The largest organ in the human body is the skin and it covers most of the whole body of individual. The skin has many functions like protecting as a barrier against external elements; radiation and pathogens, thermoregulation and etc. It consists mainly of three layers namely epidermis, dermis and hypodermis. The epidermis is the outermost layer of the skin and consists of epithelial cells with no blood vessels can be found in this layer. The basal or deepest layer of epidermis close to the dermis in which between these two layers are separated by the basement membrane. Generally there are two categories of skin cancers; primary cutaneous malignant melanoma and non melanoma skin cancers. The malignant melanoma develops from the melanocytes which are found in basal layer of skin. The melanocytes also produce pigment called melanin which caused the pigmentation of the skin and become tanned when they are exposed to ultraviolet ray or radiation (UV). When it comes to non melanoma cancers, there are mainly two types of these, which are Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Basal cell carcinoma (BCC) is accounting for 75% of all skin cancers. It can be found on mainly the sun exposed area like face, neck, ears and arms. Various lesions of BCC can be found and few examples are nodular, ulcerative, pigmented, superficial, cystic and multi-centric. In BCC metastases is rarely found and is locally invasive. When it comes to SCC, it contributes to the 20% of all skin cancers. This kind of skin cancer SCC has faster growing rate when compared to BCC. There may be ulceration, bleeding and invasion to local lymph nodes in SCC. Another type of cancer in skin is Merkel cell carcinoma. It is rare but highly malignant neuro-endocrine tumour of the skin. The clinical presentation of this kind of cancers shows nodule on the head and neck and it is common in elderly people. It is less ulcerative and can be able to spread to the regional lymph nodes and nearby skin tissues and cells.
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Structure of the skin (the figure is adapted from John Hunver, John Savin and Mark Dahl Clinical Dermatology 2003).
The most common risk factor for most of the skin cancer is Ultra Violet radiation (UVR). UV can alter the most of the signaling pathways causing the abnormal mutation. Aging; as the age grows older the more chances of the cancers to get. In this respect, SCC incidence of skin cancers is higher than BCC. Not surprisingly, smoking is one of the factors for developing epidermal carcinogenesis. Alcohol is also one of the risk factors for skin cancer. Ionizing radiation is one of the risk factors when it comes to epidermal carcinogenesis. Moreover underlying or pre-existing medical conditions plays important role in risk factor assessment. Furthermore individuals whose immune system is suppressed or impaired, particularly after receiving the transplant are at high risk of developing skin cancers especially SCC. In addition the presence of underlying several medical diseases or conditions like chronic ulcers, viral infections and heredity diseases or syndromes are also in the category of high risk. Moreover, the occupational history of individual is also important in categorizing the risk of epidermal carcinogenesis. The individuals with close contact of various kinds of carcinogens including chemical carcinogens such as Polycyclic aromatic hydrocarbons, aromatic amines, Nitrosamides, alkylating agents and radiation and UV radiation are mostly like to develop epidermal carcinogenesis.
