TY - JOUR
T1 - Modulation of the tumor suppressor protein α-catenin by ischemic microenvironment
AU - Plumb, Claire L.
AU - Adamcic, Una
AU - Shahrzad, Siranoush
AU - Minhas, Kanwal
AU - Adham, Sirin A.I.
AU - Coomber, Brenda L.
N1 - Funding Information:
Supported by the Canadian Cancer Society Research Institute (grant 016117 to B.L.C.); C.L.P. was a recipient of scholarship funding from the Natural Sciences and Engineering Research Council of Canada and the Ontario Graduate Scholarship Program.
PY - 2009
Y1 - 2009
N2 - Dysregulation or mislocalization of cell adhesion molecules and their regulators, such as E-cadherin, β-catenin, and α-catenin, usually correlates with loss of polarity, dedifferentiation, invasive tumor growth, and metastasis. A subpopulation of α-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 α-catenin in tumorigenesis. We re-established expression of α-catenin protein in an α-catenin-deficient subpopulation of the DLD-1 cell line and used it to demonstrate that loss of α-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 α-catenin showed faster growth rates because of increased cellular cycling but not increased tumor microvascular recruitment. α-Catenin-expressing cells were preferentially located in well perfused areas of xenografts when tumors were formed from mixed α-cateninpositive and -negative cells. We therefore evaluated the role of the ischemic tumor microenvironment on α-catenin expression and demonstrated that cells lose expression of α-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.
AB - Dysregulation or mislocalization of cell adhesion molecules and their regulators, such as E-cadherin, β-catenin, and α-catenin, usually correlates with loss of polarity, dedifferentiation, invasive tumor growth, and metastasis. A subpopulation of α-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 α-catenin in tumorigenesis. We re-established expression of α-catenin protein in an α-catenin-deficient subpopulation of the DLD-1 cell line and used it to demonstrate that loss of α-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 α-catenin showed faster growth rates because of increased cellular cycling but not increased tumor microvascular recruitment. α-Catenin-expressing cells were preferentially located in well perfused areas of xenografts when tumors were formed from mixed α-cateninpositive and -negative cells. We therefore evaluated the role of the ischemic tumor microenvironment on α-catenin expression and demonstrated that cells lose expression of α-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.
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U2 - 10.2353/ajpath.2009.090007
DO - 10.2353/ajpath.2009.090007
M3 - Article
C2 - 19745064
AN - SCOPUS:73549115416
SN - 0002-9440
VL - 175
SP - 1662
EP - 1674
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -