The facilitative role of the extracellular matrix in the development of colorectal cancer liver metastases
The facilitative role of the extracellular matrix in the development of colorectal cancer liver metastases
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 addition, the deposited fibrillar collagens were closely associated with increased numbers of activated hepatic stellate cells/myofibroblasts. Β1 integrins were highly expressed by both cancer and stromal cells throughout the tumour stroma. However, in poorly differentiated areas of the CRC metastases β1 integrins appeared to be down-regulated, with αv integrin (especially αbβ5) expression upregulated.
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 β1 integrin neutralising antibodies (5-10μg/ml), compared to IgG controls. In contrast, αvβ3 and αvβ5 neutralising antibodies (5-20μg.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 KM12SM cell line.
These results support a role for the desmoplastic reaction in supporting CRC metastases, mediated via β1 and αv integrins. As CRC adopt a more aggressive malignant phenotype, matrix turnover reveals specific binding epitopes which upon ligation by αv integrins plays a key growth regulatory role.
University of Southampton
Conti, John Antony
77f2ab2e-955d-4d04-ac4d-94abc1ddc5eb
2006
Conti, John Antony
77f2ab2e-955d-4d04-ac4d-94abc1ddc5eb
Conti, John Antony
(2006)
The facilitative role of the extracellular matrix in the development of colorectal cancer liver metastases.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
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 addition, the deposited fibrillar collagens were closely associated with increased numbers of activated hepatic stellate cells/myofibroblasts. Β1 integrins were highly expressed by both cancer and stromal cells throughout the tumour stroma. However, in poorly differentiated areas of the CRC metastases β1 integrins appeared to be down-regulated, with αv integrin (especially αbβ5) expression upregulated.
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 β1 integrin neutralising antibodies (5-10μg/ml), compared to IgG controls. In contrast, αvβ3 and αvβ5 neutralising antibodies (5-20μg.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 KM12SM cell line.
These results support a role for the desmoplastic reaction in supporting CRC metastases, mediated via β1 and αv integrins. As CRC adopt a more aggressive malignant phenotype, matrix turnover reveals specific binding epitopes which upon ligation by αv integrins plays a key growth regulatory role.
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Published date: 2006
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Local EPrints ID: 466453
URI: http://eprints.soton.ac.uk/id/eprint/466453
PURE UUID: 69780ccc-0beb-4cf4-9624-c4a503f6db72
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Date deposited: 05 Jul 2022 05:17
Last modified: 16 Mar 2024 20:42
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Author:
John Antony Conti
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