The long-term goal of this research is to define the mechanism(s) by which a key component of inflammation, the complement (C1) system, influences tumor establishment and progression. The relationship between inflammation, innate immunity and cancer is becoming increasingly evident. Despite the obvious link between inflammation and the C' system, the involvement of C' in cancer is still poorly understood. Preliminary work from our laboratory indicates that complement components are expressed locally in epithelial ovarian cancer. Furthermore, using a transplantation model of syngeneic murine ovarian carcinoma we have shown that tumor growth depends on C' activation, as genetic deletion of complement component 3 (C3) or pharmacologic inhibition of the C5a anaphylatoxin, a small cleavage fragments of C5 with potent inflammatory activities, hampered tumor growth. We hypothesize that massive C' activation occurs in tumors, which is harnessed by the tumors to establish themselves and grow through (i) activation of angiogenesis and (ii) direct effects on tumor cells, both of which may be in part be mediated by C' components and/or C'-activated cytokine networks. This proposal consists of three aims. The studies in Aim 1 are designed to define the role of complement in cancer establishment and progression. We will analyze the impact of complement inhibition on tumor establishment and progression through genetic approaches. We will use MISIIR-TAg, a transgenic mouse model of ovarian carcinoma with 100% phenotype penetrance, and test cancer phenotypes in MISIIR-TAg mice backcrossed onto backgrounds with various degrees of C' deficiency (C3""""""""'"""""""", C5~'~, C3aR""""""""'"""""""" or CSaR""""""""'""""""""). These studies will be complemented by pharmacologic inhibition of complement activation, or antagonism of complement anaphylatoxins.
Aim 2 will examine the role of complement in tumor vascularization. We will examine autochtonous and transplantation tumors in C' sufficient mice, in mice deficient for C' components and in mice treated with C' antagonists, and quantify the effects of the C' deletion or antagonism on tumor vascularization. In addition, we will investigate the role of C', especially C3a and C5a anaphylatoxins, in tumor vascularization through the recruitment of hematopoietic stem cells, bone marrow endothelial progenitor cells and myeloid endothelial precursors.
Aim 3 will examine the role of complement in the regulation of tumor cell death and proliferation. We will determine the ability of C3a anaphylatoxin to promote inflammatory activation, proliferation and survival in ovarian surface epithelium and ovarian cancer cells in vitro. This proposal addresses for the first time the involvement of C' as a modulator of the local inflammatory conditions that promote tumor establishment and/or progression. It will interact with Project 1 to understand how complement activation affects inflammatory networks and cell survival and proliferation differently in normal regeneration, immunopathologic repair and aberrant cancer growth. It will interact with Project 3 to test the effect of pharmacologic compounds targeting the complement cascade on cancer development and progression.
Showing the most recent 10 out of 226 publications