Cancer and the Complement Cascade

Rutkowski, Martin J.; Sughrue, Michael E.; Kane, Ari J.; Mills, Steven A.; Parsa, Andrew T.

doi:10.1158/1541-7786.mcr-10-0225

Cited by 225 publications

(265 citation statements)

References 160 publications

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“…40,41 Besides regulation of the coagulation system, complement proteins stimulate cancer invasion through enhanced EMT, degradation of ECM by proteases such as MMP-9 and induction of chemotactic stimuli and growth factors. [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.…”

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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“…Mice deficient in C3 also exhibited significantly decreased tumor proliferation compared to wild-type mice (Markiewski et al, 2008). In another study, a cleavage product of complement C3, C3a was found to demonstrate proliferative activities and increase activation of proteins whose overexpression has been strongly associated with neoplasia (Rutkowski et al, 2010;Vivanco & Sawyers, 2002). Other tumorigenic effects of C3 include production of www.ccsenet.org/cco Cancer and Clinical Oncology Vol.…”

Section: Complement C3mentioning

confidence: 99%

“…Huang, Wang, Zhang, Li, & Li, 2013) Anastellin 256 (Neskey, Ambesi, Pumiglia, & McKeown-Longo, 2008;Pasqualini, Bourdoulous, Koivunen, Woods, & Ruoslahti, 1996;M. Yi & Ruoslahti, 2001) Apolipoprotein A-1 31 (Macuks et al, 2010;Zamanian-Daryoush et al, 2013) Fibrinogen β chain 56 (Krajewska et al, 2010) Keratin type I cytoskeletal 9 62 (W. Yi et al, 2013) Others: Complement component C4b (Childo blood group) 193 (Markiewski & Lambris, 2009;Rutkowski et al, 2010) …”

Section: Biochemical and Immunological Characterizations Of Ca215-s+ mentioning

confidence: 99%

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Human Serum Proteins Recognized by CA215 and Cancerous Immunoglobulins and Implications in Cancer Immunology

Lee¹,

Liu²,

Huang³

2014

CCO

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In 1987, a monoclonal antibody, RP215, was generated against the OC-3-VGH cancer cell line and shown to react with a carbohydrate-associated epitope located mainly on the heavy chains of immunoglobulins, designated as CA215, which are expressed on the surface of almost all cancer cells and not on normal immune cells. CA215 and cancerous immunoglobulins were affinity-isolated from the shed culture media of the same ovarian cancer cell line by using RP215-linked and anti-human immunoglobulin G-linked affinity chromatography, respectively. They were then immobilized separately as general ligands to isolate any protein components from pooled human sera which demonstrated affinity to CA215 and/or cancerous immunoglobulin G. The affinity-isolated components were then subjected to molecular analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among the detected protein components, more than 72% were found to be commonly recognized by both CA215 and cancerous immunoglobulins. Some have previously been identified as endogenous proteins or fragments in human serum. They are considered generally, as cancer biomarkers, according to their pro-cancer (e.g. C4b binding protein α chain, complement C3, complement factor H, serotransferrin, and vironectin), anti-cancer (e.g. 35 kDa inter-α-trypsin inhibition heavy chain 4, anastellin, apolipoprotein A-1, fibrinogen β chain, and, keratin type I cytoskeletal 9), or autoimmune (specific immunoglobulin G) properties, respectively. Therefore, besides serving a role for the growth/proliferation of cancer cells, cancerous immunoglobulins can also interact directly or indirectly with many other serum protein components or fragments for unspecified reasons and unknown mechanisms of action.

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“…Out of the three initiator pathways that activate the complement system, our cancer profile suggests that the initiators involved with the alternate complement pathway are diminished, while the terminal C5 remains unaltered. Though its role in cancer is complex and remains inconclusive, activated complement component proteins are abundantly dispersed throughout the inflammatory tumor microenvironment [19]. Finally, there is overwhelming suggestion in the literature that induction of complement is beneficial for targeted monoclonal antibody cancer therapy [20].…”

Section: Coagulation and Complement Cascadementioning

confidence: 99%

Stroma Liquid Biopsy™ - A Proteomic Model of the Systemic Response to Cancer

Kuruc¹

2017

MOJPB

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The concept of liquid biopsy has generated much scientific and commercial enthusiasm as it starts with an accessible body fluid, typically blood. These samples can then be monitored for example, to characterize the landscape of cancer-associated DNA mutations. These contributions notwithstanding, it is now overwhelmingly apparent that throughout cancer progression, there are adaptive microenvironments to support metastatic disease that are derived from the host systemic response. We now present evidence that host mediators between stroma and proliferating cells can in part, be monitored through the protein response that tracks into the vascularized tumor and re-proportions the extracellular proteins (serum) found in the general blood circulation. This rewiring pattern is especially significant, measurable even at very early stages of cancer, for many if not most primary tumors. This new multi-parameter cancer profile of progressive disease provides opportunities to monitor risk factors, for early detection, prognosis, recurrence, and guidance for therapeutic decisions.

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Cancer and the Complement Cascade

Cited by 225 publications

References 160 publications

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

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

Human Serum Proteins Recognized by CA215 and Cancerous Immunoglobulins and Implications in Cancer Immunology

Stroma Liquid Biopsy™ - A Proteomic Model of the Systemic Response to Cancer

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