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Basal cell and squamous cell carcinoma (nonmelanoma skin cancer = NMSC) are now the most common type of cancer in the Caucasian population, and the incidence of skin cancer has reached epidemic proportions. The highest incidence rates (IR) were reported from population-based studies in Australia with an IR of more than 2% for basal cell carcinoma (BCC) in males (females 1.1%), and 1.3% for squamous cell carcinoma (SCC) (females 0.7%). In this chapter, current epidemiologic data concerning the incidence and its worldwide trends, risk factors, like UV-radiation, ionizing radiation, predisposing host conditions, ageing, smoking, alcohol, diet, medical conditions, occupation, chemical carcinogenes, as well as important aspects of prevention will be discussed.

Although this topic is still a matter of debate, actinic keratoses can now be considered to represent early squamous cell carcinomas in situ. However, it appears that only small proportion of actinic keratoses will develop into an invasive squamous cell carcinoma. Regression of some cases of actinic keratoses has also been reported, most likely as a result of immune mechanisms. 5 Metastases after transformation of actinic keratosis into invasive squamous cell carcinoma are very rare except for those tumors that arise on the ear, lip, anus and vulva, which have been reported to be often associated with a more aggressive behaviour. Actinic keratoses are characterized by dysplasia of varying degree (from mild changes through to typical carcinoma in situ), predominandy in keratinocytes of the interadnexal epidermis (Fig. 1). Parakeratosis is usually present. Variants of actinic keratosis include the hyper-plastic, the proliferating, the atrophic, the acantholytic, the epidermolytic and the bowenoid subtype. The dermis underlying and adjacent to actinic keratoses typically shows the presence of ectatic vessels and solar elastosis. 7 , 8

Exposure of the skin with ultraviolet radiation (UV) is the main cause of skin cancer development. The consistently increasing incidences of melanocytic and nonmelanocytic skin tumors is associated with recreational sun exposure. Epidemiological data indicate that excessive or cumulative sunlight exposition take place years and decades before the tumor occurs. The most important protection strategies against UV in human skin consists in melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV damage. Low pigmentation capacity in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures. The important function of nucleotide excision DNA repair (NER) to avoid skin cancer becomes obvious by the rare genetic disease xeroderma pigmentosum, in which diverse NER genes are mutated. In animal models it has been demonstrated that UVB is more effective to induce skin cancer than UVA. UV-induced DNA photoproducts are able to cause specific mutations (UV-signature) in susceptible genes for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In SCC development UV-signature mutations in the p53 tumor suppressor gene are the most common event, as precancerous lesions reveal ∼ 80% and SCCs > 90% UV-specific p53 mutations. In BCC mutations in Hedgehog pathway related genes, especially PTCH1, represent the most significant pathogenic event in BCC; specific UV-induced mutations can be found only in ∼ 50% of sporadic BCC. Thus, cumulative UVB radiation is considered not to be the single factor for BCC development. An interesting new perspective in DNA damage and repair research, as recent publications suggest, lies in the participation of mammalian mismatch repair (MMR) in UV damage correction. As MMR enzyme hMSH2 displays a p53 target gene, is induced by UVB radiation and is involved in NER pathways, studies have been initiated to elucidate the physiological and pathophysiological role in skin cancer development.

Human papillomaviruses (HPVs) are a large group of infectious agents that induce various lesions of skin and mucosae. The carcinogenic role of HPV types 16 and 18, mediated by inactivation of the tumor suppressor proteins p53 and pRb by the viral oncoproteins E6 and E7, is established for cervical cancer. For cutaneous carcinogenesis, a causative role of HPVs is so far recognized only for squamous cell carcinomas (SCCs) in the rare heriditary skin disease epidermodysplasia verruciformis (EV). In both cervical cancer and SCCs of EV patients HPV DNA persists in high copy numbers, and the viral oncogenes E6 and E7 are transcribed at high levels. The detection of HPV DNA in SCCs and their precursors in individuals without EV history raises the question of the oncogenic role of HPVs in cutaneous tumors of the general population and particularly in the situation of iatrogenic immunosuppression. Polymerase chain reaction procedures revealed that HPVs of all subgroups are ubiquitous agents. But in the nonEV population, HPV concentration in both skin tumors and premalignant lesions is extremely low with only 1 HPV DNA copy on 20 to 5000 host cells. A number of in vitro observations suggest a transforming potential of HPV- encoded proteins or their interaction with cell cycle control in ultraviolet radiation-damaged skin. The chapter presents a critical analysis of these data with regard to their clinical significance.

The high incidence of basal and squamous cell carcinomas is a public health concern especially in light-skinned populations. These nonmelanoma skin cancers are multi-factorial in etiology. Evidence from epidemiologic research, as well as data from in vitro and in vivo studies indicate that the host’s immune system significantly contributes to the development of these malignancies. Alterations in cutaneous immunity as brought about by ultraviolet radiation, chemotherapeutic agents and other immunosuppressive factors result in loss of appropriate immune surveillance mechanisms, leading to nonrecognition of tumor antigens, thereby creating an environment favorable for tumor growth. Likewise immunomodulatory factors from tumor cells and/or surrounding stroma influence the behavior of established lesions and may direct their outcome towards either progression or regression.

