Primary tumor-derived factors act upon normal cells to generate a pre-metastatic niche, which promotes colonization of target organs by disseminated malignant cells. Here we report that tumor-derived factor-induced activation of the p38α kinase in lung fibroblasts plays a critical role in the formation of a pre-metastatic niche in the lungs and subsequent pulmonary metastases. Activation of p38α led to inactivation of type I interferon signaling and stimulation of expression of fibroblast activation protein. Fibroblast activation protein played a key role in remodeling of the extracellular matrix as well as inducing the expression of chemokines that enable lung infiltration by neutrophils. Increased activity of p38 in normal cells was associated with metastatic disease and poor prognosis in human patients with melanoma, whereas inactivation of p38 suppressed lung metastases. We discuss the p38α-driven mechanisms stimulating the metastatic processes and potential use of p38 inhibitors in adjuvant therapy of metastatic cancers.

原发性肿瘤衍生因子作用于正常细胞以产生转移前的生态位，促进扩散的恶性细胞在靶器官的定植。在这里，我们报告肿瘤衍生因子诱导的肺成纤维细胞中 p38α 激酶的激活在肺转移前生态位的形成和随后的肺转移中起关键作用。p38α的激活导致I型干扰素信号的失活和成纤维细胞激活蛋白表达的刺激。成纤维细胞活化蛋白在细胞外基质的重塑以及诱导使中性粒细胞浸润肺的趋化因子的表达中起关键作用。正常细胞中 p38 活性的增加与人类黑色素瘤患者的转移性疾病和预后不良有关，而 p38 的失活抑制了肺转移。我们讨论了 p38α 驱动的刺激转移过程的机制以及 p38 抑制剂在转移性癌症辅助治疗中的潜在用途。