Krzeszinski Jing Y, Schwaid Adam G, Cheng Wing Yin, Jin Zixue, Gallegos Zachary R, Saghatelian Alan, Wan Yihong
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, USA.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts.
Endocrinology. 2017 Mar 1;158(3):477-489. doi: 10.1210/en.2016-1570.
Bone metastasis is a deadly consequence of cancers, in which osteoclast forms a vicious cycle with tumor cells. Bone metastasis attenuation by clinical usage of osteoclast inhibitors and in our osteopetrotic mouse genetic models with β-catenin constitutive activation or peroxisome proliferator-activated receptor γ deficiency fully support the important role of osteoclast in driving the bone metastatic niche. However, the mechanisms for this "partnership in crime" are underexplored. Here we show that osteoclasts reprogram their lipid secretion to support cancer cells. Metabolomic profiling reveals elevated prometastatic arachidonic acid (AA) but reduced antimetastatic lysophosphatidylcholines (LPCs). This shift in lipid osteoclastokines synergistically stimulates tumor cell proliferation, migration, survival, and expression of prometastatic genes. Pharmacologically, combined treatment with LPCs and BW-755C, an inhibitor of AA signaling via blocking lipoxygenase and cyclooxygenase, impedes breast cancer bone metastasis. Our findings elucidate key paracrine mechanisms for the osteoclast-cancer vicious cycle and uncover important therapeutic targets for bone metastasis.
骨转移是癌症的致命后果，其中破骨细胞与肿瘤细胞形成恶性循环。临床使用破骨细胞抑制剂以及我们在具有β-连环蛋白组成性激活或过氧化物酶体增殖物激活受体γ缺陷的石骨症小鼠遗传模型中实现的骨转移减弱，充分支持了破骨细胞在驱动骨转移微环境中的重要作用。然而，这种“犯罪伙伴关系”的机制尚未得到充分探索。在这里，我们表明破骨细胞会重新编程其脂质分泌以支持癌细胞。代谢组学分析显示促转移的花生四烯酸（AA）升高，但抗转移的溶血磷脂酰胆碱（LPCs）减少。脂质破骨细胞因子的这种转变协同刺激肿瘤细胞增殖、迁移、存活以及促转移基因的表达。在药理学上，联合使用LPCs和BW-755C（一种通过阻断脂氧合酶和环氧化酶来抑制AA信号传导的抑制剂）可阻碍乳腺癌骨转移。我们的研究结果阐明了破骨细胞 - 癌症恶性循环的关键旁分泌机制，并揭示了骨转移的重要治疗靶点。
