Upregulated integrin alpha 11 in the stroma of cutaneous squamous cell carcinoma promotes skin carcinogenesis

Integrin alpha 11 beta 1 is a collagen-binding integrin that is needed to induce and maintain the myofibroblast phenotype in fibrotic tissues and during wound healing. The expression of the alpha 11 is upregulated in cancer-associated fibroblasts (CAFs) in various human neoplasms. We investigated alpha 11 expression in human cutaneous squamous cell carcinoma (cSCC) and in benign and premalignant human skin lesions and monitored its effects on cSCC development by subjecting alpha 11-knockout (Itga11(-/-)) mice to the DMBA/TPA skin carcinogenesis protocol. alpha 11-deficient mice showed significantly decreased tumor cell proliferation, leading to delayed tumor development and reduced tumor burden. Integrin alpha 11 expression was significantly upregulated in the desmoplastic tumor stroma of human and mouse cSCCs, and the highest alpha 11 expression was detected in high-grade tumors. Our results point to a reduced ability of alpha 11-deficient stromal cells to differentiate into matrix-producing and tumor-promoting CAFs and suggest that this is one causative mechanism underlying the observed decreased tumor growth. An unexpected finding in our study was that, despite reduced CAF activation, the alpha 11-deficient skin tumors were characterized by the presence of thick and regularly aligned collagen bundles. This finding was attributed to a higher expression of TGF beta 1 and collagen crosslinking lysyl oxidases in the Itga11(-/-) tumor stroma. In summary, our data suggest that alpha 11 beta 1 operates in a complex interactive tumor environment to regulate ECM synthesis and collagen organization and thus foster cSCC growth. Further studies with advanced experimental models are still needed to define the exact roles and molecular mechanisms of stromal alpha 11 beta 1 in skin tumorigenesis.