UV damage and epidermal carcinogenesis
The ultraviolet radiation UV has the crucial role in the development of the skin cancers. There are three types of Ultraviolet radiation (UV) depending on the wavelengths. These are UVA (wavelength of 320-380nm), UVB (wavelength of 290-320nm) and UVC (wavelength of 200-290). Depending on the wavelength UVC can only penetrate into the superficial layer of the skin. When it comes to UVB, it can penetrate and even can reach the basal layer of the epidermis. Concerning UVC, it can penetrate into acellular level of the dermis. Among the three types of UV, UVB plays a significant role is epidermal carcinogenesis. In a mouse model study, UVB induced clonal expansion can be seen in hairless mouse models. Ultra violet radiation can causes the DNA damages and photoproducts such as cyclobutane pyrimidine dimers and pyrimidine pyrimidone photoproduct which might lead to mutations and then give rise to development of squamous cell carcinoma SCC and basal cell carcinoma BCC. The formation of photoproducts pyrimidine dimer will make the DNA polymerase unable to read the template of DNA by forming a bend in the helix of DNA. Then transition of CC to TT will occur. The pyrimidine dimer can be found mostly in skin cancers. Ultra violet radiation can cause mutations and aberration of the many signaling pathway like hedgehog and p53 and growth factors signal pathways. The alternation of UV induced hedgehog pathway may lead to development of BCC. However mutation in the p53 will lead to SCC and BCC but not to melanoma. However there is a study showing that the mutation in BRAF gene will contribute to 66% melanoma. (Davies et al 2002). Nucleotide excision repair failure is the major cause of carcinogenesis in skin cancers. In SCC the precancerous lesion also known as acinitic keratosis (AK) can change to malignant form, SCC due to UV induced mechanism. In this case UVB plays a crucial role in such change. Recently, it is observed that mismatch repair protein MMR protein hMSH2 protein is associated with precancerous lesion in skin in which AK and Bowen's disease. (Laing SB et al 2001). UV induced cancerous lesion of BCC are commonly found in genetic disorder like nevoid cells carcinoma syndrome (NBCCS) and xeroderma pigmentosum (XP).
Viral infections and epidermal carcinogenesis
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There are three kinds of viruses which are associated with skin carcinogenesis are human papilloma virus (HPV), Kaposi's sarcoma associated herpes virus and human T cell leukemia virus (HTLV). However HPV plays a significant role in pathogenesis of cancers when it comes to non melanoma skin cancers.
Human papilloma virus (HPV) group type HPV16 and 18 has a carcinogenic role by inactivation of p53 gene. The viral oncoproteins of HPV E6 and E7 are transcribing at high level in the SCC. There is an association between skin carcinogenesis and autosomal recessive disease epidermodysplasia verruciformis (EV) in which HPV5 and HPV8 can be found. More or less 50% of individuals with EV will change to SCC by the UV exposure or induction. However, HPV is alone is not like the sole causes of epidermal carcinogenesis. It associates with other signaling pathway and other tumour suppressor genes in contributing the process of carcinogenesis. Degradation of p53 will lead to arrest the cell cycle in G1, G2 phase and cease the nucleotide excision repair when contributing with HPV-E6. When it comes to BCC the prevalence is a lesser than in that to SCC in the process of HPV induced epidermal carcinogenesis.
Hedgehog Signal Pathway and Epidermal Carcinogenesis
The hedgehog pathway is important in embryonic development of organs, including skin. There are three proteins in mammalian hedgehog signaling pathway, called sonic hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog. When it comes to skin, sonic hedgehog (Shh) plays an important role for stem cell and hair follicle and sebaceous glands. Over expression of Shh will lead to hyperplasia of the epidermis and also lead to increased proliferation of keratinocytes in human skin. Ihh has a role in development of endochondral skeleton. Dhh has a role in maintaining spermatogenesis. The protein of hedgehog pathway is small and gets activated when it binds to cell membrane bound receptor protein patched (Ptc). There is an association between Ptc and another membrane protein, smoothened (Smo) which resembles with G protein couple receptors. Alteration in the hedgehog receptor genes such as PTCH and SMOH by mutations may lead to activation the hedgehog signaling pathway which might lead to the carcinogenesis of the skin mainly BCC (Basal Cell Carcinoma). Moreover there are 3 proteins which play as activators or repressor in the hedgehog pathway in mammals, namely Gli 1, Gli 2 and Gli 3. In Drosophila, there are serine threonine fused, suppressor of fused (Sufu) and Cubitus interruptus (Ci). The aberrant in signaling pathway due to abnormal Shh, PTCH, Smo and Gli 1 and 2 may contribute to BCC. Gli 1 and Gli 2 activation maintain many growth promoting and anti-apoptotic genes namely forkhead domain transcription genes FOXM 1 and also cyclin genes CCDN 1 and CCDN2.The PTCH gene is located on the chromosome 9 q22.34 and plays as a negative regulator of Shh. The nevoid basal cell carcinoma syndrome is (NBCCS) shows the germline mutation of PTCH. The activation of hedgehog pathway is started when one of the proteins ligands namely Shh, Ihh and Dhh bind to the PTCH receptor. The induction of transcription factor activators Glib 1 and Glib 2 occur in the cytoplasm and repressor Glib 3 has been inhibited. Therefore induction of transcription in target genes PTCH and HIP (hedgehog interacting protein) are important in epidermal carcinogenesis. Moreover, one study shows that Gli 1 can also activate the receptor for Platelet derived growth factor alpha (PDGFR alpha) and the effect of increased expression of this can be seen in Human and mouse model BCC. Furthermore the exposure to UV light is also a crucial part of carcinogenesis in BCC in relating to hedgehog signaling pathway. However it can be rarely found the UV induces C > T or CC > TT sequence change in sporadic BCC. But when it comes to Xeroderma Pigmentoseum (XP) the above UV sequence changes can be seen. (Jorg Reichrath 2006).
