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 8

Mechanisms regulating niche competition between PCa cells and HSCs: PCa cells drive HSCs out from the HSC niche.

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Mechanisms regulating niche competition between PCa cells and HSCs: PCa ...
(A–G) SCID mice were implanted either NMPE cells or PCa cells (PC3 or C4-2B) (n = 5 per group). After 3 weeks, the BM cells were collected. (A) Expression of stem cell survival and cell-to-cell adhesion genes in SLAM HSCs was evaluated by quantitative real-time RT-PCR (n = 5 per group). *P < 0.05, #P < 0.01 versus NMPE. (B) SLAM HSC numbers in BM were counted by FACS, and (C) HPC numbers were determined using colony-forming assays. (D and E) mRNA levels of (D) CCND1 and (E) CCNA2 in HSCs. (F) Cell cycle (Ki-67–positive cells) and (G) apoptotic state (PE-conjugated annexin V/7-ADD) of HPCs were analyzed by gating on Lin–Sca-1+ populations. (H) Peripheral blood was collected from subjects with local PCa disease (n = 18, 61.6 ± 9.2 years of age) and disseminated PCa disease (n = 39, 68.1 ± 11.1 years of age). The number of hematopoietic colonies was compared with that in healthy controls (young age, n = 13, 34.3 ± 5.6 years; age-matched, n = 11, 62.4 ± 7.1 years). Significance of differences was determined by Kruskal-Wallis test (A, D, and E) or Student’s t test (B, C, and F–H); P values in B–F are versus NMPE.