title: A BMP7 variant inhibits the tumorigenic potential of glioblastoma stem-like cells.
abstract: Glioblastoma multiforme (GBM) is among the most aggressive tumor types and is essentially an incurable malignancy characterized by resistance to chemo-, radio-, and immunotherapy. GBM is maintained by a hierarchical cell organization that includes stem-like, precursor, and differentiated cells. Recurrence and maintenance of the tumor is attributed to a small population of undifferentiated tumor-initiating cells, defined as glioblastoma stem-like cells (GSLCs). This cellular hierarchy offers a potential treatment to induce differentiation of GSLCs away from tumor initiation to a more benign phenotype or to a cell type more amenable to standard therapies. Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth and differentiation. In vitro, a BMP7 variant (BMP7v) decreased primary human GSLC proliferation, endothelial cord formation, and stem cell marker expression while enhancing neuronal and astrocyte differentiation marker expression. In subcutaneous and orthotopic GSLC xenografts, which closely reproduce the human disease, BMP7v decreased tumor growth and stem cell marker expression, while enhancing astrocyte and neuronal differentiation compared with control mice. In addition, BMP7v reduced brain invasion, angiogenesis, and associated mortality in the orthotopic model. Inducing differentiation of GSLCs and inhibiting angiogenesis with BMP7v provides a potentially powerful and novel approach to the treatment of GBM.
authors.affiliation: Cancer Biology and Patient Tailoring, Oncology Research, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Tate
authors.forename: R
authors.initials: R
authors.lastname: Pallini
authors.forename: L
authors.initials: L
authors.lastname: Ricci-Vitiani
authors.forename: M
authors.initials: M
authors.lastname: Dowless
authors.forename: T
authors.initials: T
authors.lastname: Shiyanova
authors.forename: G Q
authors.initials: GQ
authors.lastname: D'Alessandris
authors.forename: L
authors.initials: L
authors.lastname: Morgante
authors.forename: S
authors.initials: S
authors.lastname: Giannetti
authors.forename: L M
authors.initials: LM
authors.lastname: Larocca
authors.forename: S
authors.initials: S
authors.lastname: di Martino
authors.forename: S W
authors.initials: SW
authors.lastname: Rowlinson
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.forename: L
authors.initials: L
authors.lastname: Stancato
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D014183:Transplantation, Heterologous
chemical_list: D055419:Bone Morphogenetic Protein 7; D016207:Cytokines