Abstract
The complement system has demonstrated roles in regulating tumor growth, although these may differ between tumor types. The current study used two murine breast cancer models (EMT6 and 4T1) to investigate whether pharmacological targeting of receptors for complement proteins C3a (C3aR) and C5a (C5aR1) is protective in murine breast cancer models. In contrast to prior studies in other tumor models, treatment with the selective C5aR1 antagonist PMX53 had no effect on tumor growth. However, treatment of mice with a dual C3aR/C5aR1 agonist (YSFKPMPLaR) significantly slowed mammary tumor development and progression. Examination of receptor expression by quantitative polymerase chain reaction (qPCR) analysis showed very low levels of mRNA expression for either C3aR or C5aR1 by EMT6 or 4T1 mammary carcinoma cell lines compared with the J774 macrophage line or bone marrow-derived macrophages. Moreover, flow cytometric analysis found no evidence of C3aR or C5aR1 protein expression by either EMT6 or 4T1 cells, leading us to hypothesize that the tumor inhibitory effects of the dual agonist are indirect, possibly via regulation of the anti-tumor immune response. This hypothesis was supported by flow cytometric analysis of tumor infiltrating leukocyte populations, which demonstrated a significant increase in T lymphocytes in mice treated with the C3aR/C5aR1 agonist. These results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumor response in different ways depending on the cancer type, the host immune response to the tumor and levels of endogenous complement activation within the tumor microenvironment.
Highlights
Breast cancer is the most common cancer diagnosed in women world-wide, accounting for 25% of all cancers and 15% of cancer deaths in women [1]
To determine the influence of C3aR/C5aR1 signaling on tumor development, mice were injected with EMT6 mammary carcinoma cells
Caliper measurements showed that PMX53 had no significant effect on the growth of EMT6 tumors, but tumor growth was slowed by EP54 treatment (p < 0.01; Figure 1A)
Summary
Breast cancer is the most common cancer diagnosed in women world-wide, accounting for 25% of all cancers and 15% of cancer deaths in women [1]. As powerful mediators of inflammation, complement proteins have been implicated for a role in tumorigenesis [5], with elevated complement regulatory proteins and activation fragments identified as biomarkers and prognostic indicators for many cancers, including breast cancer [6,7,8]. The upregulation of complement inhibitory proteins is thought to be an important mechanism by which cancer cells evade complement-mediated destruction [12,13,14]. C5a is one of the most potent inflammatory proteins and chemoattractant for neutrophils, monocytes and macrophages [16] It binds two specific receptors, C5a receptor (CD88/C5aR1) and C5a receptor-like 2 (C5L2/C5aR2), of which the former (G-protein coupled C5aR1) is thought to be the predominant driver of biological activity [17,18]. Thought to have similar pro-inflammatory effects to C5a, C3a is known to exert a range of apparently contradictory immunomodulatory functions—attenuating neutrophil mobilization in response to injury [19] but inducing production of pro-inflammatory cytokines [20]
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