title: Bone marrow derived cells in the tumour microenvironment contain cells with primitive haematopoietic phenotype.
abstract: Infiltration of bone marrow derived cells is part of the angiogenic switch required for uncontrolled tumour growth. However, the nature of the tumour-infiltrating cells from bone marrow has not been fully elucidated. To investigate the phenotype of bone marrow derived cells within a tumour, we employed the Lewis lung carcinoma (LLC) murine tumour model. We followed bone marrow derivation of tumour-infiltrating cells through transplantation of CD45.2 bone marrow cells into pre-irradiated CD45.1 mice. We found robust CD45.2 donor type chimerism in bone marrow and blood of CD45.1 recipient tumour-bearing mice. Flow cytometric analysis of LLC tumours showed, in addition to previously described pro-angiogenic CD45(+)VEGFR2(+)'endothelial progenitor cells' (EPC), or CD45(+)Tie2(+)'Tie2-expressing monocytes' (TEM), incorporation of donor type lineage marker negative (Lin(-)) and Lin(-)Sca1(+) undifferentiated haematopoietic cell types. Immunohistochemical analysis confirmed the extravasal location of the primitive haematopoietic cells. Flow-cytometric sorting of bone marrow cells and subsequent analysis in haematopoietic colony-forming assays revealed that cells with a Lin(-)Sca1(+) phenotype, which were initially negative for VEGFR2 and Tie2, gave rise to VEGFR2(+) and/or Tie2(+) cells. Moreover, Lin(-) bone marrow cells pre-labelled with the membrane dye PKH26 (a red fluorochrome) and transplanted i.v. into tumour-bearing mice were found to extravasate and incorporate into LLC tumours within 24 hrs. Thus, primitive haematopoietic precursors which are thought to be precursors of EPC and TEMs, constitute a part of the tumour microenvironment. This makes them an attractive target cell population for tumour-directed cellular therapies.
authors.affiliation: Stem Cell Biology Group, DRK Institute of Transfusion Medicine and Immune Hematology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Erika
authors.initials: E
authors.lastname: Deak
authors.forename: Stephan
authors.initials: S
authors.lastname: Göttig
authors.forename: Brigitte
authors.initials: B
authors.lastname: Rüster
authors.forename: Virgil
authors.initials: V
authors.lastname: Paunescu
authors.forename: Erhard
authors.initials: E
authors.lastname: Seifried
authors.forename: Jens
authors.initials: J
authors.lastname: Gille
authors.forename: Reinhard
authors.initials: R
authors.lastname: Henschler
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D006410:Hematopoiesis; D051379:Mice; D010641:Phenotype