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Originally published online as doi:10.2353/ajpath.2008.070700 on May 8, 2008

Published online before print May 8, 2008
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(American Journal of Pathology. 2008;172:1740-1747.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070700

Genetic Ablation of {alpha}v Integrins in Epithelial Cells of the Eyelid Skin and Conjunctiva Leads to Squamous Cell Carcinoma

Joseph H. McCarty*, Marc Barry*, Denise Crowley*{dagger}, Roderick T. Bronson{ddagger}, Adam Lacy-Hulbert* and Richard O. Hynes*{dagger}

From the Center for Cancer Research,* and the Howard Hughes Medical Institute,{dagger} Massachusetts Institute of Technology, Cambridge; and the Rodent Histopathology Laboratory,{ddagger} Harvard Medical School, Boston, Massachusetts

Integrin-mediated cell adhesion and signaling events are essential for the proper development and homeostasis of most epithelial tissues. Dysregulation of integrin expression and function can cause abnormal epithelial cell proliferation and/or differentiation, contributing to the pathogenesis of malignant epithelial cancers. Here we report on the use of a conditional knockout strategy exploiting the Cre/Lox technology to study the in vivo functions of {alpha}v integrins during epithelial cell proliferation and differentiation. We show that genetic ablation of {alpha}v integrin expression in basal epithelial cells of the eyelid skin and conjunctiva causes the formation of tumors that are strikingly similar to the malignant epithelial cancer, squamous cell carcinoma. These data suggest a mechanism whereby {alpha}v integrins normally suppress epithelial cell proliferation, likely via adhesion to ECM ligands, as well as by the modulation of intracellular signaling cascades. We propose that {alpha}v gene deletion eliminates normal integrin-mediated growth suppression, ultimately leading to cellular transformation and tumorigenesis. Hence, these studies reveal a novel tumor suppressor-like function of {alpha}v integrins and provide a genetically tractable mouse model for studying the pathogenesis of squamous cell carcinoma and related cancers of epithelial origin, as well as to test and develop novel therapeutic compounds to treat or prevent squamous cell carcinoma of the skin.






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Copyright © 2008 by the American Society for Investigative Pathology.