV radiation. […] The development of cutaneous squamous cell carcinoma is associated with the following risk factors and etiologies: UV radiation: UVA and UVB are the most significant risk factors. […] Cutaneous squamous cell carcinoma is derived from the keratinocytes. A mutation in the tp53 tumor suppressor gene is the most common genetic abnormality observed in both squamous cell carcinoma and its precursor, actinic keratosis. Decreased immunosurveillance in immunosuppressed patients may further potentiate tumor growth. […] The prognosis for localized disease is generally excellent. The overall mortality rate for cutaneous squamous cell carcinoma is approximately 1% to 2%, with approximately 3% of cases metastasizing. The lymph nodes are the most common site of metastasis.

• #1 Squamous Cell Carcinoma – The Skin Cancer Doctor

  https://www.theskincancerdoctor.com.au/education/skincancerlesions/squamous-cell-carcinoma/

  Squamous cell carcinoma (SCC) is a cutaneous skin cancer arising from malignant proliferation of epidermal keratinocytes. […] Incidence of SCC have increased over the past 20 years probably due to high levels of sun exposure, tanning bed use, aging and early detection. […] Like Basal cell carcinoma (BCC), both environmental and genetic factors contribute to the development of cutaneous SCC. […] Sunlight UV exposure is the most important environmental cause of SCC just like BCC. […] The p53 tumor suppressor gene in particular is highly associated with damage caused by UVB radiation hence up to 45-60% of SCC cases have p53 mutation. […] Therapeutic exposure to psoralen plus ultraviolet A light (PUVA) for cutaneous disorders such as psoriasis increases the risk of non-melanoma skin cancer, particularly SCC.

• #1 Squamous Cell Carcinoma – The Skin Cancer Doctor

  https://www.theskincancerdoctor.com.au/education/skincancerlesions/squamous-cell-carcinoma/

  Chronic superficial ionizing radiation exposure has been associated with increased risk of developing non-melanoma skin cancer, especially basal cell carcinoma. […] The pathogenesis, like BCC has to do with damage to the DNA structures which ultimately lead to carcinogenesis. […] Immune suppression following HIV or medication induced after solid organ transplant have been associated with increased risk for basal cell carcinoma. […] As mentioned, the increased risk for SCC skin cancer is more significant than BCC. […] The DNA damage from UV radiation may have enhanced by both direct immune suppressive effect and decrease immune surveillance resulting in decreased ability to destroy precancerous cells in skin. […] Chronic inflammation, as seen in some lesions like burns, ulcers, sinus tracts or inflammatory skin conditions like lichen sclerosus et atrophicus have been associated with increased risk for SCC development.

• #1 Squamous Cell Carcinoma Risk Factors

  https://www.skincancer.org/skin-cancer-information/squamous-cell-carcinoma/scc-causes-and-risk-factors/

  Squamous cell carcinoma (SCC) of the skin is caused by DNA damage that leads to abnormal changes (mutations) in the squamous cells in the outermost layer of skin. […] Understanding what causes this damage and the factors that increase your risk of developing SCC can help you detect the disease early or prevent it from happening in the first place. […] Cumulative, unprotected exposure to UV radiation is the main cause of SCC as well as a risk factor for most skin cancers. […] If your immune system is weakened or suppressed, you are more likely to develop SCC than people with healthy immune systems. […] If you’ve had SCC, you have a high chance of recurrence. […] The risk of developing SCC increases as you age, and there is a reason why the disease most commonly occurs in people over 50.

• #1 Squamous Cell Carcinoma Risk Factors

  https://www.skincancer.org/skin-cancer-information/squamous-cell-carcinoma/scc-causes-and-risk-factors/

  Although people of all skin types can develop SCC, people with light skin — especially individuals with red or blond hair, blue or green eyes or skin that freckles or easily burns — have a heightened risk for the disease. […] Squamous cell carcinomas occur at least twice as frequently in men as in women. […] People with xeroderma pigmentosum – a rare disorder that makes the skin less able to repair DNA damage caused by the sun – or other photosensitivity conditions such as polymorphous light eruption or solar urticaria have an elevated risk for skin damage, SCC and other skin cancers. […] Certain precancerous growths, often resulting from cumulative sun damage, are linked with SCC. […] HPV, which can arise in the mucous membranes of the nose and mouth as well as on the skin has been documented as a cause of Bowen’s disease on the genitals.

