Compression-induced expression of glycolysis genes in CAFs correlates with EMT and angiogenesis gene expression in breast cancer

Baek Gil Kim,Nam Hoon Cho,Nam Hoon Cho,Yeonsue Jang,Suki Kang,Joo Hyun Lee,Hyun Ho Han,Yoon Jin Cha,Jin Sol Sung

doi:10.1038/s42003-019-0553-9

Baek Gil Kim, Nam Hoon Cho + Show 7 more

Open Access

https://doi.org/10.1038/s42003-019-0553-9

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Abstract

Tumor growth increases compressive stress within a tissue, which is associated with solid tumor progression. However, very little is known about how compressive stress contributes to tumor progression. Here, we show that compressive stress induces glycolysis in human breast cancer associated fibroblast (CAF) cells and thereby contributes to the expression of epithelial to mesenchymal (EMT)- and angiogenesis-related genes in breast cancer cells. Lactate production was increased in compressed CAF cells, in a manner dependent on the expression of metabolic genes ENO2, HK2, and PFKFB3. Conditioned medium from compressed CAFs promoted the proliferation of breast cancer cells and the expression of EMT and/or angiogenesis-related genes. In patient tissues with high compressive stress, the expression of compression-induced metabolic genes was significantly and positively correlated with EMT and/or angiogenesis-related gene expression and metastasis size. These findings illustrate a mechanotransduction pathway involving stromal glycolysis that may be relevant also for other solid tumours.

Highlights

Tumor growth increases compressive stress within a tissue, which is associated with solid tumor progression
Some proteins known to contribute to tumor progression like LAMC2, ITGA6, and ITGB4 are overexpressed in the interface zone (IZ) of invasive ductal carcinoma (IDC) compared to the counterpart of ductal carcinoma in situ[5]
It was previously demonstrated using an in vitro compression model that compressive stress induces the overexpression of LAMC2 and ITGA6 in some breast cancer and cancer-associated fibroblast (CAF) cells, which lead to the production of VEGFA, a proangiogenic factor, in cancer associated fibroblast (CAF) cells[6]

Summary

Introduction

Tumor growth increases compressive stress within a tissue, which is associated with solid tumor progression. In patient tissues with high compressive stress, the expression of compression-induced metabolic genes was significantly and positively correlated with EMT and/or angiogenesis-related gene expression and metastasis size These findings illustrate a mechanotransduction pathway involving stromal glycolysis that may be relevant for other solid tumours. Some proteins known to contribute to tumor progression like LAMC2, ITGA6, and ITGB4 are overexpressed in the IZ of invasive ductal carcinoma (IDC) compared to the counterpart of ductal carcinoma in situ[5] It was previously demonstrated using an in vitro compression model that compressive stress induces the overexpression of LAMC2 and ITGA6 in some breast cancer and cancer-associated fibroblast (CAF) cells, which lead to the production of VEGFA, a proangiogenic factor, in CAF cells[6]. We demonstrated how compressive stress induces biological processes using functional assays and further validated our findings using patient tissues with a high compressive stress and a cancer database

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