Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Sun Yat-sen University Sixth Affiliated Hospital, Guangzhou, 510655, China.
Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Cancer Lett. 2018 Apr 1;418:109-118. doi: 10.1016/j.canlet.2018.01.018. Epub 2018 Jan 11.
TGF-β plays a central role in prostate cancer (PCa) bone metastasis, and it is crucial to understand the bone cell-specific role of TGF-β signaling in this process. Thus, we used knockout (KO) mouse models having deletion of the Tgfbr2 gene specifically in osteoblasts (Tgfbr2 KO) or in osteoclasts (Tgfbr2 KO). We found that PCa-induced bone lesion development was promoted in the Tgfbr2 KO mice, but was inhibited in the Tgfbr2 KO mice, relative to their respective control Tgfbr2 littermates. Since metastatic PCa cells attach to osteoblasts when colonized in the bone microenvironment, we focused on the mechanistic studies using the Tgfbr2 KO mouse model. We found that bFGF was upregulated in osteoblasts from PC3-injected tibiae of Tgfbr2 KO mice and correlated with increased tumor cell proliferation, angiogenesis, amounts of cancer-associated fibroblasts and osteoclasts. In vitro studies showed that osteoblastogenesis was inhibited, osteoclastogenesis was stimulated, but PC3 viability was not affected, by bFGF treatments. Lastly, the increased PC3-induced bone lesions in Tgfbr2 KO mice were significantly attenuated by blocking bFGF using neutralizing antibody, suggesting bFGF is a promising target inhibiting bone metastasis.
TGF-β 在前列腺癌（PCa）骨转移中发挥核心作用，了解 TGF-β 信号在这一过程中在骨细胞中的特异性作用至关重要。因此，我们使用了敲除（KO）小鼠模型，这些模型特异性地在成骨细胞（Tgfbr2 KO）或破骨细胞（Tgfbr2 KO）中缺失了 Tgfbr2 基因。我们发现，与各自的对照 Tgfbr2 同窝仔鼠相比，PCa 诱导的骨病变发展在 Tgfbr2 KO 小鼠中得到促进，而在 Tgfbr2 KO 小鼠中受到抑制。由于转移性 PCa 细胞在骨微环境中定植时附着在成骨细胞上，我们专注于使用 Tgfbr2 KO 小鼠模型进行机制研究。我们发现，Tgfbr2 KO 小鼠的 PC3 注射胫骨中的成骨细胞中 bFGF 上调，并与肿瘤细胞增殖、血管生成、癌相关成纤维细胞和破骨细胞的数量增加相关。体外研究表明，bFGF 处理抑制成骨细胞形成，刺激破骨细胞形成，但不影响 PC3 活力。最后，使用中和抗体阻断 bFGF 显著减轻了 Tgfbr2 KO 小鼠中 PC3 诱导的骨病变增加，表明 bFGF 是抑制骨转移的一个有前途的靶点。
