Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo

Adarsh Shankar, Sanath Kumar, Asm Iskander, Nadimpalli R S Varma, Branislava Janic, Ana deCarvalho, Tom Mikkelsen, Joseph A. Frank, Meser M. Ali, Robert A. Knight, Stephen Brown, Ali Syed Arbab

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)148-158
Number of pages11
JournalChinese Journal of Cancer
Volume33
Issue number3
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Glioblastoma
Cell Movement
Cell Proliferation
Radiation
Neoplasms
Nude Rats
Matrix Metalloproteinase 2
Microvessels
Magnetic Resonance Imaging
Radiation Effects
von Willebrand Factor
Growth
Radiotherapy
Immunohistochemistry
Staining and Labeling
Brain
Therapeutics

Keywords

  • Glioblastoma multiforme
  • Invasion
  • Radiation
  • Treatment resistance

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo. / Shankar, Adarsh; Kumar