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C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack of effective preventive treatments. Here, we investigated the role of complement system, a key regulator of immune surveillance and homeostasis, in colorectal tumorigenesis. 

Methods: The prototypical CRC model was induced by combined administration of azoxymethane (AOM)/ dextran sulfate sodium (DSS) in Wild-type (WT), C3-, C5-, C5ar1-, and C5ar2-deficient mice. Using flow cytometry, immunohistochemical staining and multiplex bead assay, we profiled the immune cells, cytokines and chemokines. Bone marrow transplantation was employed to determine the contribution of immune cells in colorectal tumorigenesis. Further, we used C5aR1 antagonist PMX205 to investigate the protective role in colorectal tumorigenesis. 

Results: Complement was extensively activated in inflamed tissues of AOM/DSS-induced murine CRC model, leading to multifaceted consequences. The deficiency of complement C5 or especially C5ar1, but not C3 almost completely prevented CRC tumorigenesis. C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8+ T cells, and modulated the production of critical cytokines and chemokines, thus initiating CRC. Moreover, the C5aR1 antagonist PMX205 strongly impeded colorectal tumorigenesis. Bone marrow transplantation further revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis. 

Conclusion: Our study identifies C5a/C5aR1 signaling as a vital immunomodulatory program in CRC tumorigenesis and suggests a feasible preventive strategy.

 

Comments:

The study you described investigates the role of the complement system in colorectal tumorigenesis using a mouse model of colorectal cancer (CRC) induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) administration. The complement system is a key regulator of immune surveillance and homeostasis. The researchers aimed to determine the specific mechanisms through which the complement system contributes to CRC development and explore potential preventive strategies.

In the study, the researchers analyzed the immune cells, cytokines, and chemokines present in the inflamed tissues of the CRC mouse model. They found that the complement system was extensively activated in these tissues, leading to various consequences. Interestingly, the deficiency of complement component C5 or its receptor C5aR1 (but not C3) significantly prevented CRC tumorigenesis in the mice.

The researchers discovered that C5a, a complement component, and its receptor C5aR1 played crucial roles in the development of CRC. C5a/C5aR1 signaling recruited myeloid-derived suppressor cells (MDSCs) into the inflamed colorectal tissue, which impaired the function of CD8+ T cells, a type of immune cell involved in tumor surveillance. Additionally, C5a/C5aR1 signaling influenced the production of important cytokines and chemokines involved in CRC development.

To further investigate the contribution of immune cells, the researchers conducted bone marrow transplantation experiments. They found that the expression of C5aR1 by immune cells was critical for colorectal tumorigenesis, suggesting that immune cell-mediated processes are involved in CRC development.

Finally, the researchers used a C5aR1 antagonist called PMX205 to assess its potential protective role in CRC tumorigenesis. The antagonist significantly impeded the development of colorectal tumors, suggesting that targeting C5aR1 may be a viable preventive strategy for CRC.

In conclusion, this study highlights the importance of C5a/C5aR1 signaling in CRC tumorigenesis. The activation of complement components in inflamed colorectal tissue leads to the recruitment of MDSCs, impairment of CD8+ T cells, and modulation of cytokine and chemokine production, ultimately promoting CRC development. The findings suggest that targeting C5aR1 or the complement system could serve as a potential preventive approach for colorectal cancer.

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P1208 PMX 205 acetate

PMX 205 acetate is a cyclic hexapeptide that acts as a potent C5a receptor (C5aR, CD88) antagonist with an IC50 of 31 nM.

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