The epithelial FGFR2b isoform is a positive regulator of the entire program of keratinocyte differentiation, while the aberrant expression of the mesenchymal FGFR2c isoform in human keratinocytes induce impairment of differentiation, EMT and tumorigenic features.
Actinic Keratosis (AK) is the UV-induced preneoplastic skin lesion, characterized by cutaneous dysplasia of epidermal keratinocytes, whose progression toward SCC is characterized by impaired differentiation. Recently it has been also found that the activation of EMT is a typical feature of more aggressive SCCs directly developing from low grade AK (KIN I).
In addition, it has been proposed that, during AK progression toward SCC, the up-regulation of FGFs could take place in both epithelial cancer cells and CAFs, generating autocrine/paracrine loops and aberrant FGF/FGFR signalling crucial for tumour progression.
On the light of these evidences, the aims of this research project are: i) to analyze the expression profile of FGF and FGFR families, and that of genes involved in proliferation, differentiation, EMT and CAF induction, in the epidermal and dermal portion of AK biopsies; ii) to extend the analysis above described on primary cultures of keratinocytes and fibroblasts derived from biopsies; iii) to relate the results of these gene expression analysis with the histopathological and RCM parameters and to determine if specific gene profiles could be correlated to more aggressive AK.
Our results could help to assess whether the identification of specific gene expression profiles in AK lesions might represent an useful prognostic tool to identify AK lesions with highest probability to progress to SCC.
AK represents the most common sun-induced preneoplastic lesions that may progress toward SCC, however the histopathological analysis and in vivo reflectance confocal microscopy (RCM), that are the gold standard methods of AK evaluation and clinical grading, are not able to predict their possible progression toward SCC.
Several reports have definitely assessed the crucial contribution of the out-of-context paracrine FGF signaling consequent to the FGFR isoform switching in the acquisition of tumorigenic features in epithelial cells. In this regard, the introduction of the FGF1 and FGF2 inhibitor (Dobesilate) as a therapeutic strategy in AK treatment suggest that deregulation of FGFR expression and signalling have a role also in AK pathogenesis. Moreover, some recent reports appear to suggest that the deregulation of FGF/FGFR axis could contribute to the deregulation of proliferation, differentiation, as well as to the induction of EMT and CAF, in AK context.
Therefore, this research project could significantly contribute to the advancement of the knowledge of the complex molecular events that lead to AK progression, allowing to determine whether specific expression profiles of FGFRs and differentiation-, proliferation-, EMT- and CAF-related genes can represent a useful prognostic tool to identify those AK lesions with greater probability to progress toward SCC.