Modulation of the Tumor Suppressor Protein α-Catenin by Ischemic Microenvironment
Modulation of the Tumor Suppressor Protein α-Catenin by Ischemic Microenvironment
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DOI：
10.2353/ajpath.2009.090007
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发表时间：
2009-10-01
影响因子：
6
通讯作者：
Coomber, Brenda L.
中科院分区：
文献类型：
--
作者：
Plumb, Claire L.;Adamcic, Una;Coomber, Brenda L.
细胞粘附分子及其调节剂的失调或错误定位，例如E-钙粘着蛋白，β-钙蛋白和α-钙蛋白，通常与极性丧失，降解性肿瘤，侵入性肿瘤生长和转移相关。 DLD-1结直肠癌细胞系中α-catenin阴性细胞的亚群导致其显示出异质的形态化妆，从而提供了一种出色的模型系统，以研究α-钙蛋白在肿瘤发生中的作用。我们在DLD-1细胞系的Alpha-catenin缺陷型亚群中重新建立了α-catenin蛋白的表达，并用它来证明α-钙蛋白的丧失导致体外肿瘤特征的增加（软琼脂糖菌落形成的增加，增加悬浮后的克隆生存和悬浮液生存）。当细胞被用于形成肿瘤异种移植物时，缺乏α-钙蛋白的人由于细胞循环增加而显示出更快的生长速率，但没有增加肿瘤微血管募集。当肿瘤由混合α-连环蛋白阳性和阴性细胞形成时，表达α-连环蛋白的细胞优先位于异种移植物的灌注良好区域。因此，我们评估了缺血性肿瘤微环境在α-钙蛋白表达中的作用，并证明细胞在体外暴露于降血糖条件下，在促成长时间暴露后失去了α-catenin的表达。我们的发现表明，肿瘤微环境是肿瘤抑制剂表达的有效调节剂，对局部营养缺乏症和缺血诱导的癌症进展有影响。 （Am J Pathol 2009，175：1662-1674; doi：10.2353/ajpath.2009.090007）
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 pro-longed 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. (Am J Pathol 2009, 175:1662-1674; DOI: 10.2353/ajpath.2009.090007)