title: alpha vbeta 6 Integrin promotes the invasion of morphoeic basal cell carcinoma 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, 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 alpha v beta 6 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 alpha v beta 6 expression than the nodular type (P = 0.0009). In order to examine the function of alpha v beta 6, we transfected the transcription factors Gli1 or Gli2 into NTERT, human keratinocytes to generate a BCC model. These cells expressed alpha v beta 6 and were invasive, although inhibition of alpha v beta 6 had no direct effect on cell invasion. However, the cells showed alpha v beta 6-dependent activation of transforming growth factor-beta1, 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 alpha v beta 6-dependent transforming growth factor-beta1 activation induces both the infiltrative growth pattern and fibrotic stroma so characteristic of morphoeic BCC.
authors.affiliation: Centre for Tumour Biology, Institute of Cancer, The London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Marsh
authors.forename: Sarah
authors.initials: S
authors.lastname: Dickinson
authors.forename: Graham W
authors.initials: GW
authors.lastname: Neill
authors.forename: John F
authors.initials: JF
authors.lastname: Marshall
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hart
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism / Q000502:physiology*; D002280:Basal Cell Carcinoma / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008907:Mink; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; C400551:GLI1 protein, human; C082593:GLI2 protein, human; D016023:Integrins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C073878:integrin alphavbeta6; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met