Resumen
Breast cancer progression is prominently regulated by the persistent presence of inflammatory mediators and by stromal cells that are located in the tumors. Here, we connected these two elements by demonstrating that potent pro-inflammatory cytokines (tumor necrosis factor a and interleukin 1ß) lead to the conversion of mesenchymal stem cells (MSCs) to inflammatory cancer-associated fibroblasts (CAFs). These inflammation-driven CAFs secrete metastasis-promoting factors that elevate the dispersion, scattering, and migration of breast cancer cells via activation of tumor cell receptors that signal through Ras proteins and via Gai proteins; the latter receptors were identified as the chemokine receptors CCR2, CCR5, and CXCR1/2. Together, these findings demonstrate that, in breast tumors, chronic inflammation can induce the deleterious process of MSC-to-CAF conversion and thus sets pro-inflammatory mediators as key targets for inhibition, potentially leading to lower levels of pro-metastatic CAFs in breast tumors.