Physiologic and oncogenic Hedgehog Signaling (adapted from Andrzej A. Dlugosz, M.D., and Moshe Talpaz, M.D, New England Journal of Medicine 2009).
P53 and skin cancers
Tumor suppressor gene P53 is located on the short arm of the chromosome 17 in human. It has 4 functional domains namely, Transcription domain (the region where regulatory protein MDM2 binds), DNA binding domain, Oligomerisation domain and C terminal domain. There is also a relation between the occurrence of epidermal carcinogenesis and UV radiation. If there is stress or disturbance like UV radiation or DNA damage, p53 induction occurs by serine kinases containing Ser 15, Ser20, Ser33, Ser37, Ser46 and Ser392 causing the release of binding with MDM2. P53 tumor suppressor gene has an important role in cell cycle arrest especially G1 phase and programmed cell death (apoptosis). In almost half of all human cancers, p53 mutation can be found and most of the carcinomas have misense mutations. When it comes to non-melanoma skin cancers, elevated expression of p53 protein can be seen in AK (Acinitic Keratoses) and SCC in situ in many studies. The mutations of p53 seen in non-melanoma skin cancers are cytosine to thymine transition at pyrimidine generally. In a recent study by Agar et al, it is found that solar activation of UVA component is a significant carcinogen in skin stem cells. There are some slight difference between BCC and SCC when UV induced carcinogenesis is concerned. In BCC the cell of originating comes from the deep interfollicular basal cells, or sebaceous glands compared to SCC. Moreover it can be seen that p 53 in precancerous lesions AK displaying hot spot region of amino acid between 200 and 280. On the other hand, SCC has the most mutation of p53 in the 241 to 280 of hot spot regions. In BCC, the minor region of hot spot display at 161-200 which would be specific development for BCC. Furthermore it is found there is an association between the FasL mediated apoptosis and chronic UV irradiation. Chronic UV exposure will lead to loss of FasL expression and on the other hand there is gain in p53. It might lead to apoptosis. Mutated expression of p53 gains of function and which also lead to apoptosis and mutated keratinocytes expression are initiating the skin cancers. There is a fact that p53 is also important in the programmed cell death or apoptosis. It controls the number of abnormal or damage cells by arresting and repairing or causing death of the cells. There is a study that p53 has an anti-oxidant function. (Sablina et al 2005). Several radicals are causing the damage to DNA and then leading to chromosome or genomic instability. When the damage of DNA is not get repaired in time, the damage cells are removed by p53 under the process of apoptosis. The damage to DNA is not only a risk factor for skin cancers but also lead to the aggregating factor if individual has an underlying genetic disease like Xeroderma Pigmentosum, in which the autosomal recessive disorder causing the development of skin cancer after the exposure to prolong or excessive UV light followed by DNA damage and failure to repair the faulty DNA damage.
Growth factors and epidermal carcinogenesis
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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 dysegulated 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 the 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 over expression 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 shows 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 an initiating factor. 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 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 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 correlated 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).
