The long-term goal of this research is to define the mechanism(s) by which a key component of inflammation, the complement (C') system, influences tumor progression. The relationship between inflammation, innate immunity and cancer is becoming increasingly evident. However, many of the molecular and cellular mechanisms that mediate this relationship remain unresolved. Monocytes recruited into the tumor often provide stimulatory signals that promote, rather than inhibit tumor growth. Angiogenesis, an essential process for wound healing, is crucial for continuous tumor growth and is stimulated by cytokines released from infiltrated inflammatory cells. Despite the obvious link between these processes and the C' system, which has long been recognized to play a major role in mediating local and systemic inflammatory responses, the involvement of C' in cancer is still poorly understood. Preliminary experiments carried out in our laboratory using an in vivo syngeneic model of murine ovarian carcinoma have shown that mice deficient in complement component 3 (C3) display inhibited ovarian tumor growth. Findings from an additional experiment suggested that the observed effect was mediated by the C5a anaphylatoxin, a small cleavage fragment of C5 with potent inflammatory activities. This proposal consists of two aims. The studies in Aim 1 are designed to define the contribution of C' to ovarian cancer and dissect the pathways (s) by which C' may be activated using mice deficient in individual complement components.
Aim 2 will focus on dissecting the mechanisms by which the anaphylatoxins C3a and C5a may contribute to tumor growth; the role of other C' components, identified in Aim 1 to be involved in tumor progression, will be studied using similar approaches to those outlined below for the anaphylatoxins. The experiments in Aim 2 will assess the role of the anaphylatoxins in specific processes, such as: i) Tumor angiogenesis, by studying the effects of C3a and C5a on tumor vascularization, cytokine milieu, and recruitment and activation of inflammatory and endothelial cells, ii) Tumor cell proliferation and survival, by examining the role of C3a and C5a as direct or indirect regulators of cell proliferation and apoptosis. iii) Anti-tumor immune responses, by investigating the effects of C3a and C5a on Th1/Th2 lymphocyte balance and anti-tumor T cell responses. This proposal addresses for the first time the involvement of C' as a modulator of the local inflammatory conditions that promote tumor progression. It is designed to dissect critical interactions of C' with the tumor microenvironment and should elucidate the specific role of complement in ovarian carcinogenesis.
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