title: Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo.
abstract: Tumor cell proliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme (GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77 (baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation (n = 8), or underwent no radiation (n = 8). Brain tissues were obtained on day 112 (nonirradiated) or day 133 (irradiated). Immunohistochemistry was performed to determine tumor cell proliferation (Ki-67) and to assess the expression of infiltration marker (matrix metalloproteinase-2, MMP-2) and cell migration marker (CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor (vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was (71 +/- 15)% compared with (25 +/- 12)% in the nonirradiated group (P = 0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance following radiation therapy for GBM.
authors.affiliation: Department of Radiology, Henry Ford Hospital, Detroit, MI 48202, USA. skumar4@hfhs.org.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Shankar
authors.forename: Sanath
authors.initials: S
authors.lastname: Kumar
authors.forename: A S M
authors.initials: AS
authors.lastname: Iskander
authors.forename: Nadimpalli R S
authors.initials: NR
authors.lastname: Varma
authors.forename: Branislava
authors.initials: B
authors.lastname: Janic
authors.forename: Ana
authors.initials: A
authors.lastname: deCarvalho
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Frank
authors.forename: Meser M
authors.initials: MM
authors.lastname: Ali
authors.forename: Robert A
authors.initials: RA
authors.lastname: Knight
authors.forename: Stephen
authors.initials: S
authors.lastname: Brown
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000528:radiation effects*; D049109:Cell Proliferation / Q000528:radiation effects*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D055806:Microvessels / Q000473:pathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D011836:Radiation Tolerance; D011882:Radiotherapy, High-Energy; D051381:Rats; D011923:Rats, Nude
chemical_list: D018960:Hyaluronan Receptors; D019394:Ki-67 Antigen; D020778:Matrix Metalloproteinase 2
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