Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow
Yusuke Shiozawa, … , Kenneth J. Pienta, Russell S. Taichman
Yusuke Shiozawa, … , Kenneth J. Pienta, Russell S. Taichman
Published March 23, 2011
Citation Information: J Clin Invest. 2011;121(4):1298-1312. https://doi.org/10.1172/JCI43414.
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Research Article

Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow

Abstract

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.

Authors

Yusuke Shiozawa, Elisabeth A. Pedersen, Aaron M. Havens, Younghun Jung, Anjali Mishra, Jeena Joseph, Jin Koo Kim, Lalit R. Patel, Chi Ying, Anne M. Ziegler, Michael J. Pienta, Junhui Song, Jingcheng Wang, Robert D. Loberg, Paul H. Krebsbach, Kenneth J. Pienta, Russell S. Taichman

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Figure 9

Competition between disseminated PCa cells and HSCs for the endosteal niche facilitates metastasis.

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Competition between disseminated PCa cells and HSCs for the endosteal ni...
The endosteal (or osteoblast) niche is thought to maintain HSCs quiescence and regulate differentiation. It is also appreciated that many solid tumors metastasize to the bone. Our hypothesis is that metastatic cells shed from a primary tumor compete with HSCs to engage the endosteal niche, which suggests that solid tumors use the HSC niche as metastatic niche. Once in the niche, disseminated cells may remain in a quiescent /dormant state for extended periods of time. Eventually, however, metastatic growth exceeds the niche’s regulatory capacity, and clinically relevant disease occurs.