Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation.
Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation.
复制标题
癌症相关的间充质基质通过NF-κB激活对肿瘤内酸中毒的响应，促成骨肉瘤细胞的干性。
DOI：
10.1002/ijc.30540
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发表时间：
2017-03-15
影响因子：
6.4
通讯作者：
Baldini N
中科院分区：
文献类型：
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作者：
Avnet S;Di Pompo G;Chano T;Errani C;Ibrahim-Hashim A;Gillies RJ;Donati DM;Baldini N
间充质干细胞（MSC）在骨肉瘤（OS）中的作用，骨肉瘤是最常见的原发性骨肿瘤，尚未得到广泛阐明。我们最近发现OS的特征是间质性酸中毒，这是一种类似于伤口环境的微环境条件，其中间充质反应细胞被激活以释放促有丝分裂因子和趋化因子。因此，我们打算测试的假设，在OS中，酸活化的MSC影响肿瘤细胞的行为。条件培养基或与正常MSC的共培养物预先与短期酸中毒孵育（pH 6.8，10小时，H+-MSC）增强OS克隆形成和侵袭。这种作用是通过NF-κB通路的激活介导的。事实上，通过Real-Time PCR和ELISA证实的深度测序分析表明，H+-MSC差异诱导组织重塑表型，RelA、RelB和NF-κB1表达增加，CSF 2/GM-CSF、CSF 3/G-CSF和BMP 2集落促进因子以及趋化因子表达增加（CCL 5、CXCL 5和CXCL 1）和细胞因子（IL 6和IL 8），CXCR 4的表达增加。IL 6和IL 8的表达增加，发现只有在正常的基质细胞，而不是在OS细胞，这是证实了从OS组织中分离的肿瘤相关的基质细胞。最后，H+-MSC条件培养基差异促进OS干性（肌球数目，干相关基因表达），和化疗耐药性也通过IL 6分泌。我们的数据支持酸性OS微环境是MSC活化的关键因素的假设，反过来促进影响肿瘤行为的旁分泌因子的分泌，这一机制具有未来针对OS的治疗干预的潜力。
The role of mesenchymal stem cells (MSC) in osteosarcoma (OS), the most common primary tumor of bone, has not been extensively elucidated. We have recently shown that OS is characterized by interstitial acidosis, a microenvironmental condition that is similar to a wound setting, in which mesenchymal reactive cells are activated to release mitogenic and chemotactic factors. We therefore intended to test the hypothesis that, in OS, acid-activated MSC influence tumor cell behavior. Conditioned media or co-culture with normal MSC previously incubated with short-term acidosis (pH 6.8 for 10 hours, H+-MSC) enhanced OS clonogenicity and invasion. This effect was mediated by NF-κB pathway activation. In fact, deep-sequencing analysis, confirmed by Real-Time PCR and ELISA, demonstrated that H+-MSC differentially induced a tissue remodeling phenotype with increased expression of RelA, RelB, and NF-κB1, and downstream, of CSF2/GM-CSF, CSF3/G-CSF, and BMP2 colony-promoting factors, and of chemokines (CCL5, CXCL5, and CXCL1), and cytokines (IL6 and IL8), with an increased expression of CXCR4. An increased expression of IL6 and IL8 were found only in normal stromal cells, but not in OS cells, and this was confirmed in tumor-associated stromal cells isolated from OS tissue. Finally, H+-MSC conditioned medium differentially promoted OS stemness (sarcosphere number, stem-associated gene expression), and chemoresistance also via IL6 secretion. Our data support the hypothesis that the acidic OS microenvironment is a key factor for MSC activation, in turn promoting the secretion of paracrine factors that influence tumor behavior, a mechanism that holds the potential for future therapeutic interventions aimed to target OS.