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 6

PCa cells target the HSC niche, and disseminated PCa cells can be mobilized from the BM niche via the CXCR4/CXCL12 axis.

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PCa cells target the HSC niche, and disseminated PCa cells can be mobili...
(A) Experimental model of HSC mobilization out of the niche via AMD3100 treatment to open the HSC niche. (B) PCa cell number in BM after i.c. injection of 1 × 106 cells after AMD3100 mobilization of HSCs. *P < 0.05, #P < 0.01 versus vehicle. (C) Experimental model to determine whether AMD3100 mobilizes disseminated PCa cells from BM (n = 8 per group). (D) Peripheral blood levels of PC3 cells mobilized with AMD3100 or vehicle, evaluated by QPCR. (E) SLAM HSC numbers in the BM after AMD3100 treatment were enumerated by FACS. (F and G) mRNA levels of (F) CXCR4 and (G) CXCR7 in HSCs at peripheral blood and BM with or without AMD3100 treatment. (H) Peripheral blood levels of PC3 cells mobilized with G-CSF or vehicle, evaluated by QPCR. (I) Number of HSCs in BM after G-CSF treatment, enumerated by FACS. (J) BM mRNA levels of MMP2 and MMP9 after G-CSF treatment, determined by QPCR. *P < 0.05, #P < 0.01 versus vehicle. (K) CXCL12-immunostained BM. Original magnification, ×60. Scale bars: 50 μm. Significance of differences was determined by Kruskal-Wallis test (B, D, F–H, and J) or Student’s t test (E and I).