Burkert, J.; (2008) Studies into characteristics of cancer stem cells and their role in the origin of epithelial tumours. Doctoral thesis , University of London.

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Abstract

Tumours are organised in a cellular hierarchy, originating in and maintained by a minority of cells with stem cell characteristics, so-called 'cancer stem cells'. The Side Population (SP) phenotype, distinguished by its ability to efflux the nucleic acid dye Hoechst 33342, as well as surface markers CD44 and CD133 were evaluated as potential cancer stem cell markers in human colorectal cancer cell lines and primary adenocarcinomas by testing sorted cell fractions for phenotypical and behavioural stem cell-typical characteristics such as clonogenicity or sphere formation in vitro, tumorigenicity in vivo, and multilineage differentiation potential in vitro and in vivo. My results indicate that in human gastrointestinal cancer cell lines, the SP, albeit containing cells with stem cell characteristics, is not enriched in stem cells as compared to the non-SP and thus does not present a useful tool for the isolation and identification of stem cells. Similarly, no stem cell characteristics were detected in the CD44+, CD133+, or double positive cell fractions of primary human colorectal carcinomas. Next, tumour-initiating capacities of transplanted cells and the reciprocal effects between transplanted cells, engrafted in the skin, and the local microenvironment were investigated in human kidney transplant patients and a BM-transplanted mouse model. We were able to show that donor-derived cells engraft as epithelial cells in normal and tumour epithelium, and contribute to stromal and endothelial tumour components without any events of cell fusion in both, human and mouse skin tumours. Observations of cell clusters and proliferation activity suggested that cells from BMTs may be able to engraft at earlier differentiation stages than cells from solid organ transplants. The sporadic distribution of engrafted cells and the absence of donor-derived tumours in our large scale human study indicated that cells from kidney transplants do not engraft as stem cells or cancer stem cells in the skin, even upon HPV-infection. Rather than playing an active role in carcinogenesis or tissue remodelling, donor-derived cells appear to imitate their surrounding cells in morphology and function. Following the patterns of engraftment and tumour development strongly suggests that the local cellular host microenvironment exerts more influence on the outcome phenotype than the effect of genetic pre-disposition of engrafted transplanted cells. Finally, on a histochemical and molecular level I show that squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) show distinct developmental dynamics, presumably reflecting their origin in different stem cell pools. Moreover, evidence is provided for a common developmental origin of outer root sheath and BCC, presumably in the stem cells of the hair follicle bulge. Histochemical analysis demonstrates that the companion layer is genetically continuous with the inner root sheath lineages and can be viewed as its outermost layer. We also suggest that BCCs and their stroma may share a common origin. Together, these results provide insight into the characterisation of cancer stem cells and the role of cancer-originating cells in tumour development.

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