Telomerase, Telomere and epidermal carcinogenesis
Telomerase is an enzyme, a ribonucleoprotein complex composed of two units of protein namely, hTERT (human telomerase reverse transcriptase and telomerase associated protein TP1. Telomeres are the protective covering or caps on the chromosome. The activity of telomerase plays important steps in carcinogenesis of the skin. The UV has an important l role, especially the UVB take part in the carcinogenesis of the skin. The UV exposure can lead to DNA damage that also gives raise to mutation of tumor suppressor gene. The area of the epithelial zone of the UV affected carcinogenesis in BCC is deeper than that in SCC. The one of the important functions of the telomere is elongating the repeated TTAGGG-DNA sequences of the end of the chromosomes. If the telomerase is absent, the telomere DNA will be lost after each cell division which might lead to the shortening of the telomere. Telomere and telomerase play a significant role in carcinogenesis. (Hackett and Greider). Chromosomal instability is caused by shortening of the telomeres which can be seen in beginning of the carcinogenesis. The capacity of replication in somatic cells is limited to a certain extent. It is in the fibroblasts after about more or less 60 divisions in vitro. The dividing capacity of somatic cells activity will cease when there is alteration in the telomere length and down-regulation of telomerase. Telomerase is up-regulated in normal keratinocytes with proliferation and inhibited terminal differentiation. (Harle-Bachor and Boukamp 1996; Cerezo et al 2003). The telomerase is regulated in a tissue-dependent manner in normal and immortal keratinocytes and this can be seen in changing of the splicing pattern of hTERT (Cerezo et al, 2002). It is proved that dermis and cultured skin fibroblasts are telomerase-negative and the reproductive enzyme activity is seen epidermis and cultured skin keratinocytes (Harle-Bachor and Boukamp). The telomerase activity can be seen in many tumors thanks to the development of Telomerase Repeat Amplification Protocol by Kim et al and also observe as a prognostic marker. There are a number of studies showing that BBC telomerase activation is more or less equal or slightly higher than is SCC. But another study using TRAP with Telomerase ELISA kits by Fabricius EM et al showed that not only the incidence of telomerase in BCC tissue is higher than that of SCC but also the level of telomerase. By comparing the levels of telomerase, a study by Fabricius EM et al, showing that the mean value of telomerase level in BCC tumor free margin with infiltration of lymphocytes is lesser than that without infiltration. So it can be assumed that the telomerase activity in BCC and infiltration of lymphocytes are independent. Moreover telomerase activity in BCC with tumor free margin is can be assumed as a prognostic marker. When it comes to SCC, it showed that normally activated lymphocytes show low telomerase activation. (Hiyama et al and Shay and Wright). On the other hand, telomerase activity in SCC margins can be assumed as immune response with longer interval with no recurrence. (Shay JW, Zou Y, Hiyama E et al) This reason behind the fact is that adjuvant anti-telomerase therapy is not a suitable in such situation.
Role of telomerase in carcinogenesis (adapted from the Hackett JA, Greider CW et al 2002)
Treatment and Conclusion
When it comes to treatment options of the skin cancers, the surgery has a major role because surgery has a wide therapeutic range and the success rate of surgery is high. However, in some cases, surgery plays a little role in the treatment in some situations such as ionizing radiation. In real practice combination with surgery and radio therapy have high therapeutic rate which is about 90% in BCC. In SCC, superficial radiotherapy after adequate biopsy and histological proof will cure over 80% of early lesions. There are several signaling pathways and mutation of tumour suppressor genes and other contributing factors. By knowing and observing the signal transduction pathways, the pathogenesis and progression of the epidermal carcinogenesis can be altered by target therapy. There are several kinds of target therapeutic agent which can be used in the treatment of epidermal carcinogenesis.
(Adapted from Matthias Lauth et al; Drug Discovery Today: Disease Mechanisms 2004)Vo