Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma

Jiang, Feng; Liu, Hui; Peng, Fengping; Liu, Zhaoyun; Ding, Kai; Song, Jia; Li, Lijuan; Chen, Jin; Shao, Qing; Yan, Siyang; Veirman, Kim De; Vanderkerken, Karin

doi:10.20892/j.issn.2095-3941.2020.0430

Cited by 7 publications

(5 citation statements)

References 45 publications

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“…Here, we will discuss most recent examples of these protumor roles in pre-clinical animal models and human cancers. Extracellular complement activation product C3a induces PI3K/PDK1/p-SGK3 signalling in osteoclasts, which results in bone disease in multiple myeloma patients and is associated with poor prognosis ( Figure 2 ) ( 72 ). Properdin, which stabilizes the AP C3 convertase, increases the generation of C5a, which via its receptor C5aR1, recruits immunosuppressive MDSCs from the spleen in a mouse model of melanoma ( 73 ).…”

Section: Sites Of Complement Production and Activationmentioning

confidence: 99%

Inside-Out of Complement in Cancer

et al. 2022

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The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal role of complement in fighting microbes, complement seems to suppress antitumor immunity via regulation of host cell in the tumor microenvironment. Although most studies link complement in cancer to complement activation in the extracellular space, the discovery of intracellular activation of complement, raises the question: what is the relevance of this process for malignancy? Intracellular activation is pivotal for the survival of immune cells. Therefore, complement can be important for tumor cell survival and growth regardless of the role in immunosuppression. On the other hand, because intracellular complement (the complosome) is indispensable for activation of T cells, these functions will be essential for priming antitumor T cell responses. Here, we review functions of complement in cancer with the consideration of extra and intracellular pathways of complement activation and spatial distribution of complement proteins in tumors and periphery and provide our take on potential significance of complement as biomarker and target for cancer therapy.

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Section: Sites Of Complement Production and Activationmentioning

confidence: 99%

Inside-Out of Complement in Cancer

et al. 2022

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“…Analysis of the total proteome and comparison between the apoE4 carriers and non‐carriers revealed up‐ or downregulation of several proteins, from which three (PTPRF, TRA2A, and NISCH) correlated very well with the in vitro mRNA data (Figs 5B and 6A and B; Dataset EV2). From these, upregulation of PTPRF is involved in cell adhesion pathway upon response to complement C3a (Jiang et al , 2021). PTPRF and DCAF7 also correlate with Aβ pathology in a recent iNPH transcriptomic data indicating a major role of these proteins in apoE isoform and complement‐dependent inflammatory response (Huang et al , 2021a).…”

Section: Resultsmentioning

confidence: 99%

“…mRNA data(Figs 5B and 6A and B; Dataset EV2). From these, upregulation of PTPRF is involved in cell adhesion pathway upon response to complement C3a(Jiang et al, 2021). PTPRF and DCAF7 also correlate with Ab pathology in a recent iNPH transcriptomic data indicating a major role of these proteins in apoE isoform and complement-dependent inflammatory response(Huang et al, …”

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confidence: 88%

Reduced binding of apoE4 to complement factor H promotes amyloid‐β oligomerization and neuroinflammation

et al. 2023

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The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late‐onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform‐specific binding of apoE to FH alters Aβ1‐42‐mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of Aβ1‐42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement‐resistant oligomers with apoE/Aβ1‐42 complexes and the formation of these complexes is isoform specific with apoE2 and apoE3 showing higher affinity to FH than apoE4. These FH/apoE complexes reduce Aβ1‐42 oligomerization and toxicity, and colocalize with complement activator C1q deposited on Aβ plaques in the brain. These findings provide an important mechanistic insight into AD pathogenesis and explain how the strongest genetic risk factor for AD predisposes for neuroinflammation in the early stages of the disease pathology.

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“…The complex immune microenvironment plays an important role. Complement 3 can effectively activate macrophages, producing complement-dependent cytotoxic effects 43 . It may re ect the body's anti-tumor effects.…”

Section: Discussionmentioning

confidence: 99%

A risk-scoring system for assessing prognosis in multiple myeloma patients based on a large real-world sample

Wang,

Yang,

Wang

et al. 2023

Preprint

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Objective Multiple myeloma (MM) is an incurable malignancy with a diversity of clinical characteristics and prognoses. The commonly used staging system has obvious shortcomings. Exploring accurate prognostic models is essential. Methods A total of 1,276 newly diagnosed MM patients were selected from Zhongshan Hospital Fudan University between January 2010 and April 2021. After excluding patients with amyloidosis or other tumors, a total of 802 patients receiving standard first-line therapy were included. 703 patients in the non-transplant group (527 patients in the training set and 176 patients in the validation set) and 109 patients in the transplant group. We enrolled 41 baseline parameters including clinical, laboratory, and pathological features. We used univariate and multivariate Cox analyses to screen for factors associated with overall survival and to develop prognostic models. Results The final risk-scoring system includes ECOG score, extramedullary lesion, thrombocyte, reticulocyte, anion gap, hypercalcemia, complement C3, β2-microglobulin, cytogenetics and interleukin-2 receptor. We identify the optimal cut-off for the risk score and divide the patients into high-risk and low-risk groups. Kaplan-Meier curves and Log-rank tests showed that the risk score was significant with overall survival in the training set (P < 0.001), validation set (P < 0.001) and transplant group (P = 0.02). The time-dependent receiver operator characteristic curve shows that the risk score has a better predictive value than the commonly used staging system. Conclusion A novel MM risk score system is developed based on a large real-world sample. We have performed a comprehensive assessment of baseline disease characteristics, which is of high application and practice value.

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Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma

Cited by 7 publications

References 45 publications

Inside-Out of Complement in Cancer

Inside-Out of Complement in Cancer

Reduced binding of apoE4 to complement factor H promotes amyloid‐β oligomerization and neuroinflammation

A risk-scoring system for assessing prognosis in multiple myeloma patients based on a large real-world sample

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