title: Mitotic quiescence, but not unique "stemness," marks the phenotype of bone metastasis-initiating cells in prostate cancer.
abstract: This study aimed to identify subpopulations of prostate cancer cells that are responsible for the initiation of bone metastases. Using rapidly dividing human prostate cancer cell lines, we identified mitotically quiescent subpopulations (<1%), which we compared with the rapidly dividing populations for patterns of gene expression and for their ability to migrate to the skeletons of athymic mice. The study used 2-photon microscopy to map the presence/distribution of fluorescently labeled, quiescent cells and luciferase expression to determine the presence of growing bone metastases. We showed that the mitotically quiescent cells were very significantly more tumorigenic in forming bone metastases than fast-growing cells (55 vs. 15%) and had a unique gene expression profile. The quiescent cells were not uniquely stem cell like, with no expression of CD133 but had the same level expression of other putative prostate stem cell markers (CD44 and integrins α2/β1), when compared to the rapidly proliferating population. In addition, mitotic quiescence was associated with very high levels of C-X-C chemokine receptor type 4 (CXCR4) production. Inhibition of CXCR4 activity altered the homing of quiescent tumor cells to bone. Our studies suggest that mitotic dormancy is a unique phenotype that facilitates tumor cell colonization of the skeleton in prostate cancer.
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Freyja
authors.initials: F
authors.lastname: Docherty
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Brown
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Reeves
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Fowles
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lawson
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Penelope D
authors.initials: PD
authors.lastname: Ottewell
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Croucher
authors.affiliation: *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom; Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom; and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia c.l.eaton@sheffield.ac.uk.
authors.forename: Colby L
authors.initials: CL
authors.lastname: Eaton
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D039001:Integrin alpha Chains / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D019718:Receptors, CXCR4
keywords: CXCR4; cell quiescence; metastatic niche