Insulin-like growth factor signaling pathway as a possible therapeutic target for the maintenance of colonic tumor stem-cell character.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09381
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: Miyamoto Shin'ichi 京都大学, 医学研究科, 講師 (90378761)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 大腸腫瘍幹細胞 / インスリン様増殖因子 / MMP-7 / Dclk-1

Outline of Final Research Achievements

We performed immunostaining of Dclk-1(specific marker of colon tumor stem cell), MMP-7（IGF binding protein proteinase）in tumor organoids and human colon cancer tissues to confirm the activation of IGF signal in colon tumor stem cells. The localization of Dclk-1-positive cells and MMP-7-positive cells was completely different in both tissues, showing that MMP-7 was not secreted from Dclk-1-positive cells. MMP-7 secreted by the tumor itself may activate IGF in the tumor microenvironment, act paracrinely on Dclk-1-positive cells, and contribute to the maintenance of tumor stemness. MMP-7 is secreted from stromal cells as an inactive form and limited degradation by other proteases is required for its activation. In vitro systems, including organoid systems, do not contain stromal cells and cannot evaluate the activation of secreted MMP-7. Therefore, there is a limit in evaluating the activation of IGF signal following the activation of MMP-7 in the tumor stem cell niche in vitro.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

我が国では大腸癌は増加傾向にあり、罹患者数（総数で1位）、死亡者数ともに多い（女性の癌死の1位）。大腸癌は進行したステージでも化学療法の進歩、分子標的薬の開発などにより、かなりの予後を見込めるようになった。その反面、高額な医療費も問題となっている。一方、大腸癌は便潜血によるスクリーニングを契機として、大腸内視鏡による早期発見、早期治療が可能な癌でもある。しかしながら大腸癌検診の受診率は50%にも満たないのが現状である。そこで大腸発癌のメカニズムの一端が明らかになり、新たな治療法が開発され、大腸癌の予防効果が科学的に証明されれば、社会的貢献度はきわめて高い。