?v?6 integrin promotes invasion of morphoeic basal cell carcinoma indirectly through stromal modulation

Abstract

Basal cell carcinoma (BCC) is the most prevalent cancer in the Western world and its incidence is increasing. The pathogenesis of BCC involves deregulated sonic hedgehog signaling (shh), leading to activation of the Gli transcription factors. Most BCC have a nodular growth pattern, are indolent, slow-growing and considered 'low risk' lesions. In contrast, the 'high risk' morphoeic variant, which causes significant morbidity, has an infiltrative growth pattern, and is so-called because of its densely fibrous stroma. As ?v?6 is capable of promoting both carcinoma invasion and fibrosis, we examined expression of the integrin in BCCs and found that the morphoeic type showed significantly higher ?v?6 expression than the nodular type (p-=0.0009). In order to examine the function of ?v?6, we transfected the transcription factors Gli-1 or Gli-2 into NTERT, human keratinocytes to generate a BCC model. These cells expressed ?v?6 and were invasive, although inhibition of ?v?6 had no direct effect on cell invasion. However, the cells showed ?v?6-dependent activation of TGF-?1, which induced transdifferentiation of human fibroblasts into myofibroblasts. Paracrine secretion of HGF/SF by these myfibroblasts promoted c-Met-dependent tumor invasion in both Transwell and 3D-organotypic assays. These experimental in vitro findings were confirmed using human clinical samples where we showed that the stroma of morphoeic BCC is myofibroblast-rich compared with nodular BCC (p=0.0036), that myofibroblasts express HGF/SF, and that morphoeic BCCs are strongly c-Met-positive. These data suggest that ?v?6-dependent TGF-?1 activation induces both the infiltrative growth pattern and fibrotic stroma so characteristic of morphoeic BCC.

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