title: Differential role of EGF and BFGF in human GBM-TIC proliferation: relationship to EGFR-tyrosine kinase inhibitor sensibility.
abstract: Glioblastoma multiforme (GBM) is among the most devastating human tumors being rapidly fatal despite aggressive surgery, radiation and chemotherapies. It is characterized by extensive dissemination of tumor cells within the brain that hinders complete surgical resection. GBM tumor initiating-cells (TICs) are a rare subpopulation of cells responsible for tumor development, growth, invasiveness and recurrence after chemotherapy. TICs from human GBM can be selected in vitro using the same conditions permissive for the growth of normal neural cells, of which share some features including marker expression, self-renewal capacity, long-term proliferation, and ability to differentiate into neuronal and glial cells. EGFR overexpression and its constitutive activation is one of the most important signaling alteration identified in GBM, and its pharmacological targeting represents an attractive therapeutic goal. We previously demonstrated that human GBM TICs have different sensitivity to the EGFR kinase inhibitors erlotinib and gefitinib, depending on the differential modulation of downstream signaling cascades. In this work we investigated the mechanisms of resistance to erlotinib in two human GBM TIC cultures, analyzing EGF and bFGF individual contribution to proliferation, clonogenicity, and migration. We demonstrated the presence of a small cell subpopulation whose proliferation is supported by EGF and a larger one mainly dependent on bFGF. Thus, insensitivity to EGFR kinase inhibitors as far as TIC proliferation results from a predominant FGFR activation that hides the inhibitory effects induced on EGFR signaling. Conversely, EGF and bFGF induced cell migration with similar efficacy. In addition, unlike neural stem/progenitors cells, the removal of chondroitin sulphate proteoglycans from cell surface was unable to discern EGF- and bFGF-dependent subpopulations in GBM TICs.
authors.affiliation: Department of Internal Medicine, University of Genova, Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bajetto
authors.forename: C
authors.initials: C
authors.lastname: Porcile
authors.forename: A
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: L
authors.initials: L
authors.lastname: Scotti
authors.forename: A
authors.initials: A
authors.lastname: Aceto
authors.forename: A
authors.initials: A
authors.lastname: Daga
authors.forename: F
authors.initials: F
authors.lastname: Barbieri
authors.forename: T
authors.initials: T
authors.lastname: Florio
mesh_terms: D000368:Aged; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000378:metabolism; D002999:Clone Cells; D004354:Drug Screening Assays, Antitumor; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D014410:Tumor Stem Cell Assay
chemical_list: D047428:Protein Kinase Inhibitors; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D002809:Chondroitin Sulfates; D066246:ErbB Receptors