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

Yoneda,Masakazu; Imamura,Ryuji; Nitta,Hidetoshi; Taniguchi,Keisuke; Saito,Fumitaka; Kikuchi,Ken; Ogi,Hidenao; Tanaka,Takuya; Katabuchi,Hidetaka; Nakayama,Hideki; Imamura,Takahisa

doi:10.3892/ol.2018.9715

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

Authors:
- Masakazu Yoneda
- Ryuji Imamura
- Hidetoshi Nitta
- Keisuke Taniguchi
- Fumitaka Saito
- Ken Kikuchi
- Hidenao Ogi
- Takuya Tanaka
- Hidetaka Katabuchi
- Hideki Nakayama
- Takahisa Imamura
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Affiliations: Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan, Department of Gastroenterological Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan, Pharmaceutical Research Department, Yakult Central Institute for Microbiological Research, Tokyo 186‑8650, Japan, Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan, Operations Division, Sakurajyuji Hospital, Kumamoto 861‑4173, Japan, Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan
Published online on: November 16, 2018 https://doi.org/10.3892/ol.2018.9715
Pages: 913-920
Copyright: © Yoneda et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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