Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.
Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.
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DOI：
10.1158/0008-5472.can-18-0234
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发表时间：
2018-10-01
期刊：
影响因子：
11.2
通讯作者：
Stewart SA
中科院分区：
文献类型：
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作者：
Murali B;Ren Q;Luo X;Faget DV;Wang C;Johnson RM;Gruosso T;Flanagan KC;Fu Y;Leahy K;Alspach E;Su X;Ross MH;Burnette B;Weilbaecher KN;Park M;Mbalaviele G;Monahan JB;Stewart SA
基质间室在肿瘤进展中的作用在乳腺癌骨转移中得到了最好的说明，基质间室支持肿瘤生长，尽管其机制尚不明确。p38MAPKα在肿瘤细胞及周围基质细胞中频繁表达，其表达水平与预后不良相关。这一观察结果使我们在临床相关模型中研究抑制p38MAPKα是否可以减少乳腺癌转移。口服p38MAPKα或其下游激酶MK2的小分子抑制剂，每一种都限制了转移性乳腺癌细胞在骨骼和内脏器官的生长。这种作用主要是通过抑制间质室内的p38MAPKα途径介导的。除了有效地限制转移性肿瘤的生长，这些抑制剂还减少了肿瘤相关和化疗引起的骨质流失，这是一种毁灭性的合并症，极大地影响了癌症患者的生活质量。这些数据强调了基质来源因子在肿瘤进展中的重要作用，并确定p38MAPK-MK2途径是转移性疾病和预防肿瘤诱导的骨质流失的有希望的治疗靶点。药物靶向基质p38MAPK-MK2通路限制转移性乳腺癌的生长，保持骨质量，延长生存期。
The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2, each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically impacts quality of life for cancer patients. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss. Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival.