Identifying whether head and neck cancer contains sub-populations of cells with differing tumourigenic potential

Sarina Cameron (2010). Identifying whether head and neck cancer contains sub-populations of cells with differing tumourigenic potential PhD Thesis, Diamantina Institute, The University of Queensland.

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
s40087427_phd_finalthesis.pdf s40087427_phd_finalthesis.pdf application/pdf 5.81MB 22
Author Sarina Cameron
Thesis Title Identifying whether head and neck cancer contains sub-populations of cells with differing tumourigenic potential
School, Centre or Institute Diamantina Institute
Institution The University of Queensland
Publication date 2010-10
Thesis type PhD Thesis
Supervisor Associate Professor Nicholas Saunders
Doctor Alexander Guminski
Total pages 207
Total colour pages 30
Total black and white pages 177
Subjects 11 Medical and Health Sciences
Abstract/Summary Tumour recurrence in head and neck squamous cell carcinoma (HNSCC) occurs in 50% of patients and is a leading cause of mortality in these patients. To understand the biological determinants of tumour recurrence, tumour initiation in a xenotransplant NOD/SCID mouse was used. The investigation of tumour initiation for 6 HNSCC cell lines found tumour initiation was highly inefficient, requiring 1x104 to 3x105 cells to form a tumour. To understand the observed inefficiency in tumour initiation, the major biological determinants of tumour initiation were investigated. The major biological determinants include i) the inherent tumour initiating activity of the tumour cells and ii) the influence of the tumour microenvironment. By using the NOD/SCID mouse the immune system was excluded as a microenvironmental constraint in tumour initiation. Moreover, no effect on tumour initiation was observed with the addition of normal stromal cells such as human dermal fibroblasts (HDF) and normal epithelial cells, human epidermal keratinocytes (HEK). These findings indicated that factors other than the immune system or the presence of human fibroblasts or keratinocytes were responsible for the poor tumour initiating efficiency of the HNSCC cells. Therefore, cell based models of tumour initiation were investigated to determine whether the inherent tumour initiating activity of the cells was responsible for inefficient tumour initiation. To examine the inherent tumour initiating activity of the cells, the cancer stem cell (CSC) model and the clonal evolution (Stochastic) model were used. It was found that the HNSCC cell lines all expressed putative CSC markers however, the expression of these markers did not relate to the tumour initiating activity of the cell lines. To determine whether a rare population or most cells could form a tumour, clonal populations were isolated from 3 HNSCC cell lines. These clonal populations of cells were all able to form a tumour in a cell number dependent manner. However, the Detroit 562 and SCC 15 clones varied in their ability to form tumours, being both more and less tumourigenic than the parental cell line. Further investigation of the Detroit 562 clones demonstrated the functionally distinct clones were genetically distinct and able to interact with one another. The clonal populations were found to interact with one another to enhance the inherent tumour initiating activity of the clones. Moreover, the differently tumourigenic clones had a unique genetic profile. The most tumourigenic of the clones was found to up-regulate GPx2 and Ceacam6 and down-regulate interferon (IFN) responsive genes when compared to the least tumourigenic of the clones. Investigation of the differential expression of these genes indicated only Ceacam6 expression was able to modulate tumour growth in vivo. Moreover, Ceacam6 expression was detected in HNSCC patient samples indicating the expression of Ceacam6 in the HNSCC cell lines was representative of patient HNSCC. Therefore, tumour initiation in the HNSCC cell lines is a complex interplay between the clonal populations present within the cell line and the expression of Ceacam6 also plays an important role in the behaviour of the cells.
Keyword HNSCC, Cancer stem cell, clonal population, GPx2, Interferon responsive genes, Ceacam6
Additional Notes 4,8,13,40-42, 62, 64, 66, 73, 83, 88, 89, 91, 92, 104, 108, 110,115,120,129,134,137,141,143,173,175,201,204,205

Citation counts: Google Scholar Search Google Scholar
Created: Tue, 22 Mar 2011, 08:12:01 EST by Ms Sarina Cameron on behalf of Library - Information Access Service