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The non-melanoma skin cancers (NMSCs) encompasses cutaneous lymphomas, Merkel-cell carcinomas, adnexal tumors, and other rare primary cutaneous neoplasms, but is mainly used to define basal-cell carcinomas and squamous-cell carcinomas. Grouping of these two carcinomas under a common umbrella term poses challenges, because clear differences exist in their etiopathogenesis, clinical course, and management strategies. Non-melanoma skin cancers are the most common human cancers, and despite growing public awareness of the harmful effects of sun exposure, incidence continues to rise.
Age, male sex, skin color, UV dose, and duration of immunosuppression are key components in pathogenesis of post-transplant non-melanoma skin cancer. However, complex genetic factors affecting the extent and consequences of immunosuppression can determine individual risk. Patients with HIV/AIDS or non-Hodgkin lymphoma, specifically chronic lymphocytic leukemia, also have aggressive squamous-cell carcinomas.
Human keratinocytes turn over around once a month. Stem cells in the stratum basale divide and differentiate into squamous cells. This proliferation and differentiation program of keratinocytes is controlled by a large and coordinated range of genes; mutations in many of these genes can be a step leading to NMSC. If UV-induced DNA damage is recognized early, the cell division cycle is arrested and DNA repair pathways are activated. If the damage is too severe for repair, apoptotic pathways are activated. However, occasionally DNA damage fails to be repaired before the cell divides, resulting in the incorporation of an incorrect nucleotide, or genetic mutation, into the newly synthesized DNA strand. When sufficient genetic mutations accumulate that significantly affect cell division, death or differentiation, then this leads to NMSC. Genes in which mutations lead to NMSC in this way are referred to as tumor suppressor genes and/or oncogenes. Tumor suppressor genes negatively regulate growth and are generally autosomal recessive in that they require both copies to be inactivated before they lose their function. Generally, an inhibiting mutation in these genes contributes to NMSC. Oncogenes promote tumor growth and are generally autosomal dominant in that they require a change in just one copy to have an effect. Generally, a mutation that results in activation of these genes contributes to NMSC. Numerous tumor suppressor genes and oncogenes that are important for photocarcinogenesis have been identified. Examples include p53, Bcl-2, PTCH1, BRM, GADD45, RAS, p16, c-Fos, matrix metalloproteinases and mismatch repair genes.
PTCH1 has tumor suppressor functions and encodes a 12-pass putative transmembrane protein which acts like the receptor of the diffusible morphogen protein, sonic hedgehog. Somatic PTCH1 mutations have a high frequency in familial basal-cell carcinoma, and are present in up to 68% of sporadic basal-cell carcinomas. PTCH1 loss has also been reported as an early event in pathogenesis of squamous-cell carcinoma. The melanocortin-1 receptor (MC1R) gene variants ASIP and TYR are associated with fair skin, red hair, and increased melanoma risk, and evidence suggests that they might be important independent risk factors for non-melanoma skin cancer. UVB and UVC radiation result in DNA damage, leading to the production of signature cyclobutane-type pyrimidine dimers, which activate mechanisms for removal of damaged DNA, a delay in cell-cycle progression, DNA repair, or apoptosis by transcriptional activation of TP53 and related genes such as CDKN1A, BCL2, and BAX.
In recent decades, our understanding of the pathogenesis of NMSCs—and especially basal-cell carcinoma—has improved substantially. For most non-melanoma skin cancers, however, conventional surgical and destructive treatments remain the first-choice treatment strategies. Coupled with adequate sun-avoidance advice, behavioral modification, and sun-protection education, new non-invasive treatment approaches are a welcome addition to the management of the most common human cancers. Creative Biogene, as a leading biotechnology company, is able to offer various non-melanoma skin cancer pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.