Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow
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
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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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 1

PCa cells compete for the HSC niche and prevent HSC engraftment.

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PCa cells compete for the HSC niche and prevent HSC engraftment. (A) Exp...
(A) Experimental model of BMT in the presence or absence of disseminated PCa cells. (B) Fewer donor HSCs (CD45.2) were able to engraft into NOD/SCID mice (CD45.1) when disseminated tumor cells (PC3 or C4-2B PCa cells) were present in BM. *P < 0.05, #P < 0.01 versus NMPE, Student’s t test (n = 10 per group). (C) At 4, 8, 12, and 16 weeks after transplantation, the establishment of metastases was followed by bioluminescent imaging. Data are representative of bioluminescent imaging of mice that had developed metastases at approximately 40 weeks. Dashed circles denote where the primary s.c. tumors were implanted and removed. Arrows show metastatic PCa. (D) Representative images of BM histology of mice that developed micrometastases at 16 weeks. Original magnification, ×60. Scale bars: 50 μm. (E) Osteoblast numbers were determined in the long bones. (F and G) mRNA levels of (F) CXCR4 and (G) CXCR7 in PCa cells at peripheral blood (PB) and BM. Significance of differences was determined by Kruskal-Wallis test.