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Abstract
Complement is an effector of innate immunity and a bridge connecting innate immunity and subsequent adaptive immune responses. It is essential for protection against infections and for orchestrating inflammatory responses. Recent studies have also demonstrated contribution of the complement system to several homeostatic processes that are traditionally not considered to be involved in immunity. Thus, complement regulates homeostasis and immunity. However, dysregulation of this system contributes to several pathologies including inflammatory and autoimmune diseases. Unexpectedly, studies of the last decade have also revealed that complement promotes cancer progression. Since the initial discovery of tumor promoting role of complement, numerous preclinical and clinical studies demonstrated contribution of several complement components to regulation of tumor growth through their direct interactions with the corresponding receptors on tumor cells or through suppression of antitumor immunity. Most of this work, however, focused on a role of complement in regulating growth of primary tumors. Only recently, a few studies showed that complement promotes cancer metastasis through its contribution to epithelial-to-mesenchymal transition and the premetastatic niche. This latter work has shown that complement activation and generation of complement effectors including C5a occur in organs that are target for metastasis prior to arrival of the very first tumor cells. C5a through its interactions with C5a receptor 1 inhibits antitumor immunity by activating and recruiting immunosuppressive cells from the bone marrow to the premetastatic niche and by regulating function and self-renewal of pulmonary tissue-resident alveolar macrophages. These new advancements provide additional evidence for multifaceted functions of complement in cancer.
Highlights
In both mouse models of cancer and patients, the expression of several complement genes is increased, resulting in higher than normal concentrations of complement proteins in plasma or other body fluids [1, 2, 3]
In several mouse models of cancer, changes that appear to be essential for metastatic colonization, e.g., a final stage of the invasion-metastatic cascade, including vascular alterations, remodeling of extracellular matrix, inflammation, and immunosuppression are observed in certain organs that seem to be marked for metastasis even before the arrival of the tumor cells
Similar to Kupffer cells in the liver, another population of tissue-resident macrophages, pulmonary alveolar macrophages, were recently demonstrated to contribute to the premetastatic niche [92]. These recent developments on participation of tissue-resident macrophages to metastasis are of particular interest because roles of these cells in cancer remain unclear, in contrast to very well-studied tumor-associated macrophages (TAMs) or inflammatory monocytes/macrophages recruited to the lungs with metastases by CCL2 [101]
Summary
University of Louisville Physicians, United States Dimitrios C. National Centre of Scientific Research Demokritos, Greece. Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal
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