A possible novel anti-cancer treatment targeting CCL3-CCR5 interaction

• Project/Area Number: 15K18406
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kanazawa University
• Principal Investigator: Sasaki Soichiro 金沢大学, がん進展制御研究所, 助教 (50583473)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 大腸がん / CCR5 / マラビロック / 線維芽細胞

Outline of Final Research Achievements

We previously demonstrated that locally-produced CCL3 induce the intra-tumoral accumulation of cancer-associated fibroblast (CAFs), which express CCR5, a specific receptor for CCL3. Based on these observations, we examined the effect of a CCR5 antagonist, maraviroc, on tumor growth arising from intra-cecal injection of either a mouse or a human colon cancer cell line. Oral administration of maraviroc after tumor injection decreased tumor sizes with reductions in numbers of CAFs and epidermal growth factor (EGF) expression by CAFs, but with few effects on leukocyte infiltration. Consistently, CCL3 in vitro induced fibroblasts to migrate and to express EGF, and maraviroc reduced these in vitro effects of CCL3 on fibroblasts. These observations would indicate the potential of maraviroc or other CCR5 inhibitors as a novel therapeutic modality for colon cancer, by targeting the CCL3-CCR5 interaction.

Research Products

• [Journal Article] Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis. (2016)
  • Author(s): Sasaki S, Baba T, Nishimura T, Hayakawa Y, Hashimoto S, Gotoh N, Mukaida N.
  • Journal Title: Cancer Lett. Volume: 378 Issue: 1 Pages: 23-32
  • DOI: 10.1016/j.canlet.2016.05.005
  • NAID: 120005764205
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancer-associated fibroblast accumulation. (2016)
  • Author(s): Tanabe Y, Sasaki S, Mukaida N, Baba T.
  • Journal Title: Oncotarget Volume: 7 Issue: 30 Pages: 48335-345
  • DOI: 10.18632/oncotarget.10227
  • NAID: 120006996025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fibroblasts, an inconspicuous but essential player in colon cancer development and progression. (2016)
  • Author(s): Mukaida N, Sasaki S.
  • Journal Title: World J Gastroenterol Volume: 22 Issue: 23 Pages: 5301-16
  • DOI: 10.3748/wjg.v22.i23.5301
  • NAID: 120005851382
  • Open Access
• [Journal Article] Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization. (2015)
  • Author(s): Song Y, Baba T, Li YY, Furukawa K, Tanabe Y, Matsugo S, Sasaki S, Mukaida N.
  • Journal Title: Biochem Biophys Res Commun Volume: 458 Issue: 2 Pages: 341-346
  • DOI: 10.1016/j.bbrc.2015.01.112
  • NAID: 120005593940
  • Peer Reviewed
• [Journal Article] High-dose cyclophosphamide induces specific tumor immunity with concomitant recruitment of LAMP1/CD107a-expressing CD4-positive T cells into tumor sites. (2015)
  • Author(s): Naito, T., Baba, T., Takeda, K., Sasaki, S., Nakamoto, Y. and Mukaida, N.
  • Journal Title: Cancer Letters Volume: 366 Issue: 1 Pages: 93-99
  • DOI: 10.1016/j.canlet.2015.06.009
  • NAID: 120005663501
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Breast cancer cells derived inflammatory chemokine, CCL4, drive the bone metastasis in paracrine manner (2016)
  • Author(s): Sasaki S, Baba T, and Mukaida N.
  • Organizer: 第75回日本癌学会学術集会・総会
  • Place of Presentation: パシフィコ横浜、神奈川
  • Year and Date: 2016-10-06
• [Presentation] Blockade of a chemokine receptor, CCR5, reduces colon cancer growth by inhibiting cancer-associated fibroblast. (2016)
  • Author(s): Tanabe Y, Sasaki S, Baba T, and Mukaida N.
  • Organizer: 第75回日本癌学会学術集会・総会
  • Place of Presentation: パシフィコ横浜、神奈川
  • Year and Date: 2016-10-06
• [Presentation] 乳がんの骨転移過程におけるケモカインCCL4と線維芽細胞の関与 (2016)
  • Author(s): 佐々木宗一郎、馬場智久、向田直史
  • Organizer: 第25回日本がん転移学会学術集会・総会
  • Place of Presentation: 米子コンベンションセンター、鳥取
  • Year and Date: 2016-07-21
  • Invited
• [Presentation] 乳癌骨転移における腫瘍由来CCL4と骨内CCR5発現線維芽細胞の相互作用 (2016)
  • Author(s): 佐々木宗一郎、馬場智久、向田直史
  • Organizer: 第19回癌と骨病変研究会
  • Place of Presentation: 千代田放送会館、東京
  • Invited
• [Presentation] Tumor-derived CCL4 enhanced migration ability of mammary tumor cell lines to bone marrow in a paracrine manner (2015)
  • Author(s): Sasaki S, Baba T and Mukaida N.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] 炎症性ケモカインCCL4は傍分泌型にマウス乳がん細胞株の骨転移を促進する (2015)
  • Author(s): 佐々木宗一郎、馬場智久、向田直史
  • Organizer: 第74回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] CCL4-CCR5 interacitons have pivotal roles in survival of a murine breast cancer cell line in osseous envirionment (2015)
  • Author(s): Sasaki S, Baba T and Mukaida N
  • Organizer: 12th World Congress on Inflammation
  • Place of Presentation: Seaport Hotel and World Trade Center (Boston)
  • Year and Date: 2015-08-08
  • Int'l Joint Research
• [Remarks] 大腸がん発症進展過程での腫瘍関連線維芽細胞（CAF)の役割
  • URL: http://ganken.cri.kanazawa-u.ac.jp/bunsiseitai/JapRecentAchievement-02.html