Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow
Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow
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DOI：
10.1172/jci43414
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Taichman, Russell S.
中科院分区：
文献类型：
--
作者：
Shiozawa, Yusuke;Pedersen, Elisabeth A.;Taichman, Russell S.
造血干细胞归巢、静止和自我更新依赖于骨髓造血干细胞生态位。很大比例的实体瘤转移是骨转移，已知会篡夺HSC的归巢途径，在骨髓中建立立足点。然而，肿瘤在转移过程中是否靶向HSC生态位尚不清楚。我们在小鼠转移模型中表明，人类前列腺癌（PCa）细胞直接与HSC竞争占据小鼠HSC生态位。重要的是，增加生态位大小促进转移，而减少生态位大小损害传播。此外，弥散性PCa细胞可以通过HSC动员方案被动员出生态位并重新进入循环。最后，一旦进入生态位，肿瘤细胞通过驱动其终端分化来减少HSC的数量。这些数据提供了我们认为的第一个证据，证明HSC生态位是前列腺癌传播过程中的直接靶点，并在骨转移中发挥核心作用。我们的工作可能有助于更好地了解骨转移的分子事件，并为不治之症提供新的治疗途径。
HSC homing, quiescence, and self-renewal depend on the bone marrow HSC niche. A large proportion of solid tumor metastases are bone metastases, known to usurp HSC homing pathways to establish footholds in the bone marrow. However, it is not clear whether tumors target the HSC niche during metastasis. Here we have shown in a mouse model of metastasis that human prostate cancer (PCa) cells directly compete with HSCs for occupancy of the mouse HSC niche. Importantly, increasing the niche size promoted metastasis, whereas decreasing the niche size compromised dissemination. Furthermore, disseminated PCa cells could be mobilized out of the niche and back into the circulation using HSC mobilization protocols. Finally, once in the niche, tumor cells reduced HSC numbers by driving their terminal differentiation. These data provide what we believe to be the first evidence that the HSC niche serves as a direct target for PCa during dissemination and plays a central role in bone metastases. Our work may lead to better understanding of the molecular events involved in bone metastases and new therapeutic avenues for an incurable disease.