Enhancement of cancer invasion and growth via the C5a‑C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion

Abstract

Autoimmune diseases are caused by immune complex-induced activation of the complement system and subsequent inflammation. Recent studies have revealed an association between autoimmune diseases and worse survival in patients with cancer; however, the underlying mechanism is still unknown. The C5a-C5a receptor (C5aR) system has been shown to enhance cancer activity and recruit myeloid-derived suppressor cells (MDSCs) that suppress the anti-tumor immune response. The Arthus reaction is inflammation caused by complement system activation by the immune complex and thus is a model of autoimmune diseases. To explore the effect of the Arthus reaction on cancer progression, mouse cancer cells were inoculated in syngeneic mouse skin, where the Arthus reaction was induced simultaneously. The Arthus reaction enhanced invasion and tumor growth of C5aR-positive cancer cells, but not control cells, and induced MDSC recruitment. Intravenous injection of C5a-stimulated C5aR-positive cancer cells into nude mice resulted in more lung nodules than injection of nontreated C5aR-positive cells and C5a-stimulated C5aR-negative cells, supporting C5a-C5aR-mediated enhancement of cancer growth. C5aR expression in uterine cervical carcinoma stage I cells, which invade into the deeper tissues, was significantly higher than that in CIN3 cells, which remain in the epithelium. These results indicate that cancer promotion by the C5a-C5aR system may underlie poor prognosis in cancer patients with autoimmune diseases, particularly in patients with C5aR-positive cancer, and may be associated with cervical cancer invasion. The enhancement of cancer cell invasion and growth by the C5a-C5aR system suggests that this system is a possible target of cancer therapy.

Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD‐L1 expression by C5a

“…The two effects of C5a on CRPC cells were measured after an incubation for 24 h in the presence of C5a, thus C5a is influential in CRPC cell invasion rather than proliferation. The predominant effect of C5a on CRPC invasion over proliferation appears to agree with an observation from a mouse study, which endogenous C5a promoted cancer cell spread much earlier than tumor growth when C5aR‐positive mouse cancer cells were inoculated into the mouse skin 22 …”

“…The C5a ability to increase the CRPC PD‐L1 expression, together with the promotion of CRPC proliferation and invasion, seems to be consistent with that a combined PD‐1/C5a blockade synergistically protected lung cancer growth and metastasis in a mouse model 29 . Furthermore, C5a recruits the myeloid‐derived suppressor cells (MDSC), 12,22 which inhibit the antitumor CD8 + T‐cell response 12 and can express PD‐L1, 43 to cancer tissues 11 . It is possible that C5a elevates the MDSC expression of PD‐L1 via C5aR, thereby increasing the opportunity for CRPC cells to evade the antitumor immune responses.…”

“…Furthermore, we revealed that cancer cells were able to release C5a directly from C5 by a cell membrane protease and promoted a C5aR‐expressing cancer cell invasiveness by the C5a, 16 suggesting a self‐activation circuit via the C5a–C5aR system in the cancer cells that express C5aR and possess the protease on the cell surface. We also showed that the C5a–C5aR system was associated with cancer growth, invasion, metastasis, and poor prognosis of the patients with cancers of the breast, stomach, kidneys, urinary tract, and uterus cervix 17–22 . Thus, the C5a signal via C5aR can be linked to cancer progression and this system is therefore a possible target for cancer therapy.…”

“…For C5aR detection, sections were incubated with the primary mouse immunoglobulin G (IgG) against human C5aR (2 µg/ml; Hycult Biotechnology) or nonspecific mouse IgG (2 µg/ml; Dako Cytomation) at room temperature for an hour, followed by staining using the EnVision+ solution (Dako Cytomation) and 3,3'‐diaminobenzidine tetrahydrochloride solution containing 0.006% H 2 O 2 , as previously reported 15 . For each section, high or low C5aR expression was defined as C5aR‐positive cell area >30% or 0%–30% of the total cancer cell area, respectively, according to previous methods 22,32,33 . For PD‐L1 detection, sections were autoclaved at 120°C for 20 min and cooled slowly, followed by a treatment with 0.3% H 2 O 2 in methanol for 20 min and 2.5% normal horse serum for 20 min.…”

Potential Role of Myeloid-Derived Suppressor Cells (MDSCs) in Age-Related Macular Degeneration (AMD)

“…In addition to direct receptor binding, C5a can stimulate MDSCs also indirectly through IL-6, IL-1β, or VEGF (131). The role of C5a in cancer promotion is well known, and it is also considered as a key player in poor cancer prognosis on subjects suffering from an autoimmune disease with complement activation by immune complexes (the Arthus reaction) (132). According to a recent discovery, CFH(Y402H) also efficiently binds CD11b, preventing CD47-mediated elimination of mononuclear cells, such as macrophages and microglia, attracted to the subretinal space between the RPE and photoreceptor outer segments to restore homeostasis (133,134).…”