Research Papers:

The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma

Kazunori Tokuda, Yuji Morine _, Katsuki Miyazaki, Shinichiro Yamada, Yu Saito, Masaaki Nishi, Takuya Tokunaga, Tetsuya Ikemoto, Satoru Imura and Mitsuo Shimada

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Oncotarget. 2021; 12:333-343. https://doi.org/10.18632/oncotarget.27881

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Kazunori Tokuda1, Yuji Morine1, Katsuki Miyazaki1, Shinichiro Yamada1, Yu Saito1, Masaaki Nishi1, Takuya Tokunaga1, Tetsuya Ikemoto1, Satoru Imura1 and Mitsuo Shimada1

1 Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan

Correspondence to:

Yuji Morine,email: [email protected]

Keywords: hepatocellular carcinoma; osteopontin; cancer associated fibroblast; tumor associated macrophage; tumor microenvironment

Received: November 17, 2020     Accepted: January 19, 2021     Published: February 16, 2021

Copyright: © 2021 Tokuda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Cancer-tumor associated macrophage (TAM)-cancer associated fibroblast (CAF) interactions are an important factor in the tumor microenvironment of hepatocellular carcinoma.

Materials and Methods: Hepatic stellate cells (HSCs) were cultured with cancer cell-conditioned medium (Ca.-CM), TAM-CM and CAF-CM, and the expression of CAF markers were evaluated by RT-PCR. Whether HSCs cultured with Ca.-CM, TAM-CM and CAF-CM contributed to the enhanced malignancy of cancer cells was examined using proliferation, invasion and migration assays. Furthermore, the differences between these three types of CM were evaluated using cytokine arrays.

Results: HSCs cultured with Ca.-CM, TAM-CM and CAF-CM showed significantly increased mRNA expression of αSMA, FAP and IL-6. All HSCs cultured with each CM exhibited significantly increased proliferation, invasion and migration of cancer cells. The osteopontin concentration was significantly higher in HSCs cultured with TAM-CM than the other CAF-CMs. Osteopontin inhibition significantly reduced osteopontin secretion from HSCs cultured with TAM-CM and suppressed the proliferation and invasion of cancer cells enhanced by HSCs cultured with TAM-CM.

Conclusions: We observed enhanced osteopontin secretion from TAMs, and this increased osteopontin further promoted osteopontin secretion from HSCs cultured with TAM-CM, leading to increased malignancy. For the first time, we demonstrated the importance of cancer-TAM-CAF interactions via osteopontin in hepatocellular carcinoma.

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