Novel strategy focusing on bone marrow-derived cells in the tumor microenvironment

• Project/Area Number: 16K10537
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto University
• Principal Investigator: KAWADA KENJI 京都大学, 医学研究科, 講師 (90322651)
• Research Collaborator: TAKETO makoto ; HIRAI hideyo
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ケモカイン / 大腸癌 / 転移 / 骨髄由来細胞 / 好中球 / 間葉系幹細胞 / 小腸大腸肛門外科学

Outline of Final Research Achievements

In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1+ cells, promoting their metastatic activities to the lung. Immunohistochemical analysis of clinical samples revealed that CCL15 expression was significantly correlated with loss of SMAD4, and that CCL15-positive lung metastases recruited more numbers of CCR1+ cells than CCL15-negative metastases. Importantly, CCL15 expression was an independent predictor of shorter relapse-free survival.
We found that CCR5 ligands (i.e., CCL3/4/5) were highly produced from mesenchymal stem cells (MSCs) using a chemokine array screening. The xenografts in which CCR5-overexpressing HCT116 cells were highly promoted in vivo by a mixture with MSCs. Notably, the CCR5 inhibitor significantly abolished the MSC-induced tumor growth in vivo. In human clinical specimens, CCR5 expression was associated with patients’ prognosis. Especially, stage III/IV patients exhibited a significantly poorer prognosis.

Academic Significance and Societal Importance of the Research Achievements

大腸癌肺転移では、SMAD4の欠損によりCCL15の発現が誘導されCCR1陽性好中球が転移巣周囲に集積し、肺転移が促進されることが示唆された。肺転移巣周囲に集積するCCR1陽性好中球は大腸癌肺転移にたいする新規の治療ターゲットとなり得る。
CCR5発現は病期の進んだ大腸癌症例において予後不良因子であり、またそのリガンドであるCCL3,CCL4の血清高値は予後不良のバイオマーカーになりえる。大腸癌においてCCR5が新たな治療ターゲットとなり得る可能性が示唆された。

Research Products

• [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
• [Journal Article] Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. (2019)
  • Author(s): Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, Mizuno R, Itatani Y, Sakai Y.
  • Journal Title: Cell Death & Disease Volume: 10 Issue: 4 Pages: 264-264
  • DOI: 10.1038/s41419-019-1508-2
  • NAID: 120006596558
  • Peer Reviewed / Open Access
• [Journal Article] Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-associated Neutrophils through CCL15-CCR1 Axis (2017)
  • Author(s): Yamamoto T, Kawada K, Itatani Y, Inamoto S, Okamura R, Iwamoto M, Miyamoto E, Chen-Yoshikawa TF, Hirai H, Hasegawa S, Date H, Taketo MM, Sakai Y.
  • Journal Title: Clinical Cancer Research Volume: 23 Issue: 3 Pages: 833-844
  • DOI: 10.1158/1078-0432.ccr-16-0520
  • Peer Reviewed / Open Access / Acknowledgement Compliant