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

Content Provider	Europe PMC
Author	Tokuda, Kazunori Morine, Yuji Miyazaki, Katsuki Yamada, Shinichiro Saito, Yu Nishi, Masaaki Tokunaga, Takuya Ikemoto, Tetsuya Imura, Satoru Shimada, Mitsuo
Abstract	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.
Journal	Oncotarget
Volume Number	12
PubMed Central reference number	PMC7899554
Issue Number	4
PubMed reference number	33659044
e-ISSN	19492553
DOI	10.18632/oncotarget.27881
Language	English
Publisher	Impact Journals LLC
Publisher Date	2021-02-16
Access Restriction	Open
Rights License	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. Copyright: © 2021 Tokuda et al.
Subject Keyword	hepatocellular carcinoma osteopontin cancer associated fibroblast tumor associated macrophage tumor microenvironment
Content Type	Text
Resource Type	Article
Subject	Oncology