Role of Properdin in Tumour Growth and Cell Recruitment

Properdin, as the only positive regulator, amplifies complement activation and<br/>has been implicated in the tumour response in human lymphoma and carcinoma.<br/>This project investigated the role of properdin in a syngeneic orthotopic tumour<br/>model in mice engineered to be properdin deficient and their wildtype controls.<br/>The in vitro part of the project used macrophages differentiated from bone<br/>marrows of these mice and stimulated with conditioned medium of a syngeneic<br/>mouse melanoma cell line, B16F10. In comparison with macrophages from<br/>wildtype mice, macrophages from congenic properdin deficient mice showed<br/>skewing towards M2 profile, encompassing mRNA expression for genes involved<br/>in arginine metabolism, production of type 2 cytokines, and relatively lower<br/>surface expression of molecules needed for antigen presentation suggesting that<br/>properdin insufficiency promotes a tumour environment that helps the tumour<br/>evade the immune response.<br/>The in vivo part of this project established the immune profile of tumour bearing<br/>mice. MDSCs, C5a, CCL2, TGF-β and mRNA FOXP3 were significantly less<br/>abundant in tumours of properdin deficient compared to wildtype mice. Protein<br/>levels for CCL2, a chemokine associated with tumour progression, was higher in<br/>wildtype tumour bearing mice. In spleen, MDSCs, regulatory T cells, M2<br/>macrophages (CD206+F4/80+) and TGF-β were decreased significantly in<br/>properdin deficient compared with wildtype mice (control) after subcutaneous<br/>injection with B16F10 cells, indicating that properdin may contribute to the<br/>accumulation of MDSCs in spleen, as well as to the migration of these cells into<br/>tumours. LDLR-/- mice group were analysed in parallel because of their inherently<br/>greater M2 skewing. An advanced bioimaging technique was applied to some of<br/>the experimental animals.<br/>Analysis of the level of serum properdin in response to treatment in a group of<br/>patients with pancreatic cancer showed high levels in this group.<br/>In conclusion, this project identified complement properdin as significant in the<br/>macrophage response to conditioned melanoma cell medium, in the composition<br/>of the tumour microenvironment and systemic response to tumour in vivo and as<br/>an acute responder to chemotherapy in patients with pancreatic cancer.

Name dc:type.qualificationname

Doctoral Thesis

Level dc:type.qualificationlevel

Student thesis

Grantor dc:publisher.institution

University of Leicester

Year dc:date.issued

2017

Authors dc:creator

• Al-Rayahi, Izzat Abdulsatar Mezher
• Machado, Lee Richard

Advisors dc:contributor.advisor

• Stover, Cordula
• Machado, Lee Richard
• Browning, Michael

Language dc:language

eng

Identifier

oai:pure.atira.dk:studenttheses/241f461f-ecaf-4a38-928c-686a2b2f7653

OAI identifier oai:identifier

oai:pure.atira.dk:studenttheses/241f461f-ecaf-4a38-928c-686a2b2f7653