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.
Oncotarget. 2016 May 09 [Epub ahead of print]
Yusuke Shiozawa, Janice E Berry, Matthew R Eber, Younghun Jung, Kenji Yumoto, Frank C Cackowski, Hyeun Joong Yoon, Princy Parsana, Rohit Mehra, Jingcheng Wang, Samantha McGee, Eunsohl Lee, Sunitha Nagrath, Kenneth J Pienta, Russell S Taichman
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA., Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA., Department of Anatomic Pathology, University of Michigan, Ann Arbor, MI 48109, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA., Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA., Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA., Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.