Biological role of metadherin in liver metastases of colon cancer and development of novel molecular target therapy

• Project/Area Number: 19K09134
• 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: Teikyo University
• Principal Investigator: Shimizu Hiroaki 帝京大学, 医学部, 教授 (80272318)
• Co-Investigator(Kenkyū-buntansha): 幸田 圭史 帝京大学, 医学部, 教授 (50260477) ; 山崎 一人 帝京大学, 医学部, 教授 (60302519) ; 小杉 千弘 帝京大学, 医学部, 講師 (60375681) ; 細川 勇 帝京大学, 医学部, 助教 (60623676) ; 首藤 潔彦 帝京大学, 医学部, 准教授 (90372359) ; 野島 広之 帝京大学, 医学部, 講師 (10507320) ; 村上 崇 帝京大学, 医学部, 助教 (80621870)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 大腸癌 / 肝転移 / メタドヘリン / Snail1 / 上皮間葉転換 / メタドへリン / 転移性肝癌 / 上皮間葉転移 / 間葉上皮転移

Outline of Research at the Start

本研究では、癌転移制御の key molecule としてメタドヘリン（MTDH）に注目し、まず、大腸癌細胞を用いてin vitro でのMTDH機能解析として１）EMT-MET plasticityの観点からphenotypic switchへの関連、２）stemness, anoikis resistanceを行う。 さらに、当院の外科切除された大腸癌原発巣の切除標本を用いてMTDH発現の臨床病理学的特徴、患者予後、再発転移形式を検討、肝転移症例では原発巣、肝転移巣におけるMTDH発現を比較検討し、原発巣から肝転移形成過程におけるMTDHの生物学的役割を解明する。

Outline of Final Research Achievements

Metadherin（MTDH） and Snail1 are known to be key molecules in epithelial-mesenchymal transition(EMT) and an important process in cancer metastasis. To investigate clinical significance of EMT markers in colorectal cancer (CRC), especially relation between the expression of MTDH and Snail1 in CRC/liver metastasis and clinical outcome. Surgically resected specimens were investigated the expression of MTDH and Snail1 by immunohistochemical staining. Results: MTDH was strongly expressed in the liver metastasis, as compared to the primary CRC.Expression of Snail1 in the primary CRC with liver metastasis was significantly increased, as compared to CRC without liver metastasis. Furthermore, high Snail1 expression in liver metastases was associated with poor prognosis. These results suggest that EMT may strongly contribute to the mechanism of liver metastasis from primary CRC. Furthermore, high Snail1 expression in liver metastasis may be a significant prognostic factor after hepatectomy.

Academic Significance and Societal Importance of the Research Achievements

本研究では大腸癌の原発巣、肝転移巣を一連の実験系で検討し、肝転移メカニズムを考察することを主眼とする。転移浸潤過程でのMTDH/Snail1の転移制御機構における役割が明らかとなれば、それに応じた intervention による治療戦略の可能性も考えられる。つまり、MIDH、Snail1 を ターゲットとした治療を確立することで現行の化学療法とは異なった視点から、肝転移再発の抑制に対しての治療が考えられる。また、癌の浸潤転移のメカニズムに重要な上皮間葉転換（EMT）は、癌の転移に関する普遍 的な分子機構の謎を解く上で非常に有用であり、今後の新しい癌治療への展開の可能性切り開くものと考える。

Research Products

• [Journal Article] Sphingosine-1-phosphate Receptor-1 Promotes Vascular Invasion and EMT in Hepatocellular (2021)
  • Author(s): Yokota T, Nojima H, Kuboki S, Yoshitomi H, Furukawa K, Takayashiki T, Takano S, Ohtsuka M.
  • Journal Title: J Surg Res Volume: 259 Pages: 200-210
  • Peer Reviewed
• [Journal Article] Multicenter phaseⅡ clinical study of the efficiency and safety of capecitabine plus intermittent oxaliplatin with bevacizumab as first-line therapy in patients with metastatic colorectal cancer(VOICE trial) (2021)
  • Author(s): Kosugi C, Koda K, Denda T, Ishibashi K, Ishida H, Seike K, Sakata H, Yanagisawa S, Miyazaki A, Takayama W, Koike N, Shimizu H, Matsubara H.
  • Journal Title: Int J Colorectal Dis. Volume: 76 Issue: 12 Pages: 2637-2647
  • DOI: 10.1007/s00384-021-03995-7
  • Peer Reviewed
• [Journal Article] Liver Transection-First Approach in Left Trisectionectomy for Perihilar Cholangiocarcinoma (2020)
  • Author(s): Hosokawa Isamu、Shimizu Hiroaki、Ohtsuka Masayuki、Miyazaki Masaru
  • Journal Title: Annals of Surgical Oncology Volume: 27 Issue: 7 Pages: 2381-2386
  • DOI: 10.1245/s10434-020-08306-y
• [Journal Article] Right intersectional transection plane based on portal inflow in left trisectionectomy. (2019)
  • Author(s): Hosokawa I, Ohtsuka M, Yoshitomi H, Furukawa K, Miyazaki M, Shimizu H.
  • Journal Title: Surgical and Radiologic Anatomy Volume: 41 Issue: 5 Pages: 489-498
  • DOI: 10.1007/s00276-018-2135-9
  • Peer Reviewed
• [Journal Article] Outcomes of left trisectionectomy and right hepatectomy for perihilar cholangiocarcinoma. (2019)
  • Author(s): Hosokawa I, Shimizu H, Yoshitomi H, Furukawa K, Takayashiki T, Kuboki S, Koda K, Miyazaki M, Ohtsuka M.
  • Journal Title: HPB (Oxford). Volume: 21 Issue: 4 Pages: 489-498
  • DOI: 10.1016/j.hpb.2018.08.017
  • Peer Reviewed
• [Presentation] 大腸癌同時性肝転移切除例の原発巣と転移巣におけるMTDHおよびSnail1の発現からみたEMT関連マーカーの意義 (2021)
  • Author(s): 村上 崇、清水 宏明、野島 広之、芦澤 陽介、碓井 彰大、小杉 千弘、首藤 潔彦、山崎 将人、幸田 圭史
  • Organizer: 第76回日本消化器外科学会総会
• [Presentation] Safety and efficacy of down staging of neoadjuvant chemotherapy with modified FOLFOX6 (combination chemotherapy of infusional 5-FU/l-Leucovorin and intermittent oxaliplatin) with bevacizumab in patients with advanced lower rectal cancer . (2020)
  • Author(s): Kosugi C, Koda K, Shimizu H, Yamazaki M, Shuto K, Nojima H, Murakami T, Ashizawa Y.
  • Organizer: The 30th Biennial Congress of ISUCRS
  • Int'l Joint Research
• [Presentation] 局所進行下部直腸癌に対する術前分子標的薬併用化学療法の是非 (2020)
  • Author(s): 小杉千弘、幸田圭史、山崎将人、首藤潔彦、碓井彰大
  • Organizer: 第75回日本大腸肛門病学会
• [Presentation] Evaluation of neoadjuvant chemotherapy with modified FOLFOX6 (Combination chemotherapy of infusional 5-FU/I-Leucovorin and intermittent Oxaliplatin) with Bevacizumab/ Cetuximab in patients with advanced lower rectal cancer (2019)
  • Author(s): Kosugi C, Koda K, Shimizu H, Yamazaki M, Shuto K, Nojima H, Hosokawa I, Murakami T, Takhashi M, Miyazawa Y
  • Organizer: IASGO 2019