Pignatelli, Massimo Nicola; (1990) Control of differentiation in colorectal neoplasia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes a series of experiments conducted to elucidate some of the mechanisms by which the extracellular matrix (ECM) may control differentiation and growth of colon epithelial cells. The use of in vitro models mimicking the ECM in which some colon carcinoma cell lines express a normal differentiated phenotype permitted the analysis of the biochemical and genetic mechanisms underlying the cell-matrix interaction. The findings give an insight into some of the events occurring during the multistep progression from normal epithelium to colorectal cancer. The ability of colon carcinoma cells to express a differentiated phenotype was found to depend on the presence of a specific cell surface collagen receptor recognising the tripeptide sequence Arg-Gly-Asp (RGD) which is a cell binding site common to several ECM proteins. In order to map the gene(s) controlling the expression of this RGD receptor and hence collagen binding and morphological differentiation, a panel of somatic cell hybrids was produced by fusing a human colon carcinoma cell line able to differentiate in collagen matrix with a mouse rectal carcinoma cell line that shows no glandular organisation. The gene(s) controlling both the collagen binding and glandular differentiation was mapped to the human chromosome 15. The RGD receptor complex was then characterised using affinity chromatography and immunoprecipitation techniques and shown to be a member of the integrin superfamily of cell surface receptors. Carcinoembryonic antigen was shown to function as an accessory molecule controlling the collagen receptor activity. The collagen receptor was shown to be under the regulatory control of Transforming Growth Factor Betas which by upregulating the receptor expression, increased the adhesiveness of the cells to collagen and their morphological differentiation. Immunohistochemical studies were also performed to analyse the expression of the collagen receptor complex in normal colon epithelial cells and in colorectal adenocarcinomas. Low expression of the collagen receptor was found frequently in colorectal adenocarcinomas and was associated with a loss of tumour differentiation. These data supported the hypothesis that loss of ability to express an ECM receptor could be a key step occurring in the pathogenesis of colon cancer.

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