title: The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer.
abstract: 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.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.|Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Berry
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.|Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Eber
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yumoto
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Cackowski
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hyeun Joong
authors.initials: HJ
authors.lastname: Yoon
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.|Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Princy
authors.initials: P
authors.lastname: Parsana
authors.affiliation: Department of Anatomic Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: McGee
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Eunsohl
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Nagrath
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000502:physiology; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000473:pathology*; D055153:Stem Cell Niche / Q000502:physiology*
keywords: bone marrow microenvironment; cancer stem cells; disseminated tumor cells; hematopoietic stem cell niche; prostate cancer