Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma

Riihilä, Pilvi; Nissinen, Liisa; Farshchian, Mehdi; Kallajoki, Markku; Kivisaari, Atte; Meri, Seppo; Grénman, Reidar; Peltonen, Sirkku; Peltonen, Juha; Pihlajaniemi, Taina; Heljasvaara, Ritva; Kähäri, Veli‐Matti

doi:10.1016/j.ajpath.2017.01.006

Cited by 65 publications

(62 citation statements)

References 35 publications

(64 reference statements)

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“…Various models of tumorigenesis, including colon cancer, pancreatic cancer, squamous cell carcinoma, lung cancer and breast cancer models, support this contention by showing increased production of complement proteins in metastatic settings, followed by modulation of immune responses and establishment of an environment that suppresses effector T cells 23,58,89,90 . C3aR has been further implicated in the dissemination of cancer to the nervous system by disrupting the blood–cerebrospinal fluid (CSF) barrier and permitting the access of plasma components and other mitogens to the CSF 91 .…”

Section: Feeding Inflammation and Tumorigenesismentioning

confidence: 93%

Complement in cancer: untangling an intricate relationship

et al. 2017

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In tumour immunology, complement has traditionally been considered as an adjunctive component that enhances the cytolytic effects of antibody-based immunotherapies, such as rituximab. Remarkably, research in the past decade has uncovered novel molecular mechanisms linking imbalanced complement activation in the tumour microenvironment with inflammation and suppression of antitumour immune responses. These findings have prompted new interest in manipulating the complement system for cancer therapy. This Review summarizes our current understanding of complement-mediated effector functions in the tumour microenvironment, focusing on how complement activation can act as a negative or positive regulator of tumorigenesis. It also offers insight into clinical aspects, including the feasibility of using complement biomarkers for cancer diagnosis and the use of complement inhibitors during cancer treatment.

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Section: Feeding Inflammation and Tumorigenesismentioning

confidence: 93%

Complement in cancer: untangling an intricate relationship

et al. 2017

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“…Complement C3 has also been shown to be synthesized e.g. by keratinocytes, synoviocytes as well as by malignant skin tumor cells [23][24][25]. C3 synthesis is upregulated by various cytokines, like IL-1β, IFN-γ and TNF-α.…”

Section: Location Specific Production Of Complementmentioning

confidence: 99%

Intracellular complement activation—An alarm raising mechanism?

Reichhardt

Meri

2018

Seminars in Immunology

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It has become increasingly apparent that the complement system, being an ancient defense mechanism, is not operative only in the extracellular milieu but also intracellularly. In addition to the known synthetic machinery in the liver and by macrophages, many other cell types, including lymphocytes, adipocytes and epithelial cells produce selected complement components. Activation of e.g. C3 and C5 inside cells may have multiple effects ranging from direct antimicrobial defense to cell differentiation and possible influence on metabolism. Intracellular activation of C3 and C5 in T cells is involved in the maintenance of immunological tolerance and promotes differentiation of T helper cells into Th1-type cells that activate cell-mediated immune responses. Adipocytes are unique in producing many complement sensor proteins (like C1q) and Factor D (adipsin), the key enzyme in promoting alternative pathway amplification. The effects of complement activation products are mediated by intracellular and cell membrane receptors, like C3aR, C5aR1, C5aR2 and the complement regulator MCP/CD46, often jointly with other receptors like the T cell receptor, Toll-like receptors and those of the inflammasomes. These recent observations link complement activation to cellular metabolic processes, intracellular defense reactions and to diverse adaptive immune responses. The complement components may thus be viewed as intracellular alarm molecules involved in the cellular danger response.

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“…C3 is the central component of the complement system and promotes growth, proliferation, migration, and stemness of cutaneous squamous cell carcinoma. 18,19 Activation of C3 triggers resistance of tumor cells to programmed death-ligand 1 (PD-L1) antibody by modulating TAMs. 20 In C3-deficient mice, the growth and metastasis of primary tumors were strongly inhibited in lung cancer, which was ascribed to the increased numbers of CD4 + and CD8 + T cells.…”

Section: Introductionmentioning

confidence: 99%

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

Huang

et al. 2020

OTT

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Objective: Hepatic stellate cells (HSCs) are the important players in liver cirrhosis and liver cancer. They also act as critical mediators of immunosuppression in hepatocellular carcinoma (HCC). In this study, we hypothesized that HSCs promote HCC progression via C3. Methods: C3 in HSCs was knocked down using a shRNA retroviral plasmid. The conditioned medium from HSCs or shC3 HSCs (knockdown of C3 by shRNA in HSCs) was collected to detect their effects on bone marrow (BM) and T cells (including expansion and apoptosis) in vitro, and in an HCC in situ model in mice. Results: We found that HSCs promoted T-cell apoptosis and decreased their proliferation, inhibited dendritic cell (DC) maturation, and induced myeloid-derived suppressor cell (MDSC) expansion through the C3 pathway in vitro. In addition, the knockdown of C3 suppressed HSC-promoted HCC development in the orthotopic transplantation tumor model of HCC in mice. Conclusion: These findings provide more insights into the immunomodulatory roles of HSCs in HCC progression and indicate that modulation of the C3 pathway might be a novel therapeutic approach for liver cancer.

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Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma

Cited by 65 publications

References 35 publications

Complement in cancer: untangling an intricate relationship

Complement in cancer: untangling an intricate relationship

Intracellular complement activation—An alarm raising mechanism?

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

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