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Stroma and extracellular matrix proteins in canine tumours

By Sydney Mukaratirwa

Abstract

In this thesis, studies on temporal and spatial changes in stromal cells and extracellular matrix (ECM) molecules in canine gastrointestinal (GIT) tumours and canine transmissible venereal (CTVT) tumours are described. The mechanisms involved in the phenotypic transformation of fibroblasts to myofibroblasts, and ECM changes were investigated. We found that the myofibroblast is the most common stromal cell in canine GIT epithelial tumours and most likely originated from pre-existing fibroblasts. Tenascin-C expression was absent in the normal mucosa of the stomach, but was expressed in the normal intestine with a gradual increase in intensity from the cryptal glands to the surface epithelium, suggesting tenascin-C was involved in shedding of enterocytes. Tenascin-C expression was increased in tumours compared to normal GIT mucosa. There was a strong co-localisation of tenascin-C and ?-SMA expressing myofibroblasts, suggesting that myofibroblasts may be responsible for tenascin-C secretion. Tenascin-C has been implicated in cell proliferation and adhesion by in vitro experiments. To find out whether this also occurs in vivo, the relationship between cell proliferation and tenascin-C expression in normal GIT mucosa and tumours was investigated. There was no relation between cell proliferation and tenascin-C expression in both normal gut and tumour tissues studied. The absence of a correlation between tenascin-C and cell proliferation suggests that the main function of tenascin-C in the GIT is anti-adhesion rather than proliferation. Versican and hyaluronan are ECM components that are frequently increased in human tumours, and in vitro promote tumour progression. We analysed the histological distribution of versican and hyaluronan in colonic epithelial tumours. Versican expression was increased in the stroma of carcinomas and reduced in adenomas, and a significant correlation was observed between grade of the tumour and versican intensity and depth of invasion. Hyaluronan expression was increased in the stromal tissue of both adenomas and carcinomas. However, there was no correlation between hyaluronan stromal intensity and grade of the tumour or depth of tumour invasion. These results suggest that altered levels of both versican and hyaluronan in canine colonic tumours affect tumour progression. The role of stroma and ECM was continued in (CTVT), the only known naturally occurring tumour that can be transplanted as an allograft across MHC barriers. In CTVT, the number of stromal cell expressing ?-SMA (myofibroblasts) was significantly related to regressing tumours. The intensity of the stromal tenascin-C signal was significantly associated with regressing tumours. The intensity of stromal hyaluronan signal and tumour cell-associated hyaluronan were both significantly associated with progressing tumours. This suggests hyaluronan is involved in the tumour growth. The specific mechanisms of how tumour and stromal cells interact to modulate the microenviroment are not clear. We investigated the mutual paracrine effects of colorectal tumour cells and stromal cells. We were able to show that canine stromal cells support tumour cell growth and differentiation. We also showed that tumour cells induce differentiation of stromal cells to myofibroblasts, and increased the synthesis of ECM molecules stromal cells via TGF-ß

Topics: Diergeneeskunde, Canine, Extracellular matrix, Hyaluronan, Myofibroblast, Stroma, Tenascin, Tumour, Versican
Year: 2004
OAI identifier: oai:dspace.library.uu.nl:1874/313

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