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Abstract
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.
Highlights
In triple-negative breast cancer (TNBC) and other breast cancer subtypes, the presence of carcinomaassociated fibroblasts (CAFs) and collagen fibers correlates with high-grade malignancies and reduced survival [1]
The CAFs used for our experiments were isolated from a human invasive breast cancer of unknown subtype (CAF2; [31]), while the other CAF cell lines were isolated from human TNBC lesions [32]
Our findings show that in a 3D collagen gel the crosstalk between CAFs and BC cells promotes the www.impactjournals.com/oncotarget invasion of MDA-MB-231 cells by stimulating RhoA GTPase, cell scattering and migration
Summary
In triple-negative breast cancer (TNBC) and other breast cancer subtypes, the presence of carcinomaassociated fibroblasts (CAFs) and collagen fibers correlates with high-grade malignancies and reduced survival [1]. In response to molecular signals from cancer cells (e.g. TGF-β, SDF-1) CAFs adopt an activated www.impactjournals.com/oncotarget myofibroblast phenotype, characterized notably by an increased expression of α-smooth muscle actin (α-SMA) and synthesis of collagen [8]. This desmoplastic reaction modulates the adhesion of cancer cells, leading to the remodeling of a permissive and supportive environment for tumor progression and dissemination [9,10,11,12]
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