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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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 7

Mechanisms regulating niche competition between PCa cells and HSCs: competition for binding to osteoblasts.

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Mechanisms regulating niche competition between PCa cells and HSCs: comp...
(A) Competition binding assays to murine osteoblasts between 104 LSK HSCs and 0–105 PCa cells or NMPE control cells. (B) A fixed number of labeled NMPE control cells and PCa cells (104 cells) and 0–105 HSCs were layered onto murine osteoblasts. The binding ability of NMPE control cells and PCa cells to osteoblasts in the presence of HSCs was evaluated using a fluorescent plate reader. (C) A fixed number of fluorescently labeled HSCs (104 cells) was layered onto murine osteoblasts. At the same time, cultures were treated with 0–1 μg/μl of medium alone or conditioned medium (CM) derived from NMPE control cells and PCa cells. The binding ability of HSCs was measured by fluorescent plate reader. (D) Competition binding assays between 104 HSCs and 103 CD133+CD44+ or CD133–CD44– PCa cells. Data are from 3 independent experiments. (E–H) mRNA levels of (E) CXCR4, (F) CXCR7, (G) CCND1, and (H) CCNA1 in CD133+CD44+ or CD133–CD44– PCa cells. Significance of differences was determined by Student’s t test (A–D) or Kruskal-Wallis test (E–H).