Lin Song-Chang, Lee Yu-Chen, Yu Guoyu, Cheng Chien-Jui, Zhou Xin, Chu Khoi, Murshed Monzur, Le Nhat-Tu, Baseler Laura, Abe Jun-Ichi, Fujiwara Keigi, deCrombrugghe Benoit, Logothetis Christopher J, Gallick Gary E, Yu-Lee Li-Yuan, Maity Sankar N, Lin Sue-Hwa
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Pathology, Taipei Medical University and Hospital, Taipei 110, Taiwan.
Dev Cell. 2017 Jun 5;41(5):467-480.e3. doi: 10.1016/j.devcel.2017.05.005.
Prostate cancer (PCa) bone metastasis is frequently associated with bone-forming lesions, but the source of the osteoblastic lesions remains unclear. We show that the tumor-induced bone derives partly from tumor-associated endothelial cells that have undergone endothelial-to-osteoblast (EC-to-OSB) conversion. The tumor-associated osteoblasts in PCa bone metastasis specimens and patient-derived xenografts (PDXs) were found to co-express endothelial marker Tie-2. BMP4, identified in PDX-conditioned medium, promoted EC-to-OSB conversion of 2H11 endothelial cells. BMP4 overexpression in non-osteogenic C4-2b PCa cells led to ectopic bone formation under subcutaneous implantation. Tumor-induced bone was reduced in trigenic mice (Tie2/Osx/SCID) with endothelial-specific deletion of osteoblast cell-fate determinant OSX compared with bigenic mice (Osx/SCID). Thus, tumor-induced EC-to-OSB conversion is one mechanism that leads to osteoblastic bone metastasis of PCa.
前列腺癌（PCa）骨转移常伴有成骨病变，但其成骨病变的来源尚不清楚。我们发现，肿瘤诱导生成的骨部分源自经历了内皮细胞向成骨细胞（EC-to-OSB）转化的肿瘤相关内皮细胞。在PCa骨转移标本和患者来源的异种移植（PDX）中发现，肿瘤相关成骨细胞共表达内皮标志物Tie-2。在PDX条件培养基中鉴定出的BMP4可促进2H11内皮细胞的EC-to-OSB转化。非成骨性C4-2b PCa细胞中BMP4的过表达导致皮下植入后出现异位骨形成。与双基因小鼠（Osx/SCID）相比，在内皮细胞特异性缺失成骨细胞命运决定因子OSX的三基因小鼠（Tie2/Osx/SCID）中，肿瘤诱导生成的骨减少。因此，肿瘤诱导的EC-to-OSB转化是导致PCa成骨性骨转移的一种机制。
