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Title: Divisions of cancer science and infection, inflammation & repair : the facilitative role of the extracellular matrix in the development of colorectal cancer liver metastases
Author: Conti, John Antony
ISNI:       0000 0001 3561 5118
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2006
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We have investigated the hypothesis that a desmoplastic reaction (DR), characterised by the deposition of collagens I and III produced by activated stromal cells offers Colorectal Cancer (CRC) liver metastases a growth'and survival advantage. Immunohistochemical staining of liver specimens obtained at resection for CRC, demonstrated increased deposition of fibrillar collagens and alterations in collagen IV distribution within the tumour as part of a DR. In add~tion the deposited fibrillar collagens were closely associated with increased numbers of' activated hepatic stellate cellsl myofibroblasts. pI integrins were highly expressed by both cancer & stromal cells throughout the tumour stroma. However, in poorly differentiated ar~as of the CRC metastases pI integrins . appeared to be down-regulated, with av integrin (especially avpS) expression upregulated. Collagen I used as a tissue culture substrate significantly enhanced the growth ofthe . CRC cell lines (HT-29 & KM12 cell lines series) compared to both control (plastic)and'' collagen IV (normal basement membrane component). Clonogenic (survival) and PARP cleavage (apoptosis) assays, showed that collagen I compared to collagen IV significantly increased the survival' and reduced the rate of cellular apoptosis for CRC treated with chemotherapy (5-Fluorouracil). The adhesion and proliferation of CRC cells on collagens I and IV was significantly reduced in a dose dependent manner, after incubation with pI ; integrin neutralizing antibodies (S-lO).lg/ml), compared-to IgG controls. In contrast avp3 and avpS neutralizing antibodies (S-20).lg/ml), had no influence on the CRC cell adhesion, but significantly reduced the rate of proliferation of the CRC cell lines on collagens; especially for the highly metastatic KMI2SM cell line. By demonstrating a reduction in proliferation in response to MMP resistant rlr collagen we have further reinforced our av integrin neutralising antibody experiments, complementing them with a model using a dominant negative ligand. These results support a role for the desmoplastic reaction ill supporting CRC metastases, mediated via pI and (IV integrins. As .CRC adopt a more aggressive malignant phenotype, matrix turnover reveals specific binding epitopes which upon ligation by av integrins plays a key growth regulatory role.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available