The crosstalk between breast carcinoma-associated fibroblasts and cancer cells promotes RhoA-dependent invasion via IGF-1 and PAI-1
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Julien Daubriac1, Shiwei Han1, Jelena Grahovac1, Eve Smith1, Abdel Hosein2, Marguerite Buchanan2, Mark Basik2 and Yves Boucher1
1Edwin L. Steele Laboratory for Tumor Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
2Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Canada
Yves Boucher, email: [email protected]
Keywords: carcinoma-associated fibroblasts; RhoA/ROCK signaling; insulin-like growth factor-1; plasminogen activator inhibitor-1; cancer cell scattering and invasion
Received: December 20, 2015 Accepted: December 14, 2017 Published: December 28, 2017
Carcinoma-associated fibroblasts (CAFs) can remodel the extracellular matrix to promote cancer cell invasion, but the paracrine signaling between CAFs and cancer cells that regulates tumor cell migration remains to be identified. To determine how the interaction between CAFs and cancer cells modulates the invasiveness of cancer cells, we developed a 3-dimensional co-culture model composed of breast cancer (BC) MDA-MB-231 cell spheroids embedded in a collagen gel with and without CAFs. We found that the crosstalk between CAFs and cancer cells promotes invasion by stimulating the scattering of MDA-MB-231 cells, which was dependent on RhoA/ROCK/phospho MLC signaling in cancer cells but independent of RhoA in CAFs. The activation of RhoA/ROCK in cancer cells activates MLC and increases migration, while the genetic-down-regulation of RhoA and pharmacological inhibition of ROCK reduced cell scattering and invasion. Two distinct mechanisms induced the activation of the RhoA/ROCK pathway in MDA-MB-231 cells, the secretion of IGF-1 by CAFs and the upregulation of PAI-1 in cancer cells. In an orthotopic model of BC, IGF-1R inhibition decreased the incidence of lung metastasis, while Y27632-inhibition of ROCK enhanced the lung metastasis burden, which was associated with an increased recruitment of CAFs and expression of PAI-1. Thus the crosstalk between CAFs and BC cells increases the secretion of IGF-1 in CAFs and PAI-1 activity in cancer cells. Both IGF1 and PAI-1 activate RhoA/ROCK signaling in cancer cells, which increases cell scattering and invasion.
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