The Role of Complement in Tumor Growth

Pı́o, Rubén; Corrales, Leticia; Lambris, John D.

doi:10.1007/978-1-4614-5915-6_11

Cited by 173 publications

(176 citation statements)

References 244 publications

(264 reference statements)

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“…[42][43][44] CFD is essential for alternative pathway activation and was found to be identical to the adipokine adipsin which is expressed in monocytes/macrophages. 45,46 Since the CTC lines were established from patients with advanced SCLC characterized by large number of these cells in the circulation, CFD may be involved in cancer-associated weight loss. Cancer cachexia is a devastating syndrome that affects around half of all lung cancer patients but the underlying mechanisms have yet to be fully elucidated.…”

Section: Secretory Phenotype Of Sclc Ctc-induced Macrophagesmentioning

confidence: 99%

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

et al. 2015

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Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14 C , CD163 weak and CD68 C macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism.

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Section: Secretory Phenotype Of Sclc Ctc-induced Macrophagesmentioning

confidence: 99%

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

et al. 2015

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“…1 There is sufficient evidence to demonstrate the presence of complement deposition on tumor tissues from patients in a variety of cancer types. 2,3 Nevertheless, the role of the complement system in tumor growth and metastatic spread has not yet been sufficiently addressed, and contradictory findings are still being reported. 4,5 C1, the first component of the classical complement pathway, is a multimolecular complex composed of C1q, C1r, and C1s molecules that associate in a calcium-dependent macromolecular complex.…”

Section: Introductionmentioning

confidence: 99%

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

et al. 2016

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There is an ever increasing amount of evidence to support the hypothesis that complement C1q, the first component of the classical complement pathway, is involved in the regulation of cancer growth, in addition to its role in fighting infections. It has been demonstrated that C1q is expressed in the microenvironment of various types of human tumors, including breast adenocarcinomas. This study compares carcinogenesis progression in C1q deficient (neuT-C1KO) and C1q competent neuT mice in order to investigate the role of C1q in mammary carcinogenesis. Significantly accelerated autochthonous neu C carcinoma progression was paralleled by accelerated spontaneous lung metastases occurrence in C1q deficient mice. Surprisingly, this effect was not caused by differences in the tumor-infiltrating cells or in the activation of the complement classical pathway, since neuT-C1KO mice did not display a reduction in C3 fragment deposition at the tumor site. By contrast, a significant higher number of intratumor blood vessels and a decrease in the activation of the tumor suppressor WW domain containing oxidoreductase (WWOX) were observed in tumors from neuT-C1KO as compare with neuT mice. In parallel, an increase in Her2/neu expression was observed on the membrane of tumor cells. Taken together, our findings suggest that C1q plays a direct role both on halting tumor angiogenesis and on inducing apoptosis in mammary cancer cells by coordinating the signal transduction pathways linked to WWOX and, furthermore, highlight the role of C1q in mammary tumor immune surveillance regardless of complement system activation.Abbreviations: BALB-C1KO, BALB/c mice deficient for the C1qA; BALB-C3KO, BALB/c mice deficient for C3; C1KO, C1q deficient; C1qR, C1q receptor; CR3, complement receptor 3; EMT, epithelial-to-mesenchymal transition; KLRK1 or NKG2D, killer cell lectin-like receptor subfamily K, member 1; MDCS, myeloid-derived suppressor cells; neuT, rat Her2/neu transgenic; neuT-BKO mice, neuT mice deficient in antibody production; neuT-C1KO mice, neuT mice deficient for the C1qA molecule; neuT-C3KO mice, neuT mice deficient for the C3 molecule; NK, natural killer; pWWOX, phospho WWOX; Treg, T regulatory; WWOX, WW domain containing oxidoreductase

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“…It consists of liver-produced proteins which circulate as inactive precursors. Trigger factors, such as antigen-antibody complexes, lectin and endotoxines, induce a serial cleavage and activation of these proteins, leading to cytokine release and formation of the cell-killing membrane attack complex [4]. The adaptive immune response is specific against particular antigens, and encompasses the activation of B and T lymphocytes.…”

Section: Pathophysiological Pathwaysmentioning

confidence: 99%

“…Warning signs of impending cardiovascular collapse include hypotension, upper airway edema, wheezing or stridor and urticaria. Moreover, fever, mucous membrane lesions, abnormal pulmonary examination, joint tenderness and swelling indicate a serious reaction [4]. Epinephrine is the drug of choice for serious allergic reactions, especially in case of hypotension and airway compromise.…”

Section: Management Of Infusional Reactionsmentioning

confidence: 99%

Immediate Reactions To Monoclonal Antibodies In Clinical Hematology

Kyriazi

2016

IJMS

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Monoclonal antibodies (MoAbs) have been widely used in clinical hematology. As foreign macro-molecules, they can cause infusional reactions during the administration or within 24 hours after the infusion, which encompass a spectrum of mechanisms. Although most of these reactions are non-allergic, are often indistinguishable from true allergic reactions mediated by IgE immunoglobulins. The diagnosis is often challenging and relies mainly on clinical criteria. They occur during the first doses, soon after the initiation of treatment. The symptoms are usually well controlled by the immediate drug discontinuation or reduction of the infusion rate. The management remains largely supportive, consisting of oxygen, intravenous fluids, bronchodilators, antihistamines and steroids. Most of MoAb protocols recommend premedication with steroids and antihistamines and gradually escalating infusion rates. Increased medical and nursing vigilance is required and resuscitative equipment should always be readily available. These events affect patients' quality of life, leading to treatment delay or discontinuation and series of tests. The decision to rechallenge the treatment depends on severity grading, clinical parameters and treatment goals. This article provides an update of MoAbs used in clinical hematology. It summarizes the pathophysiology, the diagnostic approach, the preventive measures and treatment of MoAb-related reactions.

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The Role of Complement in Tumor Growth

Cited by 173 publications

References 244 publications

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

Immediate Reactions To Monoclonal Antibodies In Clinical Hematology

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