Cytogenetic analysis is a powerful tool that allows analysis of chromosomal aberrations associated with diseased states. In particular, a combination of cytogenetic techniques has allowed the identification of aberrations associated with cancer development, including cancers of the skin. This chapter provides a comprehensive overview of cytogenetic alterations in basal and squamous cell carcinomas of the skin. These two distinct lesions have altered karyotypes that are consistent with their malignant potential. Basal cell carcinomas, although relatively stable lesions, are highly associated with recurrent aberrations of chromosomes 6, 7, 9 and X, as detected by a number of cytogenetic techniques. Squamous cell carcinomas, on the other hand are associated with a much higher degree of instability, involving aberrations of chromosomes 3, 7, 8, 11, 13, 17 and 18, as detected using a number of cytogenetic techniques. Overall, the numbers and types of aberrations associated with basal and squamous cell carcinoma, define the characteristic behaviour associated with these lesions and identification of these aberrations may aid in the understanding of malignant potential, prognosis and treatment of these skin cancers.

The hedgehog signaling pathway plays an important role in the embryonic development of various organ systems including the skin. Aberrant activation of hedgehog signaling by mutations in genes encoding important members of this pathway, such the hedgehog receptor genes PTCH and SMOH , plays a crucial role in the pathogenesis of cutaneous basal cell carcinomas, the most common human cancers. Germline mutations in the PTCH gene underly the early and multifocal development of basal cell carcinomas in patients suffering from nevoid basal cell carcinoma syndrome. Somatic mutations in PTCH or SMOH , as well as upregulation of different hedgehog target genes are found in the vast majority of sporadic basal cell carcinomas. In contrast, squamous cell carcinomas of the skin rarely show genetic alterations and aberrant expression of hedgehog pathway genes. Recently, specific inhibitors of the hedgehog signaling cascade have been identified and showed promising therapeutic efficacy in preclinical studies using experimental basal cell carcinomas generated in heterozygous PTCH knock-out mice. Furthermore, immunization against the hedgehog interacting protein (Hip), a hedgehog-regulated protein specifically upregulated in basal cell carcinomas, has been suggested as a promising new approach to skin tumor prevention. However, the clinical significance of these novel, pathogenesis-based molecular therapeutic strategies remains to be evaluated.

Skin cancer is the most common type of human cancer today, and its incidence has been increasing with an astonishing rate. It is estimated that about 70% of nonmelanoma skin cancers (NMSC) are induced by ultraviolet (UV) radiation, as a consequence of exposure to sunlight. Stratospheric ozone blocks UVC (below 290 nm) radiation from reaching the surface of the earth, but UVB (290–320 nm) and UVA (320–400 nm) component of sunlight reach the earth’s surface, and causes DNA damage, sunburn, mutations, immunosuppression and skin cancer. To counteract carcinogenic effects of UV, epidermal cells activate mechanisms that control cell proliferation, DNA repair, and apoptosis.

The TGF-β family of cytokines, including TGF-βs themselves, activins/inhibins and bone morphogenetic proteins (BMPs), regulate many fundamental processes during embryonic development and in adult tissues, such as cell growth, differentiation, remodelling of the extracellular matrix, cell migration and adhesion, angiogenesis and the immune response. 1 In mammals, there are three major members of the family: TGF-β_1, -β_2 and -β_3, which are encoded by different genes but share similar biological activities and signal through the same receptor system. TGF-βs are secreted as inactive, “latent”, complexes, formed by a TGF-β dimer non-covalently bound to two TGF-β pro-domains, named as latency associated peptides (LAPs). Latent TGF-β is sequestered in the extracellular matrix, and release of the highly stable, active, TGF-β dimer is mediated by plasmin and collagenases MMP-9 and MMP-2. 2 , 3 Because of urokinase- and tissue-type plasminogen activators (uPA, tPA), that convert plasminogen into plasmin, and collagenases are often up-regulated in tmnors at sites of migration/invasion, 4 , 5 it is likely that malignant cells are exposed to significant levels of active TGF-β.

Ever since the discovery of the transforming retroviral v-sis oncogene, which encodes PDGF-B, PDGF signaling has been an interesting target for cancer treatment. In the last few years, compelling evidence supports the essential role of PDGF signaling for cancer cell proliferation and tumor angiogenesis in several types of human cancers, including nonmelanoma skin cancers. BCCs, the commonest human cancer, contain activation of the hedgehog pathway, frequently through inactivated mutations of tumor suppressor gene PTCH1. How does activation of the hedgehog pathway promote cell proliferation in the tumor? Our data indicate that PDGFRα activation is important for hedgehog signaling-mediated cell proliferation in BCCs. These findings not only detail the molecular basis of hedgehog-mediated tumorigenesis but also provide new designs for skin cancer therapeutics.