Loss of alpha-v integrin and p53 Cooperate to Induce Skin Squamous Cell Carcinomas

Abstract

Purpose: : Squamous cell carcinoma is the second most common malignant tumor of the eyelid and associated with greater morbidity and mortality due to perineural invasion and metastasis. Integrins are heterodimers consisting of α and β subunits involved in maintaining a dynamic adhesion between the cells and their microenvironment. The α-v integrin has been shown to regulate epithelial cell proliferation but its contribution to the development of SCC is unclear.

Methods: : The role of α-v integrin in the development of SCC was tested using a conditional deletion of the α-v gene in the mouse epidermis. As more than 50% of the human skin SCCs carry mutations in the p53 gene, we also induced deletion of α-v in the context of p53 inactivation. Mice were monitored for skin tumor development and tumors were analyzed to elucidate the mechanism involved in carcinogenesis. Cell lines derived from these tumors were tested for proliferation and survival in the absence of serum and when cultured in suspension.

Results: : Mice with homozygous deletion of both α-v integrin and p53 developed skin tumors, often of the periocular and head and neck region, at a significantly faster rate than mice with a single deletion or those heterozygous for either gene. Histologically, most of the SCCs were classified as acantholytic SCC, an aggressive phenotype observed in the clinical setting. These tumors were characterized by high proliferation and differentiation rates based on molecular markers. Further analysis of the tumors revealed activation of the Erk and Akt pathways, suggesting the contribution of receptor tyrosine kinase activity in their pathogenesis. Cell lines derived from the skin tumors harvested from mice with the co-deletion proliferated equally well in the absence of serum while cell lines with the p53 deletion alone did not. Moreover, cell lines with the co-deletion appeared to survive and form colonies following culture for long periods in suspension.

Conclusions: : These observations indicate that loss of the α-v integrin and p53 cooperate during SCC development. This cooperation induces tumors in vivo that proliferate and differentiate at higher rates with higher expression levels of members of the TGF-β pathway. In addition, cell lines derived from these tumors appear to survive and proliferate in the absence of survival signals from the extracellular matrix or in the form of growth factors.

Keywords: tumors • pathology: experimental