targeting strategy for chemokine signaling in colorectal cancer microenvironment

• Project/Area Number: 19K09170
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyoto University
• Principal Investigator: Kawada Kenji 京都大学, 医学研究科, 准教授 (90322651)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 大腸癌 / ケモカイン / 転移 / 骨髄細胞 / 腫瘍微小環境 / 骨髄球 / CCR1 / CXCR2

Outline of Research at the Start

本研究では、大腸癌においてSMAD4欠損を起因とするTGF-betaシグナル異常が腫瘍微小環境におよぼす影響について、1)CCL15-CCR1、2）CXCL1/8-CXCR2の2つのケモカイン・シグナルと骨髄球集簇の観点から解析を行い、それらが新規治療ターゲットになりえるかを検証する。
前臨床試験として同系マウスモデルを用いたin vivo実験で 検討することを予定している。あわせて、大腸癌患者血液および大腸癌組織からFACSで好中球を単離して、その機能解析を進めることも予定している。

Outline of Final Research Achievements

In two syngeneic mouse models (MC38 transplanted tumor model and CMT93 liver metastasis model), lack of the Ccr1 gene in host mice dramatically reduced MC38 tumor growth as well as CMT93 liver metastasis. We further investigated the role of CCR1 depletion in myeloid cells using bone marrow (BM) transfer experiments, and found that mice reconstituted with Ccr1-/- BM exhibited marked suppression of MC38 tumor growth and CMT93 liver metastasis. Consistent with these results, administration of a neutralizing anti-CCR1 Ab significantly suppressed MC38 tumor growth and CMT93 liver metastases.
Using clinical specimens and human colorectal caner (CRC) cell lines, we found that loss of SMAD4 from CRC cells resulted in the secretion of CXCL1 and CXCL8 to recruit CXCR2+ neutrophils, and that, in turn, the recruited neutrophils abundantly produced CXCL1 and CXCL8, which could help to further accumulate CXCR2+ neutrophils. Serum CXCL8 levels in CRC patients were associated with patients’ prognosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では大腸癌において癌抑制遺伝子SMAD4欠損を起因とするTGF-betaシグナル異常が癌微小環境における骨髄球集簇にどのように関与するかに焦点を当てて、①CCR1+骨髄球をターゲットにしたCCL15-CCR1シグナル、②CXCR2+好中球をターゲットとしたCXCL1/8-CXCR2シグナル、の２つのケモカイン・シグナルが大腸癌に対する新規治療ターゲットになりうる可能性が示唆された。

Research Products

• [Journal Article] Disruption of CCR1-mediated myeloid cell accumulation suppresses colorectal cancer progression in mice (2020)
  • Author(s): Kiyasu Yoshiyuki、Kawada Kenji、Hirai Hideyo、Ogawa Ryotaro、Hanada Keita、Masui Hideyuki、Nishikawa Gen、Yamamoto Takamasa、Mizuno Rei、Itatani Yoshiro、Kai Masayuki、Taketo Makoto Mark、Sakai Yoshiharu
  • Journal Title: Cancer Letters Volume: 487 Pages: 53-62
  • DOI: 10.1016/j.canlet.2020.05.028
  • NAID: 120006878497
  • Peer Reviewed
• [Journal Article] Loss of SMAD4 Promotes Colorectal Cancer Progression by Recruiting Tumor-Associated Neutrophils via the CXCL1/8-CXCR2 Axis. (2019)
  • Author(s): Ogawa R, Yamamoto T, Hirai H, Hanada K, Kiyasu Y, Nishikawa G, Mizuno R, Inamoto S, Itatani Y, Sakai Y, Kawada K.
  • Journal Title: Clinical Cancer Research Volume: － Issue: 9 Pages: 2887-2899
  • DOI: 10.1158/1078-0432.ccr-18-3684
  • Peer Reviewed