Russell M R, Jamieson W L, Dolloff N G, Fatatis A
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Oncogene. 2009 Jan 22;28(3):412-21. doi: 10.1038/onc.2008.390. Epub 2008 Oct 13.
Bone resorption by osteoclasts is thought to promote the proliferation of prostate cancer cells disseminated to the skeleton (Mundy, 2002). Using a mouse model of experimental metastasis, we found that although late-stage metastatic tumors were indeed surrounded by osteoclasts, these cells were spatially unrelated to the small foci of cancer cells in early-stage metastases. This is the first evidence that survival and growth of disseminated prostate cancer cells immediately after their extravasation may not depend on osteoclast involvement. Interestingly, prostate cancer cells expressing the alpha-receptor for platelet-derived growth factor (PDGFRalpha) progress during early-stages of skeletal dissemination, whereas cells expressing lower levels or lacking this receptor fail to survive after extravasation in the bone marrow. However, non-metastatic cells acquire bone-metastatic potential upon ectopic overexpression of PDGFRalpha. Finally, functional blockade of human PDGFRalpha on prostate cancer cells utilizing a novel humanized monoclonal antibody -- soon to undergo phase-II clinical trials -- significantly impairs the establishment of early skeletal metastases. In conclusion, our results strongly implicate PDGFRalpha in prostate cancer bone tropism through its promotion of survival and progression of early-metastatic foci, providing ground for therapeutic strategies aimed at preventing or containing the initial progression of skeletal metastases in patients affected by prostate adenocarcinoma.
破骨细胞引起的骨吸收被认为会促进扩散到骨骼的前列腺癌细胞的增殖（芒迪，2002年）。利用实验性转移的小鼠模型，我们发现尽管晚期转移性肿瘤确实被破骨细胞包围，但这些细胞在空间上与早期转移中癌细胞的小病灶并无关联。这是首个证据表明，播散的前列腺癌细胞外渗后立即存活和生长可能不依赖破骨细胞的参与。有趣的是，表达血小板衍生生长因子α受体（PDGFRα）的前列腺癌细胞在骨骼播散的早期阶段进展，而表达较低水平或缺乏该受体的细胞在骨髓中外渗后无法存活。然而，非转移性细胞在异位过表达PDGFRα后获得骨转移潜能。最后，利用一种新型人源化单克隆抗体（即将进行II期临床试验）对前列腺癌细胞上的人PDGFRα进行功能阻断，会显著损害早期骨骼转移的建立。总之，我们的结果强烈表明PDGFRα通过促进早期转移灶的存活和进展而参与前列腺癌的骨嗜性，为旨在预防或控制前列腺腺癌患者骨骼转移初始进展的治疗策略提供了依据。
