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vβ6 Integrin Promotes the Invasion of Morphoeic Basal Cell Carcinoma through Stromal Modulation

¹ Centre for Tumour Biology, Institute of Cancer, ² Cutaneous Research, Institute of Cell and Molecular Sciences, ³ Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Bart's and The London School of Medicine and Dentistry, London, United Kingdom

Requests for reprints: Gareth J. Thomas, Centre for Tumour Biology, Institute of Cancer, Bart's and The London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom. Phone: 44-20-7014-0409; Fax: 44-20-7014-0401; E-mail: gareth.thomas{at}cancer.org.uk.

Key Words: BCC • integrin • TGF-β • invasion • myofibroblast

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, leading to activation of the Gli transcription factors. Most BCCs have a nodular growth pattern, and 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 vβ6 is capable of promoting both carcinoma invasion and fibrosis, we examined the expression of this integrin in BCCs and found that the morphoeic type showed significantly higher vβ6 expression than the nodular type (P = 0.0009). In order to examine the function of vβ6, we transfected the transcription factors Gli1 or Gli2 into NTERT, human keratinocytes to generate a BCC model. These cells expressed vβ6 and were invasive, although inhibition of vβ6 had no direct effect on cell invasion. However, the cells showed vβ6-dependent activation of transforming growth factor-β1, which induced transdifferentiation of human fibroblasts into myofibroblasts. Paracrine secretion of hepatocyte growth factor/scatter factor by these myofibroblasts promoted c-Met–dependent tumor invasion in both Transwell and three-dimensional organotypic assays. These experimental in vitro findings were confirmed using human clinical samples in which we showed that the stroma of morphoeic BCC is myofibroblast-rich compared with nodular BCC (P = 0.0036), that myofibroblasts express hepatocyte growth factor/scatter factor, and that morphoeic BCCs are strongly c-Met–positive. These data suggest that vβ6-dependent transforming growth factor-β1 activation induces both the infiltrative growth pattern and fibrotic stroma so characteristic of morphoeic BCC. [Cancer Res 2008;68(9):3295–303]

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