Life science
Drug development, Biomarker

Elucidation of the mechanism of liver cancer progression focusing
on tumor microenvironment and its clinical application
Department of Gastroenterology and Hepatology, Graduate School of Medicine
Associate Professor Hayato Hikita

https://researchmap.jp/hikitahayato?lang=en

Professor Tetsuo Takehara

https://researchmap.jp/takeharatetsuo?lang=en

Life science

Abstract
Cancers contain not only cancer cells but also various stromalcells such as immune cells, fibroblasts, and vascular endothelial
cells. These cells interact with cancer cells to form an environment
favorable for cancer progression, which is called the tumor microenvironment. We are working to elucidate the molecular mechanisms of liver cancer progression in the tumor microenvironment.
We have found and reported that GDF15 (3), IL-6 family cytokines(1), and CTGF (1,4) are important molecules for the interaction
between liver cancer cells and stromal cells in the liver tumor microenvironment.
Meanwhile, we are also working on the development of new
biomarkers to stratify patients with high and low risk of future liver
carcinogenesis. We found that GDF15, found in the liver tumor microenvironment, is elevated in sera of patients with chronic hepatitis. We found that patients with high serum GDF15 are more likely
to develop liver cancer even after elimination of hepatitis C virus
and reported that GDF15 is a new biomarker to stratify the risk ofliver carcinogenesis (2).

▍ Background & Results
In many cancers, including liver cancers, the cancer cells themselves interact with stromal cells such as immune cells, fibroblasts,
and vascular endothelial cells surrounding the cancer cells toform the tumor microenvironment promoting cancer development.
However, it was not known how hepatic stellate cells (HSCs), whichplay a central role in fibrosis in the liver, interact with cancer cells in
the liver tumor microenvironment.
We found that autophagy of HSCs is promoted by liver cancer
cells in the liver tumor microenvironment, and that GDF15 is secreted from HSCs via autophagy promotion, thereby promoting theproliferation of liver cancer cells (Fig.1). We found that the deletionof GDF15 in HSCs in xenograft mouse models or liver carcinogenesis mouse model suppressed liver cancer progression, and that
GDF15 would be a new therapeutic target for liver cancer (Fig.2).
We found that HSCs expressing GDF15 are present in the humanliver cancers and revealed that liver cancer patients with high serum GDF15 have a poor prognosis (3).
Hepatitis C patients, on the other hand, can now be eliminatedwith oral medication, and elimination of the virus suppress theprogression to liver cancer. However, some hepatitis C patients
progresses to liver cancer even after the virus is eliminated. Interestingly, we found that high serum GDF15 is a risk factor for liver
carcinogenesis after viral elimination, independent of high serum
AFP and high FIB-4 index, an index of liver stiffness (Fig.3). We reported that GDF15 can be used as a new predictive biomarker forliver carcinogenesis (3).

▍ Significance of the research and Future perspective
For patients with liver cancer, the development of new therapeutic methods or drugs targeting the cancer microenvironment isexpected. For patients with chronic liver disease, it is expected toestablish a new biomarker to narrow down patients at high risk ofliver carcinogenesis.

Fig.1 The interaction between tumor cells and stellate cells in tumor microenvironment

Fig.2 The liver tumor growth was attenuated by GDF15 knockout in hepatic stellate cells.

Fig.3 Serum GDF15 is a predictive factor for HCC occurrence after HCV elimination

P a t e n t Japanese Patent Application No. 2021-12187, Japanese Patent Application No. 2022-106996
1)Makino, Yuki; Hikita, Hayato; Kato, Seiya et al. STAT3 is activated by CTGF-mediated tumor-stroma cross talk to promote HCC progression. Cell Mol
Gastroenterol Hepatol. 2022, in press, doi: 10.1016/j.jcmgh.2022.09.006
2)Myojin, Yuta; Hikita, Hayato; Tahata, Yuki et al. Serum growth differentiation factor 15 predicts hepatocellular carcinoma occurrence after hepatitis Cvirus elimination. Aliment Pharmacol Ther. 2022, 55(4): 422-433. doi: 10.1111/apt.16691
Tr e a t i s e3)Myojin, Yuta; Hikita, Hayato; Sugiyama, Masaya et al. Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via GrowthDifferentiation Factor 15 Production. Gastroenterology. 2021, 160(5): 1741-1754. e16. doi: 10.1053/j.gastro.2020.12.015
4)Makino, Yuki; Hikita, Hayato; Kodama, Takahiro et al. CTGF Mediates Tumor-Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells toAccelerate HCC Progression. Cancer Res. 2018, 78(17): 4902-4914. doi: 10.1158/0008-5472
URL https://resou.osaka-u.ac.jp/en/research/2020/20201224_2
K e y w o r d liver cancer, tumor microenvironment, chronic hepatitis, GDF15, CTGF