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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acquisition of invasiveness is a crucial step in the malignant progression of cancer. In cancers of the colon and of other organs the E-cadherin/catenin complex, which is implicated in homotypic cell-cell adhesion as well as in signal transduction, serves as a powerful inhibitor of invasion. We show here that one allele of the alphaE-catenin (CTNNA1) gene is mutated in the human colon cancer cell family HCT-8, which is identical to HCT-15, DLD-1 and HRT-18. Genetic instability, due to mutations in the HMSH6 (also called GTBP) mismatch repair gene, results in the spontaneous occurrence of invasive variants, all carrying either a mutation or exon skipping in the second alphaE-catenin allele. The alphaE-catenin gene is therefore, an invasion-suppressor gene in accordance with the two-hit model of Knudsen for tumour-suppressor genes.
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PMID:The alphaE-catenin gene (CTNNA1) acts as an invasion-suppressor gene in human colon cancer cells. 1002 66

Cancer is a genetic disease. The unstable genome of cancer cells causes tumour progression through multiple alterations in suppressor and promoter genes, leading to loss of homeostatic and gain of oncogenic functions. Invasion is the critical step in the acquisition of malignancy. It implicates a continuous molecular conversation of the cancer cells with other cells and with the extracellular matrix in which adhesion molecules are crucial. One of these, E-cadherin, is discussed in the present review. E-cadherin is a transmembrane glycoprotein that forms a complex with cytoplasmic proteins, termed catenins because they link E-cadherin to the actin cytoskeleton. E-cadherin/catenin-mediated intercellular adhesion and communication is mainly homophylic homotypic. There is compelling evidence from experiments in vitro as well as in vivo to accept that the E-cadherin/catenin complex acts as an invasion suppressor. The mechanism of this action is not only through cell-cell adhesion but also through transduction of signals to the cell's motility system. In the replication error positive human colon cancer cell line HCT-8, the alpha E-catenin gene CTNNA1 is an invasion suppressor gene. Here, the transition from the non-invasive to the invasive state was prevented by introduction into the unstable non-invasive cells of either an extra CTNNA1 or a wild type hMSH6 mismatch repair gene. beta-catenin also participates at a complex which comprises the adenomatous polyposis cancer protein APC. In colorectal cancer, mutation of either APC or beta-catenin is oncogenic. Downregulation of the E-cadherin/catenin complex may occur in several ways amongst which are gene mutations, methylation of 5'CpG dinucleotides within the promotor region of E-cadherin, tyrosine phosphorylation of beta-catenin, cell surface expression of proteoglycans sterically hindering E-cadherin and proteolytic release of fragments from the extracellular part of E-cadherin. Upregulation of the E-cadherin/catenin complex has been realized with a series of agents, some of which can be used therapeutically. In most human gastrointestinal cancers the E-cadherin/catenin or related complexes are disturbed and this underscores their pivotal role in the progression of these tumours. Mutations of the E-cadherin gene, including germline mutations, occur in diffuse gastric carcinoma, CpG methylation around the promotor region of E-cadherin in hepatocellular carcinomas and mutations of the APC tumour suppressor gene or in the beta-catenin oncogene in most colorectal cancers. The literature agrees about the disturbance of immunohistochemical patterns of E-cadherin and catenin expression in gastrointestinal cancers. Conflicting opinions do, however, exist about the prognostic value of such immunohistochemical aberrations. We doubt that immunohistochemistry of E-cadherin or catenins add prognostic value to the already used histological grading systems. In our opinion the major benefit from understanding of the E-cadherin/catenin-mediated pathways of invasion will be the development of new anti-invasive treatment strategies.
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PMID:The role of the E-cadherin/catenin complex in gastrointestinal cancer. 1069 69

Transition from an epithelioid (E) to a round (R) morphotype, in the human colon cancer cell line HCT-8, is associated with loss or truncation of alphaE-catenin and acquisition of invasiveness in organ culture. In E clones, like in parental HCT-8 cells, one allele of the alphaE-catenin gene (CTNNA1) is mutated. HCT-8 cells have also a 'Microsatelite Instability-High' (MSI-H) phenotype presumably due to a mutated hMSH6 gene. Fusion of E type cells doubles the wild type CTNNA1 alleles and prevents the loss of alphaE-catenin. Introduction of an extra chromosome 2, carrying a wild type hMSH6 gene, restores post-replicative mismatch repair and also prevents the frequent inactivation of the remaining wild type CTNNA1 allele.
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PMID:hMSH6 deficiency and inactivation of the alphaE-catenin invasion-suppressor gene in HCT-8 colon cancer cells. 1091 11