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 4

HSCs and PCa cells colocalize to BM niches, and alteration of niche size regulates tumor dissemination.

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HSCs and PCa cells colocalize to BM niches, and alteration of niche size...
(A and B) To determine whether metastatic cells and HSCs colocalize to the same niche, multiphoton imaging was used to track prelabeled LSK HSCs (red) and (A) prelabeled PCa cells (green) or (B) NMPE control cells 24 hours after transplantation. Nuclei were stained with DAPI (blue). Original magnification, ×200. (C) Statistical analyses of A. (D) SLAM HSCs and PC3 or C4-2B PCa cells colocalized to a single osteoblast in vitro, as imaged by confocal microscopy. (E) Statistical analyses of in vitro adhesion assays to Anxa2+/+ versus Anxa2–/– osteoblasts (see D). (F) SLAM HSCs, but not NMPE cells, in vitro localized to a single osteoblast. NMPE cells were unable to bind to Anxa2+/+ or Anxa2–/– osteoblasts. (G) To expand the osteoblast numbers, animals were pretreated with vehicle or PTH prior to establishing primary tumors, and the number of metastatic PC3 cells was determined at 3 weeks (n = 8 per group). *P < 0.05, #P < 0.01 versus vehicle. (H) Homing of PC3 cells to Col2.3Δ-TK versus control vossicles with or without ganciclovir (n = 8 per group). The number of disseminated PCa cells homed to vehicle-treated control vossicles was set as 100%. Significance of differences was determined by Student’s t test (C and E) or Kruskal-Wallis test (G and H). Scale bars: 10 μm (A and B); 50 μm (D and F).