Modulation of the tumor suppressor protein alpha-catenin by ischemic microenvironment.

Abstract

Dysregulation or mislocalization of cell adhesion molecules and their regulators, such as E-cadherin, beta-catenin, and alpha-catenin, usually correlates with loss of polarity, dedifferentiation, invasive tumor growth, and metastasis. A subpopulation of alpha-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 alpha-catenin in tumorigenesis. We re-established expression of alpha-catenin protein in an alpha-catenin-deficient subpopulation of the DLD-1 cell line and used it to demonstrate that loss of alpha-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 alpha-catenin showed faster growth rates because of increased cellular cycling but not increased tumor microvascular recruitment. alpha-Catenin-expressing cells were preferentially located in well perfused areas of xenografts when tumors were formed from mixed alpha-catenin-positive and -negative cells. We therefore evaluated the role of the ischemic tumor microenvironment on alpha-catenin expression and demonstrated that cells lose expression of alpha-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.

• Authors: Claire L Plumb, Una Adamcic, Siranoush Shahrzad, Kanwal Minhas, Sirin A I Adham, Brenda L Coomber
• Journal: The American journal of pathology (Am J Pathol) Vol. 175 Issue 4 Pg. 1662-74 (Oct 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19745064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Tumor Suppressor Proteins
• alpha Catenin
• beta Catenin

Topics

• Animals
• Base Sequence
• Cadherins (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Shape
• Clone Cells
• Fluorescent Antibody Technique
• Ischemia (metabolism, pathology)
• Mice
• Molecular Sequence Data
• Mutation (genetics)
• Tumor Suppressor Proteins (metabolism)
• Xenograft Model Antitumor Assays
• alpha Catenin (genetics, metabolism)
• beta Catenin (metabolism)