Human stromal cells are required for an anti-breast cancer effect of zoledronic acid

Hilde H. Nienhuis; Marlous Arjaans; Hetty Timmer-Bosscha; Elisabeth G.E. de Vries; Carolina P. Schröder

doi:10.18632/oncotarget.4421

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Research Papers:

Human stromal cells are required for an anti-breast cancer effect of zoledronic acid

Hilde H. Nienhuis _, Marlous Arjaans, Hetty Timmer-Bosscha, Elisabeth G.E. de Vries and Carolina P. Schröder

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Oncotarget. 2015; 6:24436-24447. https://doi.org/10.18632/oncotarget.4421

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Abstract

Hilde H. Nienhuis1,*, Marlous Arjaans1,*, Hetty Timmer-Bosscha1, Elisabeth G.E. de Vries1 and Carolina P. Schröder1

1 Department of Medical Oncology, University of Groningen and University Medical, Center Groningen, Groningen, The Netherlands

* These authors have contributed equally to this work

Correspondence to:

Carolina P. Schröder, email:

Keywords: breast cancer, microenvironment, zoledronic acid, TGF-β, CAM model

Received: February 16, 2015 Accepted: May 30, 2015 Published: June 10, 2015

Abstract

Previous studies suggested that bisphosphonate zoledronic acid exerts an anti-tumor effect by interacting with the microenvironment. In this study, we aimed to elucidate the mechanism behind the anti-breast cancer effect of zoledronic acid.

Here we showed that zoledronic acid did not influence in vitro human breast cancer cell survival, but did affect human stromal cell survival. Breast cancer cell death in co-culture with stromal cells was analyzed in vitro by fluorescent microscopy and flowcytometry analysis. In co-culture, the addition of stromal cells to breast cancer cells induced tumor cell death by zoledronic acid, which was abolished by transforming growth factor (TGF)-β. In the in vivo chicken chorioallantoic membrane model, zoledronic acid reduced the breast cancer cells fraction per tumor only in the presence of human stromal cells. Zoledronic acid decreased TGF-β excretion by stromal cells and co-cultures. Moreover, supernatant of zoledronic acid treated stromal cells reduced phospho-Smad2 protein levels in breast cancer cells. Thus, zoledronic acid exerts an anti-breast cancer effect via stromal cells, accompanied by decreased stromal TGF-β excretion and reduced TGF-β signaling in cancer cells.

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Research Papers:

Human stromal cells are required for an anti-breast cancer effect of zoledronic acid

Abstract