Published online before print September 10, 2009

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(American Journal of Pathology. 2009;175:1662-1674.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090007

Modulation of the Tumor Suppressor Protein -Catenin by Ischemic Microenvironment

From the Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Canada

Dysregulation or mislocalization of cell adhesion molecules and their regulators, such as E-cadherin, β-catenin, and -catenin, usually correlates with loss of polarity, dedifferentiation, invasive tumor growth, and metastasis. A subpopulation of -catenin-negative cells within the DLD-1 colorectal carcinoma cell line causes it to display a heterogeneous morphological makeup, thus providing an excellent model system in which to investigate the role of -catenin in tumorigenesis. We re-established expression of -catenin protein in an -catenin-deficient subpopulation of the DLD-1 cell line and used it to demonstrate that loss of -catenin resulted in increased in vitro tumorigenic characteristics (increased soft agarose colony formation, clonogenic survival after suspension, and survival in suspension). When the cells were used to form tumor xenografts, those lacking -catenin showed faster growth rates because of increased cellular cycling but not increased tumor microvascular recruitment. -Catenin-expressing cells were preferentially located in well perfused areas of xenografts when tumors were formed from mixed -catenin-positive and -negative cells. We therefore evaluated the role of the ischemic tumor microenvironment on -catenin expression and demonstrated that cells lose expression of -catenin after prolonged exposure in vitro to hypoglycemic conditions. Our findings illustrate that the tumor microenvironment is a potent modulator of tumor suppressor expression, which has implications for localized nutrient deficiency and ischemia-induced cancer progression.