Transition from the noninvasive to the invasive phenotype and loss of alpha-catenin in human colon cancer cells.

Loss of epithelioid organization in carcinoma cell lines has been related to invasiveness and poor differentiation of tumors. We investigated the invasion in vitro of various human colon cancer cell lines. Most cell lines were noninvasive into chick heart fragments, and this correlated with an epithelioid morphotype. Only cell lines COLO320DM, SW620, and variants of HCT-8 and DLD-1 were invasive and nonepithelioid. We examined in these cell lines whether invasiveness was related to changes in the structure and function of the E-cadherin/catenin complex. E-cadherin functions as an invasion suppressor and as a cell-cell adhesion molecule when linked to the cytoskeleton via alpha-catenin plus beta- or gamma-catenin. All noninvasive cell lines showed E-cadherin linked to these catenins. The E-cadherin-dependent cell-cell adhesion function in these cell lines was demonstrated by two assays in vitro. It was interesting that all invasive cell lines showed a dysfunctional E-cadherin/catenin complex. COLO320DM, SW480, and SW620 cells were defective in E-cadherin expression, whereas the invasive variants of HCT-8 and DLD-1 lacked the alpha-catenin protein. From clonal epithelioid HCT-8 cultures with functional E-cadherin/catenin complexes, we subcloned, repeatedly, round cell variants that were again invasive and expressed no alpha-catenin protein. Our data suggest that reproducible transformations toward a more invasive phenotype in HCT-8 cells are associated with down-regulation of alpha-catenin. The mechanisms of this transformation and the level of alpha-catenin down-regulation are currently investigated.

[1]  G. Cowley,et al.  Modulation of E‐cadherin expression and morphological phenotype in the intravascular component of adenocarcinomas , 2006, International journal of cancer.

[2]  M. Mareel,et al.  Activation of the E-cadherin/catenin complex in human MCF-7 breast cancer cells by all-trans-retinoic acid. , 1995, British Journal of Cancer.

[3]  Y. Niitsu,et al.  Loss of E-cadherin-dependent cell-cell adhesion due to mutation of the beta-catenin gene in a human cancer cell line, HSC-39 , 1995, Molecular and Cellular Biology.

[4]  H. Shimada,et al.  Host organ specifically determines cancer progression. , 1995, Cancer research.

[5]  M. Mareel,et al.  In vivo and in vitro invasion in relation to phenotypic characteristics of human colorectal carcinoma cells. , 1995, British Journal of Cancer.

[6]  M. Mareel,et al.  Cancer metastasis: negative regulation by an invasion-suppressor complex. , 1995, Cancer detection and prevention.

[7]  W. Birchmeier,et al.  E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton , 1994, The Journal of cell biology.

[8]  S. Hirohashi,et al.  A Truncated β-Catenin Disrupts the Interaction between E-Cadherin and α-Catenin: A Cause of Loss of Intercellular Adhesiveness in Human Cancer Cell Lines , 1994 .

[9]  H Weissig,et al.  Assembly of the cadherin-catenin complex in vitro with recombinant proteins. , 1994, Journal of cell science.

[10]  M. Takeichi,et al.  Induction of polarized cell-cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line , 1994, The Journal of cell biology.

[11]  S. Ishihara,et al.  The roles of catenins in the cadherin-mediated cell adhesion: functional analysis of E-cadherin-alpha catenin fusion molecules , 1994, The Journal of cell biology.

[12]  H. Höfler,et al.  E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. , 1994, Cancer research.

[13]  J. Papkoff,et al.  Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly , 1994, The Journal of cell biology.

[14]  W J Nelson,et al.  Defining interactions and distributions of cadherin and catenin complexes in polarized epithelial cells , 1994, The Journal of cell biology.

[15]  B. Chauffert,et al.  In vivo and in vitro invasiveness of a rat colon‐cancer cell line maintaining E‐cadherin expression: An enhancing role of tumor‐associated myofibroblasts , 1994, International journal of cancer.

[16]  S. Tsukita,et al.  The Loss of the Expression of α Catenin, the 102 kD Cadherin Associated Protein, in Central Nervous Tissues during Development , 1994, Development, growth & differentiation.

[17]  M. Mareel,et al.  Downregulation in vivo of the invasion-suppressor molecule E-cadherin in experimental and clinical cancer. , 1993, Princess Takamatsu symposia.

[18]  A. Mercurio,et al.  Poorly differentiated colon carcinoma cell lines deficient in alpha-catenin expression express high levels of surface E-cadherin but lack Ca(2+)-dependent cell-cell adhesion. , 1993, Cell adhesion and communication.

[19]  M. Mareel,et al.  Immunohistochemical analysis of E-cadherin expression in human colorectal tumours. , 1993, Pathology, research and practice.

[20]  M. Takeichi.  Cadherins in cancer: implications for invasion and metastasis. , 1993, Current opinion in cell biology.

[21]  W. Isaacs,et al.  Reduction of E-Cadherin Levels and Deletion of the α-Catenin Gene in Human Prostate Cancer Cells , 1993 .

[22]  M. Mareel,et al.  Insulin-like growth factor I activates the invasion suppressor function of E-cadherin in MCF-7 human mammary carcinoma cells in vitro. , 1993, British Journal of Cancer.

[23]  A. Kinsella,et al.  The role of the cell-cell adhesion molecule E-cadherin in large bowel tumour cell invasion and metastasis. , 1993, British Journal of Cancer.

[24]  R. Poulsom,et al.  E-cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study. , 1993, The American journal of pathology.

[25]  H. Hibshoosh,et al.  Isolation and characterization of a highly malignant variant of the SW480 human colon cancer cell line. , 1992, Cancer research.

[26]  S. Hirohashi,et al.  Cadherin dysfunction in a human cancer cell line: possible involvement of loss of alpha-catenin expression in reduced cell-cell adhesiveness. , 1992, Cancer research.

[27]  M. Takeichi,et al.  Cadherin-mediated cell-cell adhesion is perturbed by v-src tyrosine phosphorylation in metastatic fibroblasts , 1992, The Journal of cell biology.

[28]  S. Hirohashi,et al.  Identification of a neural α-catenin as a key regulator of cadherin function and multicellular organization , 1992, Cell.

[29]  W. Fiers,et al.  Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role , 1991, Cell.

[30]  Y. Doki,et al.  Expression of immunoreactive E-cadherin adhesion molecules in human cancers. , 1991, The American journal of pathology.

[31]  R. Bronson,et al.  Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene , 1991, Cell.

[32]  M. Takeichi,et al.  Cadherin cell adhesion receptors as a morphogenetic regulator. , 1991, Science.

[33]  M. Mareel,et al.  Numerical evaluation of the invasion of closely related cell lines into collagen type I gels. , 1991, Invasion & metastasis.

[34]  W. Birchmeier,et al.  Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion , 1989, The Journal of cell biology.

[35]  Michael Stoker,et al.  Scatter factor is a fibroblast-derived modulator of epithelial cell mobility , 1987, Nature.

[36]  B. Sordat,et al.  Human primary colon carcinomas xenografted into nude mice. II. Modulation of tumor plasminogen activator activity by the host tissue environment. , 1986, Journal of the National Cancer Institute.

[37]  M. Brattain,et al.  Heterogeneity of malignant cells from a human colonic carcinoma. , 1981, Cancer research.

[38]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.