A laminin-collagen complex drives human epidermal carcinogenesis through phosphoinositol-3-kinase activation

EA Waterman, N Sakai, NT Nguyen, BAJ Horst… - Cancer research, 2007 - AACR
EA Waterman, N Sakai, NT Nguyen, BAJ Horst, DP Veitch, CN Dey, S Ortiz-Urda…
Cancer research, 2007AACR
Abstract Laminin-332 (formerly laminin-5) and collagen VII are basement membrane
proteins expressed at the invasive front of human squamous cell carcinoma (SCC) tumors.
These proteins have protumorigenic properties, but whether laminin-332 and collagen VII
promote SCC tumors by providing adhesion or other nonadhesive extracellular cues, or
whether laminin-332 and collagen VII interact together in this process remains unknown. In
this study, we examined the role of these molecules by a structural approach using an in …
Abstract
Laminin-332 (formerly laminin-5) and collagen VII are basement membrane proteins expressed at the invasive front of human squamous cell carcinoma (SCC) tumors. These proteins have protumorigenic properties, but whether laminin-332 and collagen VII promote SCC tumors by providing adhesion or other nonadhesive extracellular cues, or whether laminin-332 and collagen VII interact together in this process remains unknown. In this study, we examined the role of these molecules by a structural approach using an in vivo model of human SCC tumorigenesis. Here, we show that individual domains (VI and V-III) on the laminin-332 β3 chain provide distinct and highly divergent cell adhesion and tumor-promoting functions. We found that laminin β3 domain VI provided a critical role in the assembly of stable adhesion complexes, but this domain was not required in SCC tumors. Instead, we found that laminin β3 domain V-III played an essential role in SCC carcinogenesis/invasion through binding to collagen VII, which in turn, led to phosphoinositol-3-kinase activation and protection from apoptosis. Overexpression of constitutively active p110 phosphoinositol-3-kinase subunit was sufficient to restore invasion and tumorigenesis in transformed cells lacking laminin-332/collagen VII interaction in a manner independent of cellular adhesion. These studies show distinctive adhesive and signaling functions in individual domains of laminin-332, one which is required for normal epithelial adhesion and one which is required for SCC tumorigenesis. This uncoupling of stable adhesion from tumor progression in our studies suggests that laminin-332/collagen VII interaction promotes epidermal carcinogenesis through signaling rather than adhesion. [Cancer Res 2007;67(9):4264–70]
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