Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation

摘要: The role of mesenchymal stem cells (MSC) in osteosarcoma (OS), the most common primary tumor bone, has not been extensively elucidated. We have recently shown that OS is characterized by interstitial acidosis, a microenvironmental condition similar to wound setting, which reactive are activated release mitogenic and chemotactic factors. therefore intended test hypothesis that, OS, acid-activated MSC influence cell behavior. Conditioned media or co-culture with normal previously incubated short-term acidosis (pH 6.8 for 10 hr, H+ -MSC) enhanced clonogenicity invasion. This effect was mediated NF-κB pathway activation. In fact, deep-sequencing analysis, confirmed Real-Time PCR ELISA, demonstrated -MSC differentially induced tissue remodeling phenotype increased expression RelA, RelB NF-κB1, downstream, CSF2/GM-CSF, CSF3/G-CSF BMP2 colony-promoting factors, chemokines (CCL5, CXCL5 CXCL1), cytokines (IL6 IL8), an CXCR4. An IL6 IL8 were found only stromal cells, but this tumor-associated isolated from tissue. Finally, conditioned medium promoted stemness (sarcosphere number, stem-associated gene expression), chemoresistance also via secretion. Our data support acidic microenvironment key factor activation, turn promoting secretion paracrine factors behavior, mechanism holds potential future therapeutic interventions aimed target OS.