title: Activation of Hematopoietic Stem/Progenitor Cells Promotes Immunosuppression Within the Pre-metastatic Niche.
abstract: Metastatic tumors have been shown to establish microenvironments in distant tissues that are permissive to disseminated tumor cells. Hematopoietic cells contribute to this microenvironment, yet the precise initiating events responsible for establishing the pre-metastatic niche remain unclear. Here, we tracked the developmental fate of hematopoietic stem and progenitor cells (HSPC) in tumor-bearing mice. We show that a distant primary tumor drives the expansion of HSPCs within the bone marrow and their mobilization to the bloodstream. Treatment of purified HSPCs cultured ex vivo with tumor-conditioned media induced their proliferation as well as their differentiation into immunosuppressive myeloid cells. We furthered tracked purified HSPCs in vivo and found they differentiated into myeloid-derived suppressor cells in early metastatic sites of tumor-bearing mice. The number of CD11b(+)Ly6g(+) cells in metastatic sites was significantly increased by HSPC mobilization and decreased if tumor-mediated mobilization was inhibited. Moreover, pharmacologic mobilization of HSPCs increased metastasis, whereas depletion of Gr1(+) cells abrogated the metastasis-promoting effects of HSPC mobilization. Finally, we detected elevated levels of HSPCs in the circulation of newly diagnosed cancer patients, which correlated with increased risk for metastatic progression. Taken together, our results highlight bone marrow activation as one of the earliest steps of the metastatic process and identify circulating HSPCs as potential clinical indicators of metastatic niche formation.
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland.
authors.forename: Amber Jin
authors.initials: AJ
authors.lastname: Giles
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland.
authors.forename: Caitlin Marie
authors.initials: CM
authors.lastname: Reid
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland.
authors.forename: Justin DeWayne
authors.initials: JD
authors.lastname: Evans
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland.
authors.forename: Meera
authors.initials: M
authors.lastname: Murgai
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland.
authors.forename: Yorleny
authors.initials: Y
authors.lastname: Vicioso
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland.
authors.forename: Steven Lorenz
authors.initials: SL
authors.lastname: Highfill
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland.
authors.forename: Miki
authors.initials: M
authors.lastname: Kasai
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, New York.
authors.forename: Linda
authors.initials: L
authors.lastname: Vahdat
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland.
authors.forename: Crystal Lee
authors.initials: CL
authors.lastname: Mackall
authors.affiliation: Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Leonard
authors.initials: L
authors.lastname: Wexler
authors.affiliation: Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland. kaplanrn@mail.nih.gov.
authors.forename: Rosandra Natasha
authors.initials: RN
authors.lastname: Kaplan
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology; D007165:Immunosuppression Therapy / Q000379:methods; D007223:Infant; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology*; D013234:Stem Cells / Q000473:pathology*; D055815:Young Adult