title: Chimeric Mouse model to track the migration of bone marrow derived cells in glioblastoma following anti-angiogenic treatments.
abstract: Bone marrow derived cells (BMDCs) have been shown to contribute in the tumor development. In vivo animal models to investigate the role of BMDCs in tumor development are poorly explored. We established a novel chimeric mouse model using as low as 5 × 10(6) GFP+ BM cells in athymic nude mice, which resulted in >70% engraftment within 14 d. In addition, chimera was established in NOD-SCID mice, which displayed >70% with in 28 d. Since anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in glioblastoma (GBM), which resulted into marked hypoxia and recruited BMDCs to the tumor microenvironment (TME). We exploited chimeric mice in athymic nude background to develop orthotopic U251 tumor and tested receptor tyrosine kinase inhibitors and CXCR4 antagonist against GBM. We were able to track GFP+ BMDCs in the tumor brain using highly sensitive multispectral optical imaging instrument. Increased tumor growth associated with the infiltration of GFP+ BMDCs acquiring suppressive myeloid and endothelial phenotypes was seen in TME following treatments. Immunofluorescence study showed GFP+ cells accumulated at the site of VEGF, SDF1 and PDGF expression, and at the periphery of the tumors following treatments. In conclusion, we developed a preclinical chimeric model of GBM and phenotypes of tumor infiltrated BMDCs were investigated in context of AATs. Chimeric mouse model could be used to study detailed cellular and molecular mechanisms of interaction of BMDCs and TME in cancer.
authors.affiliation: a Tumor Angiogenesis Laboratory, Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University , Augusta , GA , USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Achyut
authors.affiliation: a Tumor Angiogenesis Laboratory, Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University , Augusta , GA , USA.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Shankar
authors.affiliation: a Tumor Angiogenesis Laboratory, Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University , Augusta , GA , USA.
authors.forename: A S M
authors.initials: AS
authors.lastname: Iskander
authors.affiliation: a Tumor Angiogenesis Laboratory, Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University , Augusta , GA , USA.
authors.forename: Roxan
authors.initials: R
authors.lastname: Ara
authors.affiliation: b NMR Center, Henry Ford Health System , Detroit , MI , USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Knight
authors.affiliation: c Cellular and Molecular Imaging Laboratory, Henry Ford Health System , Detroit , MI , USA.
authors.forename: Alfonso G
authors.initials: AG
authors.lastname: Scicli
authors.affiliation: a Tumor Angiogenesis Laboratory, Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University , Augusta , GA , USA.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D018183:Transplantation Chimera; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors
keywords: Bone marrow; Glioblastoma; VEGF; microenvironment; resistance; tumor angiogenesis