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

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

doi:10.18632/oncotarget.27881

Kazunori Tokuda, Shinichiro Yamada + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.27881

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Journal: Oncotarget	Publication Date: Feb 16, 2021
Citations: 20	License type: cc-by

Affiliation: Tokushima University

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.

Highlights

The tumor progression has been regarded as a multistep process involving genetic and epigenetic changes targeting only cancer cells
Hepatic stellate cells (HSCs) cultured with Ca.-conditioned medium (CM), tumor associated macrophage (TAM)-CM and cancer associated fibroblast (CAF)-CM showed significantly increased messenger ribonucleic acid (RNA) (mRNA) expression of αSMA, fibroblast activation protein (FAP) and IL-6
Osteopontin inhibition significantly reduced osteopontin secretion from HSCs cultured with TAM conditioned medium (TAM-CM) and suppressed the proliferation and invasion of cancer cells enhanced by HSCs cultured with TAM-CM

Summary

Introduction

The tumor progression has been regarded as a multistep process involving genetic and epigenetic changes targeting only cancer cells. Recent research has identified that the tumor microenvironment (TME) is an important factor of tumor behavior [1]. Tumor tissues mainly contain cancer cells and fibroblasts, macrophages and vascular components that form the TME, which regulates interaction and differentiation induction. Fibroblast is a multifunctional cell type in connective tissue that deposit basement membrane components and extracellular matrix (ECM) and regulate differentiation in associated epithelial cells. In addition to enhancing angiogenesis and the proliferation of cancer cells, CAFs have been implicated in enhancing cancer cells invasiveness, possibly through the induction of epithelial-mesenchymal transition (EMT) [4]. Cancer-tumor associated macrophage (TAM)-cancer associated fibroblast (CAF) interactions are an important factor in the tumor microenvironment of hepatocellular carcinoma

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Conclusion