establishment of cancer treatment targeting C5a receptor and proteinase releaed by cancer cells

• Project/Area Number: 16K10503
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: NITTA Hidetoshi 熊本大学, 医学部附属病院, 非常勤診療医師 (90555749)
• Co-Investigator(Kenkyū-buntansha): 石本 崇胤 熊本大学, 医学部附属病院, 特任准教授 (00594889) ; 岩槻 政晃 熊本大学, 大学院生命科学研究部(医), 助教 (50452777) ; 小澄 敬祐 熊本大学, 医学部附属病院, 非常勤診療医師 (50594884) ; 藏重 淳二 熊本大学, 医学部附属病院, 非常勤診療医師 (90594474)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 補体C5a / C5a受容体 / 肝星細胞 / 大腸癌肝転移 / 肝stellate cell / CAFs / C5a / C5aR

Outline of Final Research Achievements

The aim of this study was to evaluate a tumor-stromal interaction via C5aR in colorectal liver metastasis. Several human colon cancer cell lines and HSC cell line (LX2) expressed C5a receptor. C5a increasedαSMA expression on HSC in time dependent manner, which suggested that C5a activated HSC via C5a receptor. Moreover, invasion assay analysis revealed that the activated HSC by C5a enhanced invasiveness of human cancer cells.
These results illustrate a novel activity of the C5a-C5aR axis that promotes cancer cell invasion through activation of HSC. Targeting this signaling pathway may provide a useful therapeutic option for colorectal liver metastasis treatment.

Academic Significance and Societal Importance of the Research Achievements

大腸癌肝転移は近年増加の一途をたどっており、新規抗癌剤・分子標的薬の導入で生存期間は延びてきているが治癒にいたることは稀であり、新たな治療法の確立が望まれる。今回の研究結果において肝星細胞（HSC）は免疫系を担う補体の一種であるC5aで活性化し、C5aにより活性化したHSCは癌細胞の浸潤能を亢進させることが分かった。
よってC5a-C5aRをターゲットとすること（C5aR-antagonist等）により癌の進展を抑制させる可能性があり新しい大腸癌肝転移の治療につながる可能性がある。