• #1 Squamous Cell Carcinoma – The Skin Cancer Doctor

  https://www.theskincancerdoctor.com.au/education/skincancerlesions/squamous-cell-carcinoma/

  Xeroderma pigmentosum (XP) is a rare genetic disorder due to multigenic, multiallelic autosomal recessive disease mutations that affect the DNA repair system (Nucleotide excision repair), resulting in an impaired ability to repair UV-induced DNA damage. […] Individuals with XP have an increased risk of skin cancer up to 2000 times than patient without. […] Human papillomavirus (HPV) infection can cause Squamous Cell Carcinoma in individuals who have genetic predisposition such as individuals with epidermodysplasia verruciformis and verrucous carcinoma (penis). […] The mechanism might be due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in cells with preexisting RAS or receptor tyrosine kinase mutations which contribute to rapid proliferation of SCC.

• #1

  https://journals.lww.com/jdnaonline/fulltext/2010/01000/squamous_cell_carcinoma__a_review_of_etiology,.2.aspx

  Intrinsic factors associated with squamous cell carcinoma include age, lighter skin pigmentation, scars, and dermatoses associated with photosensitivity (chronic cutaneous lupus), ulcerations, and lichen planus. There are two hereditary conditions that increase the risk of developing squamous cell carcinoma. Xeroderma pigmentosa is an autosomal recessive condition leading to an inability to repair UV-induced DNA damage. Oculocutaneous albinism results in insufficient melanin production, thereby decreasing the body’s defense against UV damage. Immunosuppressed individuals, whether by AIDS or organ transplant, have shown not only an increased incidence of squamous cell carcinoma but also a tendency to develop more aggressive tumors.

• #1 Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma

  https://www.mdpi.com/1422-0067/23/7/3478

  Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies. […] Most cSCCs arise in a progressive fashion from premalignant/noninvasive precursor lesions. The earliest clinically detectable precursor lesion is actinic keratosis (AK). […] The evolution of malignant properties that underlies this progression is a current focus of research and encompasses the concept of field cancerization, which proposes that precancerous lesions such as AKs and SCCIS arise from mutated, subclinical clones of keratinocytes within a clinically unremarkable epidermis.

• #1 Squamous Cell Carcinoma (SCC): Symptoms and Treatment

  https://patient.info/doctor/squamous-cell-carcinoma-of-skin

  Primary cutaneous squamous cell carcinoma (SCC) is a malignant tumour that arises from the keratinising cells of the epidermis or its appendages. It is locally invasive and has the potential to metastasise to other organs of the body. […] Chronic UVR exposure is the most important risk factor. This helps to explain the very high rates of skin cancer in countries like Australia, where fair-skinned, susceptible people are put at risk by sun exposure. The rise in UVR exposure produces more cases of squamous cell carcinoma in populations in equatorial zones. […] Factors affecting metastatic potential of cutaneous squamous cell carcinoma include site, diameter, depth, histological differentiation, perineural involvement, host immunosuppression, and previous treatment. […] The overall mortality rate of cutaneous squamous cell carcinoma metastasis is low (5%), but where distant metastases are present, the five-year survival rate is poor at around 25-40%.

