Requirement of both mucins and proteoglycans in cell‐cell dissociation and invasiveness of colon carcinoma HT‐29 cells

Abstract

Key words: colon carcinoma cells; E-cadherin; mucins; heparan sulfate proteoglycansEpithelial E-cadherin, a component of the adherens junctions, is crucial for the organization and maintenance of differentiated epithelia. 1 The extracellular NH2-terminal domain of this transmembrane glycoprotein mediates cell-cell adhesion in a homophilic and Ca 2ϩ -dependent way. The COOH-terminal domain binds to the actin cytoskeleton via ␣-catenin and ␤-catenin or plakoglobin. 2 Studies in cancer cell lines have shown that changes in the structure or in the expression of the components of the E-cadherin/␤-catenin complex result in the suppression of cell-cell adhesion and in the expression of an invasive phenotype. [3][4][5][6][7][8] In cancer, the maintenance of the epithelia is lost and dissociation of cells is associated with metastatic dissemination. This phenomenon can occur through a decrease in the expression level of E-cadherin and, regarding colon cancer, such decrease has been related to the tumor grade and clinical outcome. 9 At the genomic level, loss of E-cadherin expression does not occur as a result of mutation of E-cadherin gene, whereas mutations of ␤-catenin were found in a small proportion of colon cancers. 10 -12 In another way, E-cadherin-mediated cell-cell adhesion may be modulated by the mucin-like glycoprotein MUC1, which is often overexpressed in cancer. MUC1, also termed episialin, is a membrane-associated glycoprotein composed of a membrane anchor and a mucin-like ectodomain. 13 In human ZR-75-1 breast cancer cells, the cytoplasmic domain of MUC1 was shown to bind ␤-catenin, leading to a decrease of E-cadherin-catenin complex and an anti-adhesion effect. 14 On the other hand, MUC1 was shown to cause steric hindrance of adhesion molecules like E-cadherin, through its large negatively charged extracellular domain, which contains many oligosaccharide side chains. 15,16 Proteoglycans were also shown to disturb the function of E-cadherin through steric hindrance in variants of the murine mammary gland cell line NMuMG and the canine epithelial kidney cell line MDCK. 17 During colorectal carcinogenesis, the expression of MUC1 was found upregulated, particularly in later stages of the disease. 18 -20 On the other hand, de novo appearance of a secreted mucin normally found in the stomach, MUC5AC, has been described in colon carcinomas. [21][22][23] Thus, mucinous differentiated cells are present in colorectal carcinomas and more particularly in mucinous carcinomas and in signet ring cell carcinomas. Until now, the significance of a differentiation characteristic into a mucin-secreting phenotype with regard to the tumor development is still unknown.To investigate the role of mucins in the invasive properties of colon carcinoma cells, the HT-29 cell line is an appropriate model, as the cells of this cell line express different phenotypes: besides a majority of undifferentiated cells (Ͼ95%), a small proportion of cells presents a capacity to differentiate into a mucinous phenotype or into an enterocyte-like ...

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

“…These results reveal a new link between GLI1 and E-cadherin/b-catenin signaling, and this interaction might mechanistically account for the fact that MUC5AC is a biomarker for poor prognosis in PDA patients. Indeed, Truant et al previously reported that MUC5AC attenuated E-cadherin-mediated cellcell adhesion in human colon cancer HT29 cells (Truant et al, 2003), which supports our present study. Does this finding mean that MUC5AC per se promotes the malignant behavior of cancer cells?…”

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

“…In contrast to HT-29 cells which are drug-sensitive and undifferentiated (15,16), the drugresistant HT29-5F7 and HT29-5M21 clones exhibited differentiation features associated with either an enterocytelike phenotype or a mucus-secreting phenotype, respectively (13,14). Notably, the mucus-secreting HT29-5M21 clone, selected by resistance to methotrexate, displayed a spontaneous invasive phenotype in a type I collagen layer, whereas parental HT-29 cells are noninvasive under the same conditions (17). Recently, we demonstrated that conditioned medium from HT29-5M21 cells, but not from parental HT-29 cells, induced various colon epithelial cells to invade a collagen layer, supporting a potential role of secreted factor(s) in this spontaneous invasive behavior (18).…”

Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells

“…We have previously shown that the HT-29-derived subclone 5M21 displayed a constitutive invasive behavior in type I collagen whereas the parental HT-29 STD cells were not spontaneously invasive in this extracellular matrix component (Truant et al, 2003). In order to verify the possibility that this spontaneous invasive behavior could be mediated by autocrine proinvasive factor(s) secreted by HT-29 5M21 cells, we have analysed the proinvasive potential of the conditioned medium (CM) prepared from these cells.…”

“…To our knowledge, the possible contribution of TATI in the molecular and cellular mechanisms involved in cancer progression are unknown. We have previously reported that the mucin-secreting cell clone (HT-29 5M21) isolated from a subpopulation of human colon cancer cells HT-29 cells resistant to methotrexate (Lesuffleur et al, 1998) displayed spontaneous cellular self-aggregation and invasive phenotypes in type I collagen gels (Truant et al, 2003). We, therefore, investigated the molecular and cellular mechanisms underlying this aggressive behavior.…”