Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Oncogene. 2012 Oct 18;31(42):4527-35. doi: 10.1038/onc.2011.573. Epub 2011 Dec 12.
Although increasing evidence suggests a critical role for platelet-derived growth factor (PDGF) receptor β (β-PDGFR) signaling in prostate cancer (PCa) progression, the precise roles of β-PDGFR and PDGF isoform-specific cell signaling have not been delineated. Recently, we identified the PDGF-D isoform as a ligand for β-PDGFR in PCa and showed that PDGF-D is activated by serine protease-mediated proteolytic removal of the CUB domain in a two-step process, yielding first a hemidimer (HD) and then a growth factor domain dimer. Herein, we demonstrate that the expression of PDGF-D in human PCa LNCaP cells leads to enhanced bone tumor growth and bone responses in immunodeficient mice. Histopathological analyses of bone tumors generated by PDGF-D-expressing LNCaP cells (LNCaP-PDGF-D) revealed osteolytic and osteoblastic responses similar to those observed in human PCa bone metastases. Importantly, we discovered a novel function of PDGF-D in the regulation of osteoclast differentiation, independent of the RANKL/RANK signaling axis. Although both PDGF-B and -D were able to activate β-PDGFR, only PDGF-D was able to induce osteoclastic differentiation in vitro, and upregulate the expression and nuclear translocation of nuclear factor of activated T cells 1, a master transcription factor for osteoclastogenesis. Taken together, these results reveal a new function of PDGF-D as a regulator of osteoclastic differentiation, an activity critical for the establishment of skeletal metastatic deposit in PCa patients.
虽然越来越多的证据表明血小板衍生生长因子（PDGF）受体β（β-PDGFR）信号在前列腺癌（PCa）进展中起着关键作用，但β-PDGFR 和 PDGF 同工型特异性细胞信号的确切作用尚未确定。最近，我们鉴定出 PDGF-D 同工型是 PCa 中β-PDGFR 的配体，并表明 PDGF-D 通过丝氨酸蛋白酶介导的两步过程中 CUB 结构域的蛋白水解去除而被激活，首先产生半二聚体（HD），然后是生长因子结构域二聚体。在此，我们证明 PDGF-D 在人前列腺癌细胞系 LNCaP 中的表达可导致免疫缺陷小鼠中骨肿瘤生长和骨反应增强。用表达 PDGF-D 的 LNCaP 细胞（LNCaP-PDGF-D）生成的骨肿瘤的组织病理学分析显示出溶骨性和成骨反应，类似于在人 PCa 骨转移中观察到的反应。重要的是，我们发现 PDGF-D 在破骨细胞分化的调节中有一个新的功能，与 RANKL/RANK 信号轴无关。虽然 PDGF-B 和 -D 都能够激活β-PDGFR，但只有 PDGF-D 能够在体外诱导破骨细胞分化，并上调核因子激活 T 细胞 1 的表达和核易位，核因子激活 T 细胞 1 是破骨细胞生成的主要转录因子。总之，这些结果揭示了 PDGF-D 作为破骨细胞分化调节剂的新功能，这一活性对 PCa 患者骨骼转移沉积的建立至关重要。
