Interaction between cancer associated fibroblasts and immune cells in tumor microenvironment of HCC

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16559
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: MANO yohei 九州大学, 大学病院, 助教 (10792244)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 肝癌 / 肝線維化 / 癌微小環境

Outline of Final Research Achievements

We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection.
The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC.

Free Research Field

肝癌

Academic Significance and Societal Importance of the Research Achievements

今回、肝細胞癌の癌関連線維芽細胞において、BMP4がその活性化や癌の悪性化に関与していることが明らかになり、新たな治療ターゲットとして意義のある発見であったと考えられます。新たな治療法として、癌細胞だけでなく線維芽細胞を制御することにより、既存の治療に加えてより高い治療効果が得られると期待されます。