Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma

Xi, Wei; Liu, Li; Wang, Jiajun; Yu, Xinbing; Bai, Qi; Xiong, Ying; Qu, Yang; Long, Qilai; Guo, Jianming

doi:10.18632/oncotarget.13108

Cited by 20 publications

(20 citation statements)

References 26 publications

(34 reference statements)

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“…Taken together, our results in ccRCC and in the mouse model demonstrated that classical complement pathway activation occurs in cancer and has a pro-tumoral effect. Our data fit with the findings that positive C5a/C5aR staining is associated with a poor prognosis in ccRCC (48,49)…”

Section: Discussionsupporting

confidence: 91%

Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth

Roumenina

Daugan

Noé

et al. 2019

Cancer Immunology Research

164

133

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Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from 3 patient cohorts (n=106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The in situ orchestrated production of C1q by tumor-associated macrophages (TAMs) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data has identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.

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Section: Discussionsupporting

confidence: 91%

Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth

Roumenina

Daugan

Noé

et al. 2019

Cancer Immunology Research

164

133

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“…Indeed, the used antibodies did not allow to determine the exact nature of the fragments, the anti-C3d recognizing C3, C3b, iC3b as well as the C3dg and C3d fragments, each having different function. In another cohort, though, the C5a-positive staining (marking indistinguishably the presence of the anaphylatoxin C5a and the intact C5) and the presence of C5aR+ staining were correlated with poor prognosis 96,97 . The malignant cells in KIRC, therefore, hijack macrophage-produced C1q to complement the remaining components made by the cancer cell, to promote tumor growth.…”

Section: Cancers With "Protective C3"mentioning

confidence: 92%

Context-dependent roles of complement in cancer

et al. 2019

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The tumor microenvironment (TME) highly influences the growth, spreading of tumors and therefore patient's clinical outcome. In this context, complement system plays a major and complex role. It may either kill antibody-coated tumor cells or support local inflammation, hamper anti-tumor T cell responses favoring cancer spreading. Recent studies demonstrate that these opposite effects depend of the sites of its activation, the composition of the TME and the tumor cell sensitivity to complement attack. In this review, we present the implication of complement activation and its effects on cancer control and clinical outcome in different TME contexts. We also provide an overview of the publicly available transcriptomic data on the prognostic value of complement genes expression in 30 cancer types. We argue that the interplay of complement within each cancer is unique, governed by the properties of the tumor cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies.

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“…More and more evidence has shown that C5aR is found in tumor cells of various common cancers. The survival rate of patients with C5aR positive or highly expressed nonsmall cell lung cancer 14 , breast cancer, transparent cell kidney cancer 15 , gastric cancer and other patients is lower than that of corresponding patients with C5aR1 negative. A variety of cancer cells have abnormal expression of C5aR in different organs, specific binding of C5a and C5aR, activation of downstream pathways, enhancement of the mobility of cancer cells, secretion of matrix metalloproteinase (MMP) and other beneficial processes of cancer cells.…”

Section: C5a and Tumor Formationmentioning

confidence: 87%

Important roles of C5a and C5aR in tumor development and cancer treatment

Wang

2019

E3S Web Conf.

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The complement system is part of the body's innate defense immune system, which can identify and eliminate invasive pathogenic microorganisms to maintain normal life activities. Complement Component 5a (C5a) is an active anaphylatoxin produced after complement system activation, closely related to tumor formation. C5a is highly expressed in a variety of tumors, and combines with its Complement Component 5a Receptor (C5aR) to increase the proliferation and migration of tumor cells. This review will comprehensively elaborate the important role of C5a/C5aR in the process of tumor genesis and development from the three aspects of signal transduction pathways related to tumor, C5a/C5aR and tumor formation, and C5a/C5aR inhibitors and tumor therapy. Finally, the principle of complement inhibition is used to inhibit tumor metastasis, reduce the rate of tumor diffusion, and control the trend of tumor deterioration.

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Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma

Cited by 20 publications

References 26 publications

Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth

Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth

Context-dependent roles of complement in cancer

Important roles of C5a and C5aR in tumor development and cancer treatment

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