The role of TGFbeta signaling in pancreatic cancer progression via nerve signaling

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22797
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Takahashi Ryota 東京大学, 保健・健康推進本部, 助教 (80647660)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: 膵臓癌 / TGFβ / 神経

Outline of Final Research Achievements

We analyzed the effect of TGF beta signaling on nerves in pancreatic cancer microenvironment using a mouse model of pancreatic cancer with pancreas-specific expression of oncogenic Kras and knockout of TGF beta receptor type 2. We observed increased number of sympathetic nerves within pancreatic cancer from PKF mice. The expression pattern of neurotrophins in tumor cells of PKF mice was distinct from that of the mice with oncogenic Kras and mutant p53. On the other hand, when we treated PKF mice with either an antagonist of adrenergic beta 2 receptors (ADRB2) or vehicle, we did not observe a significant therapeutic effect. These results suggested that pancreatic cancer in PKF mice has higher resistance to ADRB2 blockade, although the mechanism needs to be elucidated in future studies.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

膵臓癌における腫瘍内神経を介した腫瘍促進機序は膵臓癌の治療標的となる可能性があるとされる一方、実際の膵臓癌で高頻度に認められるTGFβシグナルの異常と腫瘍内神経との関連はこれまで明らかになっていない。本研究によってその一端が明らかになり、癌細胞の持つ遺伝子変異により腫瘍内神経の性質や神経シグナル阻害治療への感受性が影響を受けている可能性が示唆された。一方その詳細な機序や、神経シグナルへの介入が有効な腫瘍が持つ特徴を明らかにすることなどは今後の検討課題と考えられた。