Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis

Ding, Peipei; Xu, Yanqing; Li, Luying; Lv, Xinyue; Li, Ling; Chen, Jianfeng; Zhou, Danlei; Wang, Xiaochao; Wang, Qi; Zhang, Wei; Liao, Tian; Ji, Qinghai; Lei, Qun‐Ying; Hu, Weiguo

doi:10.1016/j.celrep.2022.110851

Cited by 57 publications

(56 citation statements)

References 65 publications

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“…The importance of modulating anti-tumour immune host responses following C5aR1 targeting has been highlighted in previous studies and ourselves and others have observed reduced tumour burden in C5aR1 -/mice (data not shown) (Ding et al, 2022;Markiewski et al, 2008;Surace et al, 2015). The defect in tumour uptake displayed by C5aR1 -/mice complicates the investigation of tumour radiation responses in this model and might have contributed to some of the previous conflicting reports on the effects of targeting the complement system on tumour radiation responses.…”

Section: Discussionmentioning

confidence: 77%

Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

Beach

MacLean

Majorova

et al. 2023

Preprint

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An immunosuppressive microenvironment causes poor tumour T-cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumours is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identify complement receptor C5aR1 as a druggable target which when inhibited improves radiotherapy even in tumours displaying immunosuppressive features and poor CD8+ T-cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we find that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumour-cell specific functions. C5aR1 targeting results in increased NF-κB-dependent apoptosis specifically in tumours and not normal tissues; indicating that in malignant cells, C5aR1 primarily regulates cell fate. Collectively, these data reveal that increased complement gene expression is part of the stress response mounted by irradiated tumours and that targeting C5aR1 can improve radiotherapy even in tumours displaying immunosuppressive features.

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Section: Discussionmentioning

confidence: 77%

Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

Beach

MacLean

Majorova

et al. 2023

Preprint

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“…More work is required to fully explain and therefore firmly establish the hypothesis of intracellular complement as an important regulator of cellular function and homeostasis. Understanding the contribution of intracellular complement to various physiological and pathological processes will be of great potential future benefit, and could drive the development of new therapeutics that could potentially target mechanisms of intracellular complement function, not only in autoimmunity, 30 but also in recently identified intracellular complement‐mediated pathological mechanisms in infectious disease, 101,102 as well as in cancer 35,42 …”

Section: Solutions: Future Directions and Modern Methodsmentioning

confidence: 99%

“…In this scenario, cathepsin L cleaves and activates cell‐intrinsic C3 and allows its deposition on the apoptotic cell surface, presumably triggered during the process of apoptosis induction, either by fusion of C3‐containing endosomes and cathepsin L‐containing lysosomes, or by the leakage of their contents into the cytosol during apoptosis induction, 33 allowing their interaction. In addition, cathepsins have been demonstrated to cleave C3 intracellularly within hypoxic gut epithelial cells, causing anaphylatoxin release and contributing to inflammation during ischemia, 34 and cathepsin D was also recently identified as directly cleaving C5 within lysosomal/endosomal compartments in colonic epithelial cells, driving tumorigenesis via C5aR1 signaling 35 …”

Section: Intracellular Complement: Specific Components or Complete Pa...mentioning

confidence: 99%

“…to cleave C3 intracellularly within hypoxic gut epithelial cells, causing anaphylatoxin release and contributing to inflammation during ischemia, 34 and cathepsin D was also recently identified as directly cleaving C5 within lysosomal/endosomal compartments in colonic epithelial cells, driving tumorigenesis via C5aR1 signaling. 35 Cell-intrinsic (i.e., de novo synthesized, not internalized) C3…”

Section: Intracellular Roles Of C3mentioning

confidence: 99%

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Intracellular complement: Evidence, definitions, controversies, and solutions

King

Blom

2022

Immunological Reviews

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The traditionally understood roles of complement in innate immunity take place in the extracellular environment, directly opsonizing and even lysing some pathogens via the action of C3 deposition and formation of the terminal membrane attack complex 1 but also acting as a danger sensing mechanism, transmitting signals to cells via cell-surface receptors of activated complement components. 2 While these functions have largely been attributed to circulating complement proteins secreted mainly from the liver, it has been recognized that local expression of complement proteins can also have an important role in tissues, 3 for example, in infection 4,5 and in complement-dependent pathologies. [6][7][8] The discovery that some cell types express multiple complement proteins required for complete activation pathways, leading to spontaneous activation, also opened the possibility for autocrine complement activation playing roles in cellular homeostasis, activation, and inflammation. 9,10 For example, more recently, cell-intrinsic C3 expression in fibroblasts has been shown to play an important role in priming tissue sites for inflammation. 11 In autoinflammatory disease, repeated attacks can increase in severity. It was shown that mice injected at the same site with identical doses of sterile inflammatory danger-or pathogenassociated molecular patterns (DAMPs or PAMPs) suffered increasing levels of inflammation, while injection at different sites did not. This was not dependent on the adaptive immune system, as shown using SCID and RAG1-KO mice, but was dependent on C3, as shown using C3-KO mice. In addition, adoptive transfer of exposed fibroblasts from WT but not C3-KO mice "primed" the recipient site for increased inflammation, indicating the importance of fibroblastexpressed C3 in this priming process. This detailed and clear study indicates a role for local, or cell-intrinsic C3 in fibroblasts in sterile inflammation. The exact function of C3 was not however defined,

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“…In fact, in human T-cells, intracellular stores of complement proteins have been shown to be responsible to guide T-cell differentiation towards different subsets [ 101 ]. This suggests that the activation of the complement cascade could happen intracellularly in the epithelial pancreatic compartment, like in colorectal cancer, where intracellular complement participates actively in the tumorigenic process [ 102 ]. So far, mechanisms underlying its intracellular activation and regulation and its functional outcomes, in particular concerning the pancreas, are largely unexplored [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

Section: Pilot Study: Complement and Malassezia In Pdacmentioning

confidence: 99%

Complement and Fungal Dysbiosis as Prognostic Markers and Potential Targets in PDAC Treatment

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is still hampered by a dismal prognosis. A better understanding of the tumor microenvironment within the pancreas and of the factors affecting its composition is of utmost importance for developing new diagnostic and treatment tools. In this context, the complement system plays a prominent role. Not only has it been shown to shape a T cell-mediated immune response, but it also directly affects proliferation and apoptosis of the tumor cells, influencing angiogenesis, metastatic spread and therapeutic resistance. This makes complement proteins appealing not only as early biomarkers of PDAC development, but also as therapeutic targets. Fungal dysbiosis is currently the new kid on the block in tumorigenesis with cancer-associated mycobiomes extracted from several cancer types. For PDAC, colonization with the yeast Malassezia seems to promote cancer progression, already in precursor lesions. One responsible mechanism appears to be complement activation via the lectin pathway. In the present article, we review the role of the complement system in tumorigenesis, presenting observations that propose it as the missing link between fungal dysbiosis and PDAC development. We also present the results of a small pilot study supporting the crucial interplay between the complement system and Malassezia colonization in PDAC pathogenesis.

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Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis

Cited by 57 publications

References 65 publications

Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

Intracellular complement: Evidence, definitions, controversies, and solutions

Complement and Fungal Dysbiosis as Prognostic Markers and Potential Targets in PDAC Treatment

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