Human Prostate Cancer Metastases Target the Hematopoietic Stem Cell Niche to Establish Footholds in Mouse Bone Marrow

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2011 Mar 26

PMID 21436587

Citations 383

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

Affiliations

Soon will be listed here.

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.

Citing Articles

The Tight Relationship Between the Tumoral Microenvironment and Radium-223.

Conte M, Tomaciello M, De Feo M, Frantellizzi V, Marampon F, De Cristofaro F Biomedicines. 2025; 13(2).

PMID: 40002869 PMC: 11853176. DOI: 10.3390/biomedicines13020456.

Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction.

Verona F, Di Bella S, Schirano R, Manfredi C, Angeloro F, Bozzari G Front Immunol. 2025; 16:1529847.

PMID: 39981232 PMC: 11839637. DOI: 10.3389/fimmu.2025.1529847.

Amorphous calcium phosphate-coated surfaces as a model for bone microenvironment in prostate cancer.

San Martin R, Das P, Xue T, Brown M, Dos Reis Marques R, Essington M Heliyon. 2025; 11(3):e41929.

PMID: 39931470 PMC: 11808503. DOI: 10.1016/j.heliyon.2025.e41929.

Components of the Endosome-Lysosome Vesicular Machinery as Drivers of the Metastatic Cascade in Prostate Cancer.

Nturubika B, Logan J, Johnson I, Moore C, Li K, Tang J Cancers (Basel). 2025; 17(1.

PMID: 39796673 PMC: 11718918. DOI: 10.3390/cancers17010043.

Immunotherapy in the Battle Against Bone Metastases: Mechanisms and Emerging Treatments.

Hamza F, Mohammad K Pharmaceuticals (Basel). 2025; 17(12.

PMID: 39770433 PMC: 11679356. DOI: 10.3390/ph17121591.

References

Taichman R, Emerson S . Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med. 1994; 179(5):1677-82. PMC: 2191506. DOI: 10.1084/jem.179.5.1677. View

Wu T, Sikes R, Cui Q, Thalmann G, Kao C, Murphy C . Establishing human prostate cancer cell xenografts in bone: induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines. Int J Cancer. 1998; 77(6):887-94. DOI: 10.1002/(sici)1097-0215(19980911)77:6<887::aid-ijc15>3.0.co;2-z. View

Al-Hajj M, Wicha M, Benito-Hernandez A, Morrison S, Clarke M . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003; 100(7):3983-8. PMC: 153034. DOI: 10.1073/pnas.0530291100. View

Kiel M, Yilmaz O, Iwashita T, Yilmaz O, Terhorst C, Morrison S . SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005; 121(7):1109-21. DOI: 10.1016/j.cell.2005.05.026. View

Havens A, Pedersen E, Shiozawa Y, Ying C, Jung Y, Sun Y . An in vivo mouse model for human prostate cancer metastasis. Neoplasia. 2008; 10(4):371-80. PMC: 2288546. DOI: 10.1593/neo.08154. View

Zhang J, Niu C, Ye L, Huang H, He X, Tong W . Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003; 425(6960):836-41. DOI: 10.1038/nature02041. View

Paget S . The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989; 8(2):98-101. View

Raaijmakers M, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker J . Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 2010; 464(7290):852-7. PMC: 3422863. DOI: 10.1038/nature08851. View

Park I, Qian D, Kiel M, Becker M, Pihalja M, Weissman I . Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003; 423(6937):302-5. DOI: 10.1038/nature01587. View

10.

Wilson A, Trumpp A . Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006; 6(2):93-106. DOI: 10.1038/nri1779. View

11.

Calvi L, Adams G, Weibrecht K, Weber J, Olson D, Knight M . Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003; 425(6960):841-6. DOI: 10.1038/nature02040. View

12.

Yin T, Li L . The stem cell niches in bone. J Clin Invest. 2006; 116(5):1195-201. PMC: 1451221. DOI: 10.1172/JCI28568. View

13.

Roodman G . Mechanisms of bone metastasis. N Engl J Med. 2004; 350(16):1655-64. DOI: 10.1056/NEJMra030831. View

14.

Jung Y, Song J, Shiozawa Y, Wang J, Wang Z, Williams B . Hematopoietic stem cells regulate mesenchymal stromal cell induction into osteoblasts thereby participating in the formation of the stem cell niche. Stem Cells. 2008; 26(8):2042-51. PMC: 3513687. DOI: 10.1634/stemcells.2008-0149. View

15.

Pantel K, Cote R, Fodstad O . Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst. 1999; 91(13):1113-24. DOI: 10.1093/jnci/91.13.1113. View

16.

Papayannopoulou T . Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood. 2003; 103(5):1580-5. DOI: 10.1182/blood-2003-05-1595. View

17.

Jung Y, Wang J, Song J, Shiozawa Y, Wang J, Havens A . Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood. 2007; 110(1):82-90. PMC: 1896130. DOI: 10.1182/blood-2006-05-021352. View

18.

Sun Y, Fang M, Wang J, Cooper C, Pienta K, Taichman R . Expression and activation of alpha v beta 3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells. Prostate. 2006; 67(1):61-73. DOI: 10.1002/pros.20500. View

19.

Taichman R, Loberg R, Mehra R, Pienta K . The evolving biology and treatment of prostate cancer. J Clin Invest. 2007; 117(9):2351-61. PMC: 1952634. DOI: 10.1172/JCI31791. View

20.

Broxmeyer H, Orschell C, Clapp D, Hangoc G, Cooper S, Plett P . Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005; 201(8):1307-18. PMC: 2213145. DOI: 10.1084/jem.20041385. View