title: A highly invasive human glioblastoma pre-clinical model for testing therapeutics.
abstract: Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM) mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino)-17-demethoxy geldanamycin (17AAG). Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM) to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2). These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents.
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503, USA. qian.xie@vai.org
authors.forename: Qian
authors.initials: Q
authors.lastname: Xie
authors.forename: Ryan
authors.initials: R
authors.lastname: Thompson
authors.forename: Kim
authors.initials: K
authors.lastname: Hardy
authors.forename: Lisa
authors.initials: L
authors.lastname: DeCamp
authors.forename: Bree
authors.initials: B
authors.lastname: Berghuis
authors.forename: Robert
authors.initials: R
authors.lastname: Sigler
authors.forename: Beatrice
authors.initials: B
authors.lastname: Knudsen
authors.forename: Sandra
authors.initials: S
authors.lastname: Cottingham
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Karl
authors.initials: K
authors.lastname: Dykema
authors.forename: Brian
authors.initials: B
authors.lastname: Cao
authors.forename: James
authors.initials: J
authors.lastname: Resau
authors.forename: Rick
authors.initials: R
authors.lastname: Hay
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016227:Benzoquinones / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin