The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer
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Yusuke Shiozawa1,2, Janice E. Berry1,*, Matthew R. Eber1,2, Younghun Jung1, Kenji Yumoto1, Frank C. Cackowski1, Hyeun Joong Yoon3, Princy Parsana4,5, Rohit Mehra6, Jingcheng Wang1, Samantha McGee1, Eunsohl Lee1, Sunitha Nagrath3, Kenneth J. Pienta4, Russell S. Taichman1
1Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
2Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
3Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
4Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
5Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA
6Department of Anatomic Pathology, University of Michigan, Ann Arbor, MI 48109, USA
*Deceased on February 4, 2016
Russell S. Taichman, email: [email protected]
Keywords: prostate cancer, disseminated tumor cells, bone marrow microenvironment, hematopoietic stem cell niche, cancer stem cells
Received: March 04, 2016 Accepted: April 19, 2016 Published: May 09, 2016
Dissemination of cancer stem cells (CSCs) serves as the basis of metastasis. Recently, we demonstrated that circulating prostate cancer targets the hematopoietic stem cell (HSCs) ‘niche’ in marrow during dissemination. Once in the niche, disseminated tumor cells (DTCs) may remain dormant for extended periods. As the major function of the HSC niche is to maintain stem cell functions, we hypothesized that the niche regulates CSC activities of DTCs. Here we show that DTCs recovered from marrow were significantly enriched for a CSC phenotype. Critically, the conversion of DTCs to CSCs is regulated by niche-derived GAS6 through the Mer/mTOR; molecules previously shown to regulate dormancy. The data demonstrate that the niche plays a significant role in maintaining tumor-initiating prostate cancer in marrow and suggests a functional relationship between CSCs and dormancy. Understanding how the marrow niche regulates the conversion of DTCs to CSCs is critical for the development of therapeutics specifically targeting skeletal bone metastasis and dormancy.
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