Research Products

• [Journal Article] Impact of Repeated Hepatectomy on Liver Regeneration in Hepatocellular Carcinoma: A Propensity Score-based Analysis (2019)
  • Author(s): ARIMA KOTA、NITTA HIDETOSHI、BEPPU TORU、NAKAGAWA SHIGEKI、OKABE HIROHISA、IMAI KATSUNORI、CHIKAMOTO AKIRA、YAMASHITA YO-ICHI、YAMASHITA YASUYUKI、BABA HIDEO
  • Journal Title: Anticancer Research Volume: 39 Issue: 2 Pages: 965-970
  • DOI: 10.21873/anticanres.13200
  • Peer Reviewed
• [Journal Article] 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. (2019)
  • Author(s): Yoneda M, Imamura R, Nitta H, Taniguchi K, Saito F, Kikuchi K, Ogi H, Tanaka T, Katabuchi H, Nakayama H, Imamura T.
  • Journal Title: Oncol Lett. Volume: 17 Pages: 913-20
  • DOI: 10.3892/ol.2018.9715
  • Peer Reviewed
• [Journal Article] Serum Marker Score Based on Prognostic Nutrition Index, Carcinoembryonic Antigen, and Carbohydrate Antigen 19-9 Is Associated With Recurrence for Patients Undergoing Surgery for Pancreatic Ductal Adenocarcinoma (2018)
  • Author(s): Nakagawa Shigeki、Yamashita Yo-ichi、Umezaki Naoki、Yamao Takanobu、Okabe Hirohisa、Imai Katsunori、Nitta Hidetoshi、Hashimoto Daisuke、Chikamoto Akira、Baba Hideo
  • Journal Title: Pancreas Volume: 47 Issue: 9 Pages: 1130-1134
  • DOI: 10.1097/mpa.0000000000001146
  • Peer Reviewed
• [Journal Article] Clinical significance of half-lives of tumor markers α-fetoprotein and des-γ-carboxy prothrombin after hepatectomy for hepatocellular carcinoma. (2018)
  • Author(s): Tsukamoto M, Nitta H, Imai K, Higashi T, Nakagawa S, Okabe H, Arima K, Kaida T, Taki K, Hashimoto D, Chikamoto A, Ishiko T, Beppu T, Baba H
  • Journal Title: Hepatol Res. Volume: 48 Issue: 3
  • DOI: 10.1111/hepr.12942
  • Peer Reviewed
• [Journal Article] Pre-treatment double- or triple-positive tumor markers are predictive of a poor outcome for patients undergoing radiofrequency ablation for hepatocellular carcinoma. (2017)
  • Author(s): itta H, Nakagawa S, Kaida T, Arima K, Higashi T, Taki K, Okabe H, Hayashi H, Hashimoto D, Chikamoto A, Ishiko T, Beppu T, Baba H.
  • Journal Title: Surg Today Volume: 47(3) Issue: 3 Pages: 375-384
  • DOI: 10.1007/s00595-016-1385-6
  • Peer Reviewed
• [Journal Article] Preoperative platelet-to-lymphocyte ratio can predict recurrence beyond the Milan criteria after hepatectomy for patients with hepatocellular carcinoma. (2016)
  • Author(s): Kaida T, Nitta H, Kitano Y, Yamamura K, Arima K, Higashi T, Taki K, Nakagawa S, Okabe H, Hayashi H, Imai K, Hashimoto D, Yamashita YI, Chikamoto A, Ishiko T, Beppu T, Baba H.
  • Journal Title: Hepatol Res Volume: Epub ahead of print Issue: 10 Pages: 991-999
  • DOI: 10.1111/hepr.12835
  • Peer Reviewed
• [Journal Article] C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA. (2016)
  • Author(s): Kaida T, Nitta H, Kitano Y, Yamamura K, Arima K, Izumi D, Higashi T, Kurashige J, Imai K, Hayashi H, Iwatsuki M, Ishimoto T, Hashimoto D, Yamashita Y, Chikamoto A, Imanura T, Ishiko T, Beppu T, Baba H.
  • Journal Title: Oncotarget. Volume: 20(7) Issue: 51 Pages: 84798-84809
  • DOI: 10.18632/oncotarget.12656
  • Peer Reviewed
• [Journal Article] Degenerative hepatic hemangioma mimicking biliary cystadenocarcinoma. (2016)
  • Author(s): Kaida T, Higashi T, Kitano Y, Yamamura K, Arima K, Taki K, Imai K, Nitta H, Hashimoto D, Chikamoto A, Namimoto T, Nakahara O, Beppu T, Baba H
  • Journal Title: J Gastroenterol Hepatol Volume: 31(8) Issue: 8 Pages: 1385-1385
  • DOI: 10.1111/jgh.13325
  • Peer Reviewed
• [Journal Article] Expression of anaphylatoxin C5a receptor in gastric cancer: Implications with vascular invasion and patient outcome. (2016)
  • Author(s): Nitta, H., Shimose, T., Emi, Y., Imamura, T., Ohnishi, K., Kusumoto, T., Yamamoto. M., Fukuzawa, K., Takahashi, I., Higashi, H., Tsuji, A., Akagi, Y., Oki, E., Maehara, Y., & Baba, H.
  • Journal Title: Med. Oncol. Volume: 33 Issue: 11 Pages: 118-118
  • DOI: 10.1007/s12032-016-0834-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Chemotherapy-induced Nausea and Vomiting in Patients with Hepatobiliary and Pancreatic Cancer Treated with Chemotherapy: A Prospective Observational Study by the CINV Study Group of Japan. (2016)
  • Author(s): Nitta H, Baba H, Sugimori K, Furuse J, Ohkawa S, Yamamoto K, Minami H, Shimokawa M, Wakabayashi GO, Aiba K, Japan CSGo
  • Journal Title: Anticancer Res Volume: 36(4) Pages: 1929-35
  • Peer Reviewed
• [Presentation] Assessment and validation of functional liver resection rate considering venous occlusive area after extended hepatectomy. (2018)
  • Author(s): Hidetoshi Nitta, Toshihiko Yusa, Yosuke Nakao, Rumi Itoyama, Yuki Kitano, Shigeki Nakagawa, Hirohisa Okabe, Katsunori Imai, Yo-ichi Yamashita, Akira Chikamoto, Hideo Baba.
  • Organizer: The 30th Meeting of Japanese Society of Hepato-Biliary Pancreatic Surgery.
• [Presentation] Prognostic value and prediction of extra-tumoral microvascular invasion among candidates for hepatectomy or liver transplantation for HCC. (2017)
  • Author(s): Hidetoshi Nitta, Marc-Antoine Allard, Gabriella Pittau, Oriana Ciacio, Eric Vibert, Antonio Sa Cunha, Daniel Cherqui, Denis Castaing, Henri Bismuth, Hideo Baba, and Rene Adam
  • Organizer: EASL2017
  • Int'l Joint Research
• [Presentation] Predictive model for microvascular invasion of hepatocellular carcinoma among candidates for either hepatectomy or liver transplantation. (2017)
  • Author(s): Hidetoshi Nitta, Marc-Antoine Allard, Mylène Sebagh, Gabriella Pittau, Oriana Ciacio, Eric Vibert, Antonio Sa Cunha, Daniel Cherqui, Denis Castaing, Henri Bismuth, Catherine Guettier, Didier Samuel, Hideo Baba, and Rene Adam
  • Organizer: ASCO2017
  • Int'l Joint Research
• [Presentation] Analysis of risk factors of early recurrence and ideal surgical margin for hepatocellular carcinoma. (2017)
  • Author(s): Hidetoshi Nitta, Marc-Antoine Allard, Mylene Sebagh, Oriana Ciacio, Gabriella Pittau, Eric Vibert, Antonio Sa Cunha, Daniel Cherqui, Denis Castaing, Henri Bismuth, Hideo Baba, and Rene Adam
  • Organizer: ESMO GI 2017
  • Int'l Joint Research
• [Presentation] Establishment of predictive model for microvascular invasion of hepatocellular carcinoma and Clinical usage of the model for decision of surgical strategy. (2017)
  • Author(s): Hidetoshi Nitta, Marc-Antoine Allard, Mylene Sebagh, Gabriella Pittau, Oriana Ciacio, Eric Vibert, Antonio Sa Cunha, Daniel Cherqui, Denis Castaing, Henri Bismuth, Catherine Guettier, Didier Samuel, Hideo Baba, and Rene Adam
  • Organizer: ILTS2017
  • Int'l Joint Research
• [Presentation] Prognostic value and prediction of extra-tumoral microvascular invasion among candidates for hepatectomy or liver transplantation for HCC. (2017)
  • Author(s): H. Nitta , M.-A. Allard , G. Pittau , O. Ciacio , E. Vibert , A.S. Cunha , D. Cherqui , D. Castaing , H. Bismuth , H. Baba , R. Adam
  • Organizer: EASL2017
  • Place of Presentation: Amsterdam, Netherlands
  • Int'l Joint Research