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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 Article has an altmetric score of 15

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

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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 2

Direct competition for the HSC niche between HSCs and PCa cells.

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Direct competition for the HSC niche between HSCs and PCa cells.
(A) Com...
(A) Competitive BMT experimental model. BMT was performed in the presence or absence of PC3 or C4-2B PCa cells or NMPE control cells. TBI, total body irradiation. (B) To avoid PCa cell proliferation in vivo, NMPE control cells or PCa cells were irradiated with 8 Gy (2× 4 Gy), and the effects of irradiation on the ability of 5,000 PCa cells to form colonies of 50 cells or greater were analyzed. Nonirradiated cells served as positive controls. Irradiation inhibited the colony-forming abilities of NMPE cells and PCa cells. (C) Kaplan-Meier survival plots after BMT in the presence or absence of PC3 or C4-2B PCa cells or NMPE control cells. Survival was monitored up to 60 days. P = 0.038, PC3 versus NMPE; P = 0.041, C4-2B versus NMPE, log-rank test (n = 10 per group). (D) Representative BM histology after competitive BMT of animals in C. Original magnification, ×40. Scale bars: 50 μm. (E) Engraftment of human BM CD34+ cells into NOD/SCID Il2rg–/– mice in the presence or absence of PC3 or C4-2B PCa cells or NMPE control cells. *P < 0.05, #P < 0.01 versus NMPE (n = 10 per group, Student’s t test). Human PCa cells prevented human HSC engraftment.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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