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.
View: Text | PDF
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

×

Figure 5

The osteoblastic niche is critical for PCa cell growth in bone.

Options: View larger image (or click on image) Download as PowerPoint
The osteoblastic niche is critical for PCa cell growth in bone. Lucifera...
Luciferase-labeled PC3 cells were placed directly into Col2.3Δ-TK or control vossicles, which were subsequently implanted into the immunodeficient mice. Mice were treated with either ganciclovir or vehicle for 3 weeks to ablate the osteoblast niche. (A) Bioluminescent imaging of vossicles was performed over time, demonstrating no tumor growth in Col2.3Δ-TK vossicles in the presence of ganciclovir (n = 10 per group). (B) Cytokeratin-immunostained vossicles. Arrowheads denote cytokeratin-positive cells. (C) H&E examination of vossicles. Arrowheads denote endosteal osteoblasts. (D) Osteoblast number was quantified with H&E staining. (E) Representative TUNEL-stained vossicles. Original magnification, ×60. (F) To determine whether luciferase-labeled PC3 cells in the vossicles had undergone apoptosis, vossicles were recovered and triturated, and cells were filtered through a 40-μm cell strainer to obtain single-cell suspensions. The resulting cells were incubated first with a FITC-conjugated HLA-ABC antibody, where greater than 99% of the luciferase-labeled PC3 cells were positively stained (not shown). Thereafter, percent apoptosis of luciferase-labeled PC3 cells in the vossicles was analyzed using PE-conjugated annexin V/7-ADD by gating on HLA-ABC (n = 4 per group). Significance of differences was determined by Student’s t test. Scale bars: 50 μm (B, C, and E).