Current treatment of cutaneous squamous cancer and molecular strategies for its sensitization to new target-based drugs.

Nonmelanoma skin cancer (NMSC) is the most common cancer observed in the Caucasians, accounting approximately for 80% of basal cell cancer (BCC) and 20% cutaneous squamous cell carcinoma (cSCC) [1]. Differently from BCC, cSCC is related to a relatively high risk of metastasis occurrence. In recent years, a relative increase of cSCC incidence has been recorded, probably due to both higher exposure to sun and more frequent skin examinations [2]. Histopathologic variants show significantly different clinical behaviors [3-6]. They recognize different biological backgrounds with different prognosis. Therefore, their correct classification is critical for both diagnosis and treatment.DNA damage [15]. In details, p53 induction seems to be mainly due to both pyrimidine dimers, and DNA stands break [16]. p53 activation causes essentially cell cycle arrest, with subsequent DNA repair occurring through two major pathways: non-excision repair (NER) and base excision repair (BER). When DNAdamage is too wide, activated p53 induces apoptosis in damaged skin, through induction of various transcriptional factors related to activation of the apoptosomal complex, such as the Bcl-2 family members Bax, p53-upregulated modulator of apoptosis (PUMA), Noxa, p53-upregulated apoptosis-inducing protein 1 (p53AIP1), and PIGa (galectin- 7) [17-19]. Moreover, it has been demonstrated that UVBinduced apoptosis is related also to activation of Fas and Fas ligand, potent activators of pro-caspase 8 cleavage and, at the same time, of the cytochrome c release from mitochondria, followed by activation of the Apaf-1--pro-caspase 9 complex [20]. Chronic UV irradiation causes p53 mutation and loss of Fas--Fas ligand interaction with consequent apoptosis deregulation. p53 mutations seem to be an early genetic event in the UV-induced skin cancers, being present in approximately 53% of premalignant actinic keratosis (AK) lesions [21]. Many reports have recorded p53-mutant cell clones in nonneoplastic cells of skin exposed to sun [21-26]. Not all UV-induced p53 mutations confer a malignant phenotype to epidermal. Some in vivo experiments have demonstrated that the occurrence of the most critical p53 mutations are recorded from 17 to 80 days of exposure to UVB, and skin tumors appear from 30 to 80 weeks later (Figure 1) [27,28]. Regression of a part of precancerous p53-positive clones can be observed after discontinuation of UV irradiation [28,29] although tumor occurrence is only delayed [30]. Other proteins of p53 family, such as p63, are involved in cSCC development, because of its ability to control apoptosis through both extrinsic and intrinsic pathways. In fact, the function of p63 is, at least in part, mediated by IKKa (IkB kinase-a) [31]