Elucidation of mechanisms that hepatic microenvironment sort out pancreatic cancer cells, and management the stress in microenvironment.

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16567
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: HORIOKA Kohei 九州大学, 医学研究院, 共同研究員 (10783699)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: pancreatic cancer / liver metastasis / CAFs / NETs / DNaseⅠ / hepatic stellate cells

Outline of Final Research Achievements

NETs are extracellular DNA meshworks released from neutrophils together with proteolytic enzymes against foreign pathogens. Emerging studies suggest their contribution to liver metastasis in several types of cancer.
In this study, we showed DNase I, a NET inhibitor, suppressed liver metastasis and micrometasatasis on spontaneous pancreatic cancer mouse models and liver metastasis mouse model that was generated by intrasplenic tumor injection. We found DNaseⅠ also suppressed the recruitment of activated CAFs, which play a pivotal role in the tumor-supportive microenvironment in the micrometastatic foci. In vitro experiments showed that pancreatic cancer cells induced NET formation and consequently NETs enhanced the migration of hepatic stellate cells, which was the possible origin of CAFs in the liver metastasis. These results suggest that NETs is one of the candidate therapeutic targets to inhibit liver metastasis enhanced via CAF activation in pancreatic cancer.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

本研究によって膵癌の主要な転移先臓器である肝臓での転移成立に、微小環境内の好中球が細胞外トラップといった機構を介して、促進的に働いている可能性を明らかにし、その制御によって膵癌の肝転移を抑制できる可能性を示した。高頻度かつ早期から肝転移を起こす膵癌において、肝転移の制御が可能となればその悲惨な予後は大きく改善する可能性がある。本研究は従来の癌細胞を標的とした治療開発とは異なった新たな視点からの治療戦略を構築する一助となりうる。