• #1 Novel Topical Combination May Prevent Squamous Cell Carcinoma – The ASCO Post

  https://ascopost.com/news/january-2025/novel-topical-combination-may-prevent-squamous-cell-carcinoma/

  A recent study by Demehri et al of Mass General Brigham investigates whether calcipotriol vitamin D analog plus fluorouracil may prevent squamous cell carcinoma (SCC), with benefits lasting 5 years after treatment. […] This work highlights the potential for similar immunotherapies to prevent other cancers throughout the body. […] One of the unique challenges with squamous cell carcinoma is that individuals who develop it are at an increased risk of developing multiple new lesions over time. […] We found that this drug combination prevents cancer through a mechanism distinct from those used by current immunotherapies, suggesting that these drugs may treat and prevent cancer via distinct mechanisms. […] Recently, researchers found that using a vitamin D analog (calcipotriol) combined with chemotherapy (fluorouracil) may eliminate precancerous spots and prevent cancer occurrence via activating the patients own immune system; yet, prior to this trial, the mechanism remained unclear.

• #1 Skin cancer: understanding the journey of transformation from conventional to advanced treatment approaches | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01854-3

  Because conventional therapies have several limitations, effective alternatives must be found. […] Among the various therapeutic techniques, nanotechnology offers extraordinary potential on the molecular level through targeted interactions with cancer cells and suppression of their activity. […] The pathways involved in the development of skin cancer include the WNT signaling pathway, G-protein-coupled receptor-responsive skin cancer progression, MAPK pathway, and PI3K pathway. […] Skin cancer progression involves a complex interplay of genetic, molecular, and environmental factors that lead to the transformation of normal skin cells into cancerous ones. […] Ultraviolet radiation is the predominant root-cause of skin cancer. […] There are three types of UV radiation: UV-A, UV-B, and UV-C.

• #1 Apoptotic mechanism activated by blue light and cisplatinum in cutaneous squamous cell carcinoma cells

  https://www.spandidos-publications.com/10.3892/ijmm.2021.4881

  The results revealed that combined treatment was more effective on the A431 cells than single treatments, significantly decreasing cell viability and increasing the apoptotic rate. A higher effectiveness of BLUE + CISPL combined treatment was observed when A431 cells were exposed to both agents, which induced a significant increase in the percentage of apoptotic A431 cells (~2-fold the effect of blue light as used alone). The apoptotic effects of blue light were observed in other in vitro and in vivo studies, where blue irradiation caused a decrease in cellular growth and induced cell death in skin cancer cell lines and animal models. […] The activation of Casp-9, rather than Casp-8, in the A431 cells confirmed that cells treated with blue light and blue light combined with cisplatinum were involved in the intrinsic apoptotic pathway. The blue light activated the initiator Casp-9 but not the effector Casp-3; these results were associated with the low apoptotic rate of this treatment. The advantage of using combined treatment (BLUE + CISPL) was associated with an increased expression of active effector Casp-3 subunit.

• #2 Cutaneous Squamous Cell Carcinoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441939/

  Squamous cell carcinoma is the second most common skin malignancy in the United States, and its incidence steadily rises each year, posing a significant public health concern. […] This activity covers the etiology, epidemiology, pathophysiology, histopathological subtypes, clinical features, and management options for cutaneous squamous cell carcinoma. This activity emphasizes the critical role of photoprotection in reducing the risk of developing cutaneous squamous cell carcinoma due to its strong association with UV radiation. […] The development of cutaneous squamous cell carcinoma is associated with the following risk factors and etiologies: UV radiation: UVA and UVB are the most significant risk factors. […] Cutaneous squamous cell carcinoma is derived from the keratinocytes. A mutation in the tp53 tumor suppressor gene is the most common genetic abnormality observed in both squamous cell carcinoma and its precursor, actinic keratosis. Decreased immunosurveillance in immunosuppressed patients may further potentiate tumor growth. […] The prognosis for localized disease is generally excellent. The overall mortality rate for cutaneous squamous cell carcinoma is approximately 1% to 2%, with approximately 3% of cases metastasizing. The lymph nodes are the most common site of metastasis.

