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Epidermal growth factor (EGF) and its receptor EGFR have important role for cell proliferation which may tend to lead tumour promotion and skin carcinogenesis. Abnormal or dyregulated expression of EFGR is seen many kinds of cancers such as lungs, brain, breast and ovarian cancers. This might be probably due to amplification or mutation of the gene. On the other hand over expression of receptor ligands may also lead to carcinogenesis. EFGR is one of the members of HER receptor tyrosine kinases, including Erb2, Erb3 and Erb4. Binding of ligand with domain of EFGR causes homo or hetero dimerization and which will activate cytoplasmic tail kinase domain. This will activate the Ras/Raf , MEK and ERK signaling pathway causing cell proliferation, migration and differentiation. Furthermore, the PI3K/AKt and mammalian target for rampamycin (mTOR) pathway is also activated by EGF and its receptor EGFR. This pathway is important in cell survival and protein translation. The abnormal or faulty mechanisms of the above pathways may lead to the development of the skin cancers. Therefore it can be assumed that EGF and its receptor EGFR signaling play an important role in skin carcinogenesis.
Insulin like growth factor (IGF) There are two kinds of insulin like growth factors (IGF), which are IGF1 and IGF2. They both act on IGF-1 receptor (IGF-1R) consisting of two subunits beta (β) and alpha(α).IGF-1R signaling pathway will lead to the activation of either Ras/Raf and MAPK pathway or PI3K pathway causing the proliferation of cells or suppression or inhibition of apoptosis. (Jones JI; Clemmons, D.R 1995). In a mouse model study, transgenic mice of IGF-1 develop more tumours than non-transgenic counterpart.(Wilker E Bol et.al 1999). Therefore it can be assumed that overexpression of IGF-1 may lead to initiation of epidermal carcinogenesis and also help promote in tumourogenesis.
Transforming Growth Factor-β(TGF-β )has three members in mammals namely, TGF-β 1,2,3 . all of these 3 TGF-β are secreted as inactive latent forms which will require activation by proteolysis or change in conformation to induce the signal transduction pathway.(Koli K et al; 2001 and Derynck R et al 2001). TGF-β when active binds to the TGF-β type 2 receptor (TβRII) and causing the downstream targets phosphorylation including Smad 2,3 which again forming the complex with smad 4 leads to transcription of the gene. TGF-β acts as a tumour suppressor and it has growth inhibitory to epithelial cells. It is because of the repression of c-myc through smad3 and smad4 and also because of the cyclin dependent kinase inhibitor p15,p21. The over expression of TGF-β is seen in many cancers due to angiogenesis and epithelial mesenchymal transition(EMT). (Bierie B 2006). It is seen that the transient induced TGF-β mRNA over expression in SCC (Fowlis D J et al 1992). One of the studies show that TGF-β transgenic over expression is related with the expression of matrix metalloproteinase (MMP)(Week BH et al 2001). TGF-β signal pathway can be taken account in carcinogenesis as a initiating factors. Over expression of TGF-β in keratinocytes may convert papilloma to Squamous cell carcinoma and also in the transition of squamous spindle cell carcinoma; which is the latest stage of tumour. The role of TGF-β in signaling pathway is important in EMT induced on SCC cell lines. Since the SCC are assumed to develop from the stem cell origin of the epidermal origin then become keartinocytes of epidermis and hair follicle and tend to become abnormal due to mutations and epigenetic events. When it comes to BCC, which is rarely metastasize and locally invasive one developed from the hedgehog signaling pathway in which up regulation of TGF-β can be found.
Platelet derived growth factor (PDGF) has an important role in proliferation of cells and angiogenesis in the most of the human cancers. It is also important in wound healing and embryogenesis. When carcinogenesis is concerned, the over expression of the PDGF receptor can be found(Ostman A et al 2001). Four members of PDGF are PGDF-A,PDGF-B,PDGF-C and PDGF-D. The expression of PGDF can be seen in many cells including keratinocytes, epithelial cells and fibroblasts and the expression is regulated by cytokines and thrombin. The receptors dimers for PDGF are PDGFRαα, PDGFαβ and PDGFββ. The signaling pathway of PDGF-A and PGDFRα is important in the skin and hair for development where as the expression of PDGF-A can be found in epidermis of the skin and the latter can be in mesenchymal cells. PDGF signaling pathway help activate the hedgehog pathway by regulation of PDGFRα so that the expression of PDGF can be very high in BCC. The the expression of ligand and receptor of PDGF namely PDGF-A and PDGFRα cause the progression and development of BCC. Moreover PGDF-B can be found in SCC and melanoma in which can be assumed to promote the growth of tumour by the process of angiogenesis and and formation of stromal cells.
Tumor Necrosis factor α (TNFα) which is the member of cytokines family plays a relevant role in l carcinogenesis by the induction of inflammation. Since the TNFα is a cytokines, its signaling pathway is correlate with many other signaling pathways. In the late stage of carcinogenesis, it has a little role but the receptors for TNFα which are TNFR1 and TNFR2 they both have expression on the keratinocytes of the epidermis where as they serve as promoters in tumour promotion. (Arnott et al 2000).
Interleukins (IL) are assumed to be the members of large cytokines family. They play several relevant roles in the process of carcinogenesis. The interleukins plays important role in inflammation and immune responses, however there are some interleukins that plays relevant role in epidermal carcinogenesis. Among the several kinds of interleukins, IL-1 plays inhibit the effect of promoting in skin carcinogenesis. IL-12 is important in epidermal tumourogenesis and it has a role of counteraction in immune suppression, inflammation of UV induced epidermal cancers. (Katiyar S.K et al 2007).