Solid tumor growth triggers a dynamic host response, which recapitulates wound healing and defines the tumor microenvironment (TME). In addition to the action of the tumor cells themselves, the TME is maintained by a myriad of immune and stromal cell-derived soluble mediators and extracellular matrix components whose combined action supports tumor progression. However, therapeutic targeting of the TME has proven challenging because of incomplete understanding of the tumor-host crosstalk at the molecular level. Here, we investigated the crosstalk between mesenchymal stromal cells (MSCs) and primary cancer cells (PCCs) from human squamous cell lung carcinoma (SCC). We discovered that PCCs secrete CCL3 and stimulate IL-6, CCL2, ICAM-1 and VCAM-1 expression in MSCs and that the MSC-PCC crosstalk can be disrupted by the lipid-lowering drug simvastatin, which displays pleiotropic effects on cell metabolism and suppresses IL-6 and CCL2 production by MSCs and CCL3 secretion by PCCs. In addition, simvastatin inhibited spheroid formation by PCCs and negatively affected PCC survival. Our observations demonstrate that commonly used statins may be repurposed to target the TME in lung carcinoma.

中文翻译：

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他汀类药物可减轻肺癌来源的间充质基质细胞的促炎信号。

实体瘤的生长会触发动态的宿主反应，从而概括伤口愈合并定义肿瘤微环境（TME）。除了肿瘤细胞本身的作用外，TME还由多种免疫和基质细胞衍生的可溶性介体和细胞外基质成分维持，它们的联合作用支持肿瘤的进展。然而，由于在分子水平上对肿瘤-宿主串扰的不完全了解，对TME的治疗靶向已被证明具有挑战性。在这里，我们调查了间质基质细胞（MSCs）与人鳞状细胞肺癌（SCC）原发性癌细胞（PCCs）之间的串扰。我们发现PCC分泌CCL3并刺激MSC中的IL-6，CCL2，ICAM-1和VCAM-1表达，并且降脂药辛伐他汀可以破坏MSC-PCC的串扰，它对细胞代谢表现出多效性，并抑制MSCs分泌IL-6和CCL2以及抑制PCCs分泌CCL3。此外，辛伐他汀抑制PCC形成球状体，并对PCC存活率产生负面影响。我们的观察结果表明，常用的他汀类药物可能会重新靶向肺癌的TME。