Complement inhibition in cancer therapy

Pı́o, Rubén; Ajona, Daniel; Lambris, John D.

doi:10.1016/j.smim.2013.04.001

Cited by 118 publications

(96 citation statements)

References 144 publications

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“…Furthermore, our findings indicate upregulation of genes related to complement (C4A, C4B, and SERPING1) in BM-MSC exposed to leukemia in vivo. Consistent with our data, it has been recently shown that cancer cells can activate complement and such activation can promote an immunosuppressive microenvironment, induce angiogenesis and activate cancer-related signaling pathways [reviewed in [67]]. In this chronic inflammationlike state that resembles "a wound that does not heal" [14], stromal cells accumulate certain types of cytokines, chemokines, growth factors, matrix remodeling proteases, and reactive oxygen species critically compromising tissue homeostasis and creating a tumor-supportive microenvironment [68].…”

Section: Discussionsupporting

confidence: 91%

Untitled

2017

Oncotarget

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The genetic heterogeneity of acute myeloid leukemia (AML) and the variable responses of individual patients to therapy suggest that different AML genotypes may influence the bone marrow (BM) microenvironment in different ways. We performed gene expression profiling of bone marrow mesenchymal stromal cells (BM-MSC) isolated from normal C57BL/6 mice or mice inoculated with syngeneic murine leukemia cells carrying different human AML genotypes, developed in mice with Trp53 wild-type or null genetic backgrounds. We identified a set of genes whose expression in BM-MSC was modulated by all four AML genotypes tested. In addition, there were sets of differentially-expressed genes in AML-exposed BM-MSC that were unique to the particular AML genotype or Trp53 status. Our findings support the hypothesis that leukemia cells alter the transcriptome of surrounding BM stromal cells, in both common and genotype-specific ways. These changes are likely to be advantageous to AML cells, affecting disease progression and response to chemotherapy, and suggest opportunities for stroma-targeting therapy, including those based on AML genotype.

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Section: Discussionsupporting

confidence: 91%

Untitled

2017

Oncotarget

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“…It has been demonstrated that cancer cells establish a balance between complement activation and inhibition. 29 However, controversial and conflicting data on the complement system's tumor-promoting, 30,31 and inhibiting activities, 24 have been published, 2 and the mechanisms of complement-specific activities in the tumor microenvironment are still unclear and demands further study.…”

Section: Discussionmentioning

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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“…The main pathway involved in activation of complement inside tumors is unclear, and evidence supports activation of each complement pathway in malignant tumors (40). To make matters more complicated, cancer cell membrane-bound serine proteases can also cleave C5 and generate C5a without complement activation (41).…”

Section: Immune Function Of the Complement Systemmentioning

confidence: 99%