Complement Activation and Up-Regulated Expression of Anaphylatoxin C3a/C3aR in Glioblastoma: Deciphering the Links with TGF-β and VEGF

Ah-Pine, Franck; Septembre-Malaterre, Axelle; Bedoui, Yosra; Khettab, Mohamed; Neal, James; Freppel, S.; Gasque, Philippe

doi:10.3390/cancers15092647

Cited by 8 publications

(9 citation statements)

References 62 publications

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“…It will be important to ascertain whether the C3a-C3aR axis may also regulate the production of other pro-angiogenic factors. We and others have recently found a strong link between high levels of C3aR+ TAM and VEGF expression in human and mouse models of cancer [21,29]. Indeed, Davidson and colleagues reported that the lack of a functional C3aR leads to a reduction in the B16 tumor mass and is associated with an increase in non-differentiated pro-inflammatory monocytes [29].…”

Section: Discussionmentioning

confidence: 93%

“…However, a new antiinflammatory role has recently emerged [18,19]. Upregulated C3a levels have been found in many types of cancer, such as breast, colorectal esophageal, and brain cancers [20,21]. Additionally, in a model of breast cancer, it was shown that C3a promotes lung metastasis by activating cancer-associated fibroblasts (CAFs) [22].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, it has been demonstrated that the C3a-C3aR axis promotes breast cancer metastasis by reshaping the TME [22] and the invasion and migration of hepatocellular carcinoma cells [28]. Moreover, it has recently been shown that there is a strong link between high levels of VEGF + and C3aR + expressed by TAM in several models of cancer [21,[29][30][31]. Indeed, using WT and C3aR −/− animals, a unique subset of F4/80 high C3aR high TAM was identified as driving robust angiogenesis and metastasis [29].…”

Section: Introductionmentioning

confidence: 99%

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Deciphering the Role of the Anaphylatoxin C3a: A Key Function in Modulating the Tumor Microenvironment

Hanna¹,

Ah-Pine²,

Boina³

et al. 2023

Cancers

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The complement system plays a crucial role in cancer development. Our study investigated the role of C3a anaphylatoxin on the tumor microenvironment. Our models consisted of mesenchymal stem cells (MSC-like, 3T3-L1), macrophages (Raw 264.7 Blue, (RB)) and tumor cells (melanoma B16/F0). Recombinant mouse (Mo) C3a (rC3a) was produced in CHO cells transfected with a Mo-IL10-signal peptide-Mo C3a plasmid construct. The effects of rC3a, IFN-γ, TGF-β1, and LPS were tested on the expression of C3, C3aR, PI3K, cytokines, chemokines, transcription factors, antioxidant defense mechanisms, angiogenesis and macrophage polarization (M1/M2). 3T3-L1 expressed the highest levels of C3, while C3aR was expressed more by RB. Interestingly, expression of C3/3T3-L1 and C3aR/RB was markedly upregulated by IFN-γ. rC3a was found to upregulate the expression of anti-inflammatory cytokines (IL-10) on 3T3-L1 and TGF-β1 on RB. rC3a also upregulated the expression of pro-inflammatory cytokines in RB. The expression of CCL-5 increased in 3T3-L1 in response to rC3a. On RB, rC3a did not alter M1/M2 polarization but upregulated the expression of antioxidant defense genes, HO-1, and VEGF. C3/C3a produced mainly by MSC may play a critical role in TME remodeling by stimulating both anti-inflammatory and proangiogenic activities of tumor stromal cells.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deciphering the Role of the Anaphylatoxin C3a: A Key Function in Modulating the Tumor Microenvironment

Hanna¹,

Ah-Pine²,

Boina³

et al. 2023

Cancers

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“…These data are in line with previous reports suggesting that therapies targeting CSF-1/CSF1R and C3a/C3aR result in altered TAM polarization, recruitment, proliferation, and altered vascularity through regulation of VEGF. Previous reports established that C3aR-deficient or SB290157-treated mice display reduced vascular density [67,68], and that C3aR + TAMs located in perivascular niches display an M2-like character, and are associated with regulation of angiogenesis and tumor aggressiveness [65,66,69,70].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced Complement Component 3 Promotes Aggressive Tumor Growth in the Glioblastoma Microenvironment

Rosberg,

Smolag,

Sjölund

et al. 2024

Preprint

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Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single cell, and spatially resolved transcriptomic data from human GBM patients. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level-dependent increase in C3 and C3AR1 expression in response to hypoxia in several GBM and stromal cell types. Presence of C3 increased proliferation of GBM cells under hypoxic conditions, as well as clonal survival of GBM cells following radiation. Targeting C3aR using the antagonist SB290157 decreased GBM cell self-renewal in vitro, and prolonged survival of glioma bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM, and support a role of hypoxia-induced C3a-C3aR signaling as a contributor to glioma aggressiveness.

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“…Two reports have linked anaphylatoxin receptor overexpression to disruption of macrophage functionality ( 153 , 154 ). As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Anaphylatoxin signaling activates macrophages to control intracellular Rickettsia proliferation

Dahmani,

Zhu,

Cook

et al. 2023

Microbiol Spectr

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Pathogenic Rickettsia species proliferate within the cytoplasm of permissive host cells in vivo . The cytoplasm of these host cells is adequate to support the complex metabolic and physiological needs for Rickettsia growth. However, a dramatic host/pathogen interplay occurs when Rickettsia encounter innate immune cells, whereby the bacteria can proliferate as normal or the host can restrict bacterial growth. This interplay is most divergent within myeloid host cells, where intra- and extracellular factors can produce either successful Rickettsia parasitism or innate immune control of bacterial proliferation. With the prior knowledge that the mammalian complement system is activated during mammalian infection, we sought to determine if extracellular complement activation and anaphylatoxin signaling can modify the fate of Rickettsia within mononuclear host cells. Results indicate that supplementation of growth media with either C3a or C5a anaphylatoxin peptides is sufficient for many myeloid cells to control the proliferation of multiple different Rickettsia species. Chemical or genetic disruption of anaphylatoxin signaling or anaphylatoxin receptors eliminates complement-induced restriction of bacterial proliferation. Finally, anaphylatoxin signaling modifies macrophage physiology by inducing inflammatory phenotypes that ultimately control the intracellular proliferation of these pathogens. IMPORTANCE Pathogenic Rickettsia species are extremely dangerous bacteria that grow within the cytoplasm of host mammalian cells. In most cases, these bacteria are able to overpower the host cell and grow within the protected environment of the cytoplasm. However, a dramatic conflict occurs when Rickettsia encounter innate immune cells; the bacteria can “win” by taking over the host, or the bacteria can “lose” if the host cell efficiently fights the infection. This manuscript examines how the immune complement system is able to detect the presence of Rickettsia and alert nearby cells. Byproducts of complement activation called anaphylatoxins are signals that “activate” innate immune cells to mount an aggressive defensive strategy. This study enhances our collective understanding of the innate immune reaction to intracellular bacteria and will contribute to future efforts at controlling these dangerous infections.

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Complement Activation and Up-Regulated Expression of Anaphylatoxin C3a/C3aR in Glioblastoma: Deciphering the Links with TGF-β and VEGF

Cited by 8 publications

References 62 publications

Deciphering the Role of the Anaphylatoxin C3a: A Key Function in Modulating the Tumor Microenvironment

Deciphering the Role of the Anaphylatoxin C3a: A Key Function in Modulating the Tumor Microenvironment

Hypoxia-induced Complement Component 3 Promotes Aggressive Tumor Growth in the Glioblastoma Microenvironment

Anaphylatoxin signaling activates macrophages to control intracellular Rickettsia proliferation

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