title: The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells.
abstract: The stromal compartments of hematopoietic organs (eg, spleen) are known to influence the viability and growth of diseased hematopoietic progenitors. Here we have used Friend murine leukemia virus (F-MuLV)-induced erythroleukemia to investigate factors of the splenic microenvironment that may make it fertile for the expansion and survival of malignant erythroblasts. We found that splenectomized, erythroleukemic mice exhibited extended survival compared with age-matched sham controls. In vitro, the proliferation of primary erythroleukemic cells cocultured with leukemic-derived splenic adherent cells or their conditioned media was found to be significantly higher than that observed in cocultures with healthy-derived adherent splenic cells. Cytokine protein arrays revealed that F-MuLV-infected splenocytes secreted elevated levels of interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), macrophage chemoattractant protein-5 (MCP-5), soluble tumor necrosis factor receptor-1 (sTNFR1), IL-12p70, tumor necrosis factor-alpha (TNF-alpha), and IL-2 over normal splenocytes. Medium supplemented with both VEGF-A and MCP-5 could sustain proliferation of primary erythroleukemic cells in vitro, and significant proliferative suppression was observed upon addition of neutralizing antibodies to either of these factors. Furthermore, in vivo administration of a neutralizing antibody to VEGF-A extended survival times of erythroleukemic mice in comparison with controls. These findings suggest that VEGF-A and MCP-5 are potentially pivotal paracrine mediators occurring within the diseased splenic microenvironment capable of promoting disease acceleration and expansion of erythroleukemic blasts.
authors.affiliation: Department of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Dave
authors.initials: D
authors.lastname: Cervi
authors.forename: Manuela
authors.initials: M
authors.lastname: Neuman
authors.forename: Limor
authors.initials: L
authors.lastname: Chen
authors.forename: Giannoula
authors.initials: G
authors.lastname: Klement
authors.forename: Crystal R
authors.initials: CR
authors.lastname: Michaud
authors.forename: Mehran
authors.initials: M
authors.lastname: Haeri
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Pak
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Ben-David
mesh_terms: D042501:Angiogenic Proteins / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology*; D004915:Leukemia, Erythroblastic, Acute / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018945:Monocyte Chemoattractant Proteins / Q000276:immunology / Q000378:metabolism; D019899:Paracrine Communication; D013154:Spleen / Q000378:metabolism* / Q000473:pathology; D013156:Splenectomy; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; D000911:Antibodies, Monoclonal; D016207:Cytokines; D018836:Inflammation Mediators; D018945:Monocyte Chemoattractant Proteins; D042461:Vascular Endothelial Growth Factor A