Transcriptomic analysis of the tumour vasculature and its clinical relevance

Wragg, Joseph (2016). Transcriptomic analysis of the tumour vasculature and its clinical relevance. University of Birmingham. Ph.D.

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Abstract

The vasculature of many solid tumours is highly distinct from that of its host tissue, both structurally and in terms of functional protein expression. These differences offer an opportunity for specific targeting of therapeutics against the tumour vasculature. This thesis describes the investigation of this tumour vascular profile, in clinical samples from renal cell carcinoma, colorectal cancer and colorectal liver metastases, as well as murine breast tumours resistant to the antiangiogenic drug, sunitinib. This analysis allowed the identification of three tumour endothelial markers in renal and colorectal malignancies, MCAM, LAMA4 and GRIN2D. The expression of each of these markers was linked with patient survival with these malignancies, suggesting their utility for prognostication. MCAM and GRIN2D showed highly tumour specific expression profiles in multi-organ tissue array analysis, highlighting them as promising candidates for the targeting of therapies to the tumour vasculature. The specific localisation of monoclonal anti-MCAM antibodies to renal tumour vasculature was demonstrated, further supporting this suggestion. Putative vascular markers of tumour resistance to antiangiogenic therapy were also identified. Aquaporin-1 (AQP1) was found to be up-regulated in cases of acquired resistance, mammalian target of rapamycin (mTOR) in innate resistance and pleiotrophin (PTN) in both, highlighting their potential as diagnostic candidates for predicting therapy response, or as targets to circumvent resistance. The need for effective diagnostic tests in this indication, was demonstrated by the finding that metastasis is enhanced by sunitinib therapy, in innately resistant tumours.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):