Cancer associated fibroblasts confer shear resistance to circulating tumor cells during prostate cancer metastatic progression
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Nerymar Ortiz-Otero1, Andrea B. Clinch2, Jacob Hope2, Wenjun Wang2, Cynthia A. Reinhart-King2 and Michael R. King2
1 Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14850, USA
2 Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37202, USA
|Michael R. King,
Keywords: metastasis; cancer associated fibroblasts; circulating tumor cells; cytoprotection; collective migration
Received: July 29, 2019 Accepted: February 06, 2020 Published: March 24, 2020
Previous studies have demonstrated that CTCs do not travel in the bloodstream alone, but rather are accompanied by clusters of stromal cells such as cancer associated fibroblasts (CAFs). Our laboratory has confirmed the presence of CAFs in the peripheral blood of prostate cancer (PC) patients. The observation that CAFs disseminate with CTCs prompts the examination of the role of CAFs in CTC survival under physiological shear stress during the dissemination process using a clinically relevant, three-dimensional (3D) co-culture model. In this study, we found that “reactive CAFs” induce shear resistance to prostate tumor cells via intercellular contact and soluble derived factors. In addition, these reactive CAFs conserve the proliferative capability of tumor cells in the presence of high magnitude fluid shear stress (FSS). This reactive CAF phenotype emerges from normal fibroblasts (NF), which take on the CAF phenotype when co-cultured with tumor cells. The reactive CAFs showed higher expression of α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP) compared to differentiated CAFs, when co-cultured with PC cells at the same experimental conditions. Together, we found that the activation mechanism of NF to CAF comprises different stages that progress from a reactive to quiescent cellular state in which these two states are differentiated by the fluctuation of intensity in CAF markers. Here we determined that a reactive state of CAFs proved to be important for supporting tumor cell survival and proliferation. These findings suggest the use of CAFs as a marker for cancer progression and a potential target for novel cancer therapeutics to treat metastatic disease.
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