Role of complement in tumour formation : Friend or foe?

Turner, Rhodri Thomas Owain 2010. Role of complement in tumour formation : Friend or foe? PhD Thesis, Cardiff University.

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Abstract

The aims of this thesis were to investigate and build on recent reports implicating the complement (C) system in tumour growth and progression. The respective contributions of specific C components and regulators to this effect were assessed by the use of two tumour induction protocols. Firstly, the chemical carcinogen 3-methylcholanthrene (3-MCA) was used to induce tumours in wild type mice and in animals deficient in C1q, C3 or double deficient in CD55 and CD59. Deficiency in the classical pathway of activation (C1q"7') or in the central component (C3"7') conferred a statistically significant protective effect against 3-MCA-induced tumourigenesis, suggesting that a fully functional C system was important for promotion of tumour progression in vivo. Additionally, a protective effect was observed in CD55"7".CD59"7' mice indicating an important role for C-regulatory proteins (CRegs) in tumour progression. In the second approach, novel fibrosarcoma lines were generated from 3- MCA-induced tumours. WT, C1q"7", C3"7" and CDSS.CDS lines were cloned and tested for specific characteristics including CReg expression, synthesis of C3 and susceptibility to C-attack. Few differences were observed between lines of different genotypes though expression of terminal pathway regulator CD59 was observed in C3"7" lines only. Re-inoculation of WT and C3 lines showed no differences between the groups with comparable tumour incidence and growth rates observed. Additionally, the effect of C on progression of a pre-characterised WT fibrosarcoma line was tested by inoculation into WT and C-deficient mice. Tumours inoculated into C1q"7", C3"7" and CD55"7'.CD59"7" mice were shown to exhibit comparable growth characteristics to those in WT controls. However, depletion of the terminal pathway component C5 using a monoclonal antibody (mAb) was shown to inhibit tumour progression. Treatment of mice with anti- C5 mAb conferred a statistically significant protective effect to these mice and suggests a role for C in driving tumour pathology. In conclusion, work in this thesis demonstrates an important pro-tumour role for C whereby activation of C can result in enhanced tumour progression. Additionally, expression of the CRegs CD55 and CD59 on host cells rather than tumour cells contributes to tumour proliferation. A pro-tumour role for C is contrary to current dogma but supports an alternative hypothesis whereby cell activating effects may provide a selective advantage to tumour cells following C-activation.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
ISBN:	9781303195587
Date of First Compliant Deposit:	30 March 2016
Last Modified:	04 Jun 2017 05:52
URI:	https://orca.cardiff.ac.uk/id/eprint/54370

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