• #2 Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7916193/

  A complex network of deregulated signaling pathways plays an important role in the pathogenesis of cSCC. AK and cSCC lesions result from a multistage process, involving mutations in the genes implicated in epidermal homeostasis promoting the uncontrolled proliferation of atypical keratinocytes. […] cSCC is one of the cancers with the highest mutation rate. The commonest mutated genes belong to pathways involved in cell cycle regulation, apoptosis, senescence, differentiation, and mitogenic/survival signaling. […] The most frequently altered gene in cSCC is TP53, which encodes the tumor-suppressor protein p53. […] The mutation in TP53 sequence is an early event in cSCC pathogenesis, occurs in 54-95% of cases, and is responsible for the great genomic instability of these tumors. […] The CDKN2A locus gene encodes two alternatively spliced proteins, p16INK4a and p14ARF, which inhibit cell cycle progression and proliferation through the retinoblastoma (pRb) and p53 pathways, respectively.

• #2 Squamous cell carcinoma of the skin pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Squamous_cell_carcinoma_of_the_skin_pathophysiology

  Malignant transformation of normal epidermal keratinocytes is the hallmark of squamous cell carcinoma of the skin. […] One critical pathogenic event is the development of apoptotic resistance through functional loss of TP53, a well-studied tumor suppressor gene. […] TP53 mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as in most precursor skin lesions, suggesting that loss of TP53 is an early event in the development of cSCC. […] UVR causes deoxyribonucleic acid (DNA) damage through the creation of pyrimidine dimers, a process known to result in the genetic mutation of TP53. […] Upon subsequent UVR exposure, keratinocytes undergo clonal expansion, acquiring further genetic defects, ultimately leading to invasive cutaneous squamous cell carcinoma.

• #2 Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma

  https://www.mdpi.com/1422-0067/23/7/3478

  Both genetic and epigenetic alterations can increase the overall mutation rate, enhance proliferation, and decrease cell death. […] The primary carcinogen responsible for cSCC is cumulative lifetime exposure to ultraviolet radiation (UV). […] UV irradiation is capable of initiating and promoting the progression of all stages of squamous carcinogenesis. […] In cSCCs, reported rates of amplifications and activating mutations in Ras genes range widely from 3–30%. […] Mutations in the CDKN2A locus have been reported to occur in 24–45% of sporadic cSCCs. […] FAT1 encodes a tumor suppressor-related member of the FAT protocadherin family that is frequently mutated in numerous types of human cancers including cutaneous, head and neck, and oral SCCs. […] Aberrant DNA methylation in cSCC is associated with SCC, including CDKN2A (p14ARF and p16INK4A) promoter methylation, found in 40% of cSCC. […] Epigenetic alterations represent additional hallmarks in a cell’s transformation into cancer. […] The primary environmental risk factor for BCC, SCC, and melanoma is ultraviolet radiation, which, like arsenic, acts at the molecular level, in part, through epigenetic mechanisms.

• #2 Pathology Outlines – Squamous cell carcinoma

  https://pathologyoutlines.com/topic/skintumornonmelanocyticscc.Html

  Cutaneous squamous cell carcinoma appears to develop through a multistep process […] UV radiation, mutations involving genes (such as TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS / RAF / MEK / ERK and PI3K / AKT / mTOR) have been shown to play an important role in the pathogenesis.

• #2 Understanding Squamous Cell Carcinoma

  https://skintel.co.nz/articles/squamous-cell-carcinoma/

  SCCs develop from a complex interaction of genes and environmental influences, in particular UV-induced DNA damage. The exact mechanism of SCC development has not been identified, however, several genetic mutations have been identified, mostly related to UV-mediated DNA damage of tumour suppressor genes. The main genes involved include p53 (66%), NOTCH1/2 (40%), FAT1 (30%) and CDKN2A (35%). P53 mutations are involved in 50% of all cancers. […] Mutations in these genes within squamous cells of the epidermis allow uncontrolled replication and growth of affected cells resulting in the development of SCC.

• #2 Skin cancer: understanding the journey of transformation from conventional to advanced treatment approaches | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01854-3

  Because conventional therapies have several limitations, effective alternatives must be found. […] Among the various therapeutic techniques, nanotechnology offers extraordinary potential on the molecular level through targeted interactions with cancer cells and suppression of their activity. […] The pathways involved in the development of skin cancer include the WNT signaling pathway, G-protein-coupled receptor-responsive skin cancer progression, MAPK pathway, and PI3K pathway. […] Skin cancer progression involves a complex interplay of genetic, molecular, and environmental factors that lead to the transformation of normal skin cells into cancerous ones. […] Ultraviolet radiation is the predominant root-cause of skin cancer. […] There are three types of UV radiation: UV-A, UV-B, and UV-C.

• #2

  https://www.jci.org/articles/view/57415/

  In a chemical carcinogenesis model of cSCC, 7,12-dimethyl-1,2-benzanthracene (DMBA) initiated epidermal tumor formation in mice treated with 5-fluorouracil (5-FU), a compound that kills actively cycling cells in the epidermis. These data suggest that the tumors arose from the quiescent, 5-FUinsensitive epidermal stem cells rather than the rapidly proliferating epidermal cells. […] The role of STAT3 in UVB-induced cutaneous tumorigenesis was evaluated using transgenic and gene-deficient mouse models with constitutively active STAT3 expressed in the skin or skin-specific STAT3 deficiency. Following UVB exposure, the K5-Stat3C mice developed cSCCs at a greater frequency and with an increased multiplicity than control mice. Conversely, epidermal STAT3 deficiency protected mice from UVB tumorigenesis.

• #2 Skin cancer: understanding the journey of transformation from conventional to advanced treatment approaches | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01854-3

  The pathways are represented in Fig. 2. […] SCC or BCC expands as a precancerous lesion named actinic keratosis, which is also called keratinocyte intraepidermal neoplasia, very general in UV-exposed regions and looks like reddish macules which are further enfolded by yellowish scales. […] The pathogenic pathway which shows involvement in skin cancer is shown in Fig. 4 as such; Protein patched homolog 1 (PTCH1) plays the tumor-conquering action which encodes a protein receptor termed Sonic Hedgehog (SHH), which causes the loss of PTCH1 functionalities that impacts on working of G-Protein coupled receptor as decreasing the suppression of intracellular signaling which Smoothened (SMO) G-Protein coupled receptor. […] The ongoing research prompted advanced knowledge in the therapeutic regimen, however, the condition is still fatal.

• #2

  https://journals.lww.com/jdnaonline/fulltext/2010/01000/squamous_cell_carcinoma__a_review_of_etiology,.2.aspx

  The exact genetic alterations and numbers of mutations needed for malignant transformation are as yet unknown. The most readily accepted theory involves the transformation of the epidermal p53 gene clones by ultraviolet (UV) exposure to the precursors of squamous cell carcinoma. Early p53 mutations are believed to inhibit apoptosis of abnormal cells, allowing them to expand at the expense of normal presenting cells. Alterations of the p53 gene are the most common presenting malformation in all stages of squamous cell carcinoma, starting at the precancerous lesion and advancing to the invasive and potentially metastatic forms. Typically, this presents with one allele (DNA sequence) containing a missense point mutation with a UV signature, and the remaining allele is deleted. […] The pathogenesis of squamous cell carcinoma is multifactorial and includes many extrinsic and intrinsic factors. The most important extrinsic factor is generally recognized as UV sunlight exposure. As lifetime UV exposure increases, so does the incidence of squamous cell carcinoma. In fact, for every 8- to 10-degree decrease in latitude (e.g., Washington, DC to Tampa, FL), there is a doubling of the incidence of squamous cell carcinoma. Patients treated with psoralen with ultraviolet A are 30 times more likely to develop squamous cell carcinoma than the general population. The human papillomavirus type 16 is present in many of the genital and periungal forms of squamous cell, but human papillomavirus types 5, 8, 9, 18, 31, 33, 35, 39, 40, and 51-60, have all been isolated from squamous cell tumors. Other extrinsic factors that are related to the development of squamous cell carcinoma are industrial carcinogens, such as pitch, tar, crude paraffin oil, fuel oil, creosote, lubricating oils, arsenic, and nitrosoureas.

• #2 Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma

  https://www.mdpi.com/1422-0067/23/7/3478

  Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies. […] Most cSCCs arise in a progressive fashion from premalignant/noninvasive precursor lesions. The earliest clinically detectable precursor lesion is actinic keratosis (AK). […] The evolution of malignant properties that underlies this progression is a current focus of research and encompasses the concept of field cancerization, which proposes that precancerous lesions such as AKs and SCCIS arise from mutated, subclinical clones of keratinocytes within a clinically unremarkable epidermis.

• #2

  https://www.jci.org/articles/view/57415/

  Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with over 250,000 new cases annually in the US and is second in incidence only to basal cell carcinoma. cSCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. […] The classic multistep model of carcinogenesis is useful for understanding the progression from AK to cSCC. According to this model, mutations in one gene, often a tumor suppressor, may lead to the development of a precursor lesion with increased genetic instability or loss of cell cycle control. Additional mutations in other driver oncogenes permit the emergence of more neoplastic properties, leading to invasive carcinoma; the number of genetic changes required to transition from benign epithelium to metastatic carcinoma internal malignancies is thought to range from four to six. However, 3D models of human epidermis have shown that as few as two proto-oncogene mutations changes are sufficient to drive SCC.

• #2 Cutaneous squamous cell carcinoma: Symptoms, Causes, and Treatment — DermNet

  https://dermnetnz.org/topics/cutaneous-squamous-cell-carcinoma

  Cutaneous squamous cell carcinoma (SCC) is a common type of keratinocyte cancer, or non-melanoma skin cancer. It is derived from cells within the epidermis that make keratin the horny protein that makes up skin, hair and nails. […] Cutaneous SCC is an invasive disease, referring to cancer cells that have grown beyond the epidermis. SCC can sometimes metastasise and may prove fatal. […] More than 90% of cases of SCC are associated with numerous DNA mutations in multiple somatic genes. Mutations in the p53 tumour suppressor gene are caused by exposure to ultraviolet radiation (UV), especially UVB (known as signature 7). Other signature mutations relate to cigarette smoking, ageing and immune suppression (eg, to drugs such as azathioprine). Mutations in signalling pathways affect the epidermal growth factor receptor, RAS, Fyn, and p16INK4a signalling. […] Beta-genus human papillomaviruses (wart virus) are thought to play a role in SCC arising in immune-suppressed populations. -HPV and HPV subtypes 5, 8, 17, 20, 24, and 38 have also been associated with an increased risk of cutaneous SCC in immunocompetent individuals.

• #2 Skin microbiome influences the progression of cutaneous squamous cell carcinoma through the immune system | World Journal of Surgical Oncology | Full Text

  https://wjso.biomedcentral.com/articles/10.1186/s12957-025-03791-5

  Cutaneous squamous cell carcinoma (cSCC) is a type of skin tumor that develops in the epithelial cells. This disease has the second highest incidence of human skin cancers, with a high metastatic rate. While ultraviolet radiation significantly contributes to the genomic changes that support cSCC development, the dysbiosis of the skin microbiome and influence of the immune system also play important roles in this process. […] Overall, skin microbes play an important role in cSCC pathogenesis and progression. Here, we review the interactions between cSCC-related skin microbes and skin immunity, then discuss the prospect of applying skin symbiotic microorganisms for treating cSCC in the future. […] The immune system plays a key role in cSCC pathogenesis and progression. Clinical observational studies have found that the risk of cSCC in patients with organ transplantation and long-term immunosuppressive treatment is 100 times higher than that of the general population. In addition, immunosuppression may also cause cSCC to be more aggressive.

• #2 Squamous Cell Carcinoma Risk Factors

  https://www.skincancer.org/skin-cancer-information/squamous-cell-carcinoma/scc-causes-and-risk-factors/

  Although people of all skin types can develop SCC, people with light skin — especially individuals with red or blond hair, blue or green eyes or skin that freckles or easily burns — have a heightened risk for the disease. […] Squamous cell carcinomas occur at least twice as frequently in men as in women. […] People with xeroderma pigmentosum – a rare disorder that makes the skin less able to repair DNA damage caused by the sun – or other photosensitivity conditions such as polymorphous light eruption or solar urticaria have an elevated risk for skin damage, SCC and other skin cancers. […] Certain precancerous growths, often resulting from cumulative sun damage, are linked with SCC. […] HPV, which can arise in the mucous membranes of the nose and mouth as well as on the skin has been documented as a cause of Bowen’s disease on the genitals.

• #2 Squamous Cell Carcinoma Risk Factors

  https://www.skincancer.org/skin-cancer-information/squamous-cell-carcinoma/scc-causes-and-risk-factors/

  Squamous cell carcinoma (SCC) of the skin is caused by DNA damage that leads to abnormal changes (mutations) in the squamous cells in the outermost layer of skin. […] Understanding what causes this damage and the factors that increase your risk of developing SCC can help you detect the disease early or prevent it from happening in the first place. […] Cumulative, unprotected exposure to UV radiation is the main cause of SCC as well as a risk factor for most skin cancers. […] If your immune system is weakened or suppressed, you are more likely to develop SCC than people with healthy immune systems. […] If you’ve had SCC, you have a high chance of recurrence. […] The risk of developing SCC increases as you age, and there is a reason why the disease most commonly occurs in people over 50.

• #2 Angiogenesis and Invasion in Squamous Cell Carcinoma: Mechanisms and Implications

  https://www.jmolpat.com/jmolpat-articles/angiogenesis-and-invasion-in-squamous-cell-carcinoma-mechanisms-and-implications-104147.html

  Squamous Cell Carcinoma (SCC) is a type of cancer that arises from squamous epithelial cells. Epithelial cells form the surface layer of the skin and line various organs and cavities within the body. Squamous cell carcinoma can develop in various tissues, including the skin, lungs, esophagus, mouth, throat, and other mucous membranes. Squamous cells are flat, scale-like epithelial cells that constitute the outer layer of the skin (epidermis) and line the respiratory, digestive, and urogenital tracts. Squamous cell carcinoma arises when these cells undergo malignant transformation, losing their normal regulatory mechanisms. […] The pathogenesis of squamous cell carcinoma often involves the accumulation of genetic mutations. These mutations may be triggered by exposure to carcinogens, such as Ultraviolet (UV) radiation in the case of skin SCC, tobacco smoke for lung SCC, or Human Papillomavirus (HPV) for oral and genital SCC. The mutational events disrupt cellular homeostasis, leading to uncontrolled cell proliferation and evasion of normal cell death processes. Dysregulation of signaling pathways plays a pivotal role in squamous cell carcinoma development. The Epidermal Growth Factor Receptor (EGFR) pathway is frequently implicated. Aberrant activation of EGFR can lead to increased cell division, inhibition of apoptosis, and enhanced angiogenesis, promoting tumor growth. As squamous cell carcinoma progresses, it often induces the formation of new blood vessels (angiogenesis) to supply the growing tumor with nutrients and oxygen. Additionally, cancer cells may acquire the ability to invade surrounding tissues and metastasize to distant organs through lymphatic and blood vessels.

• #3 Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7916193/

  A complex network of deregulated signaling pathways plays an important role in the pathogenesis of cSCC. AK and cSCC lesions result from a multistage process, involving mutations in the genes implicated in epidermal homeostasis promoting the uncontrolled proliferation of atypical keratinocytes. […] cSCC is one of the cancers with the highest mutation rate. The commonest mutated genes belong to pathways involved in cell cycle regulation, apoptosis, senescence, differentiation, and mitogenic/survival signaling. […] The most frequently altered gene in cSCC is TP53, which encodes the tumor-suppressor protein p53. […] The mutation in TP53 sequence is an early event in cSCC pathogenesis, occurs in 54-95% of cases, and is responsible for the great genomic instability of these tumors. […] The CDKN2A locus gene encodes two alternatively spliced proteins, p16INK4a and p14ARF, which inhibit cell cycle progression and proliferation through the retinoblastoma (pRb) and p53 pathways, respectively.

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