Complement tumor-crosstalk: the role of C5a receptors in urothelial carcinomas

Urothelial carcinoma, the second most common urological malignancy, can arise in both the lower and upper urinary tract, with approximately 90-95% arising in the bladder, while urothelial carcinomas of the upper urinary tract account for only 5-10%. Treatment options depend on many factors, such as grade and risk factors, but include surgery, chemotherapy, and immunotherapy. Due to the unique pathological and molecular characteristics of each patient, some therapies are ineffective, and the need for targeted therapies and precision medicine is growing. The interactions of malignant cells within the tumor microenvironment can be decisive for the course of therapy. These interactions include components of the complement system, which is a highly conserved part of the innate immune system. The role of the complement system, especially the anaphylatoxin receptors C5aR1 and C5aR2, in cancer is complex. C5aR1 appears to be tumor-promoting by inhibiting the T cell response and modulating the TME, while C5aR2 plays an ambivalent role and was shown to counteract tumor development in some mouse models while in other types of cancer it stimulated tumor growth and led to chemoresistance. In urothelial carcinomas, C5aR1 has been described as a prognostic factor, while C5aR2 has not been considered to date. Here, we briefly summarize our current knowledge of the complex functions of C5a receptors in cancer. In particular, this is the first focused summary of data on C5a receptors in urothelial carcinomas.