Modulation of the tumor suppressor protein alpha-catenin by ischemic microenvironment.
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.
Plumb
Claire L
CL
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.
Adamcic
Una
U
Shahrzad
Siranoush
S
Minhas
Kanwal
K
Adham
Sirin A I
SA
Coomber
Brenda L
BL
D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D002999:Clone Cells; D005455:Fluorescent Antibody Technique; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D015820:Cadherins; D025521:Tumor Suppressor Proteins; D051178:alpha Catenin; D051176:beta Catenin