Genetic and Pharmacologic Inhibition of Complement Impairs Endothelial Cell Function and Ablates Ovarian Cancer Neovascularization

Nuñez-Cruz, Selene; Gimotty, Phyllis A.; Guerra, Matthew; Connolly, Denise C.; Wu, Yanze; DeAngelis, Robert A.; Lambris, John D.; Coukos, George; Scholler, Nathalie

doi:10.1593/neo.121262

Cited by 112 publications

(132 citation statements)

References 59 publications

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“…30,31,43 Our immunohistochemistry data showed a marked deposition of C1q on vascular endothelium and stroma of neuT tumors. On the other hand, the increased tumor vascularization observed in neuT-C1KO mice suggests that C1q could be considered an inhibitor of tumor angiogenesis, at least in our model of autochthonous Her2/neu-driven mammary cancer that display a process of angiogenesis 44 not superimposable to that observed in transplantable tumors.…”

Section: Discussionmentioning

confidence: 58%

“…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%

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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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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Complement is now thought to be a key component of cancer-related inflammation, and a recent study has suggested that exacerbated inflammation in the tumor microenvironment promotes genetic instability (25). The canonical proinflammatory mediator C5a has been widely implicated for a role in tumor growth, with both tumor-promoting and tumor-inhibitory effects reported, depending on tumor type, immune status of the host, and C5a levels (6)(7)(8)(9)26). Although these and other studies (27) have shown that tumor growth is reduced in the absence of C3 (which generates both C3a and C5a), the tumor-promoting effects have been attributed solely to C5a.…”

Section: Discussionmentioning

confidence: 99%

The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses

Nabizadeh

Manthey

Steyn

et al. 2016

The Journal of Immunology

102

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The complement peptide C3a is a key component of the innate immune system and a major fragment produced following complement activation. We used a murine model of melanoma (B16-F0) to identify a hitherto unknown role for C3a–C3aR signaling in promoting tumor growth. The results show that the development and growth of B16-F0 melanomas is retarded in mice lacking C3aR, whereas growth of established melanomas can be arrested by C3aR antagonism. Flow cytometric analysis showed alterations in tumor-infiltrating leukocytes in the absence of C3aR. Specifically, neutrophils and CD4+ T lymphocyte subpopulations were increased, whereas macrophages were reduced. The central role of neutrophils was confirmed by depletion experiments that reversed the tumor inhibitory effects observed in C3aR-deficient mice and returned tumor-infiltrating CD4+ T cells to control levels. Analysis of the tumor microenvironment showed upregulation of inflammatory genes that may contribute to the enhanced antitumor response observed in C3aR-deficient mice. C3aR deficiency/inhibition was also protective in murine models of BRAFV600E mutant melanoma and colon and breast cancer, suggesting a tumor-promoting role for C3aR signaling in a range of tumor types. We propose that C3aR activation alters the tumor inflammatory milieu, thereby promoting tumor growth. Therapeutic inhibition of C3aR may therefore be an effective means to trigger an antitumor response in melanoma and other cancers.

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“…This phenomenon has motivated several researchers to look into therapeutically inhibiting angiogenesis in an attempt to restrain tumor growth. Furthermore, the activation of both angiogenesis and immunosuppressive responses, often occur in the same cell types or are mediated by the same soluble factors (69 (72). The proangiogenic effect of complement was further supported by the finding that C5a induced vessel formation in 3LL cells (65).…”

Section: The Dual Role Of Complement In Angiogenesismentioning

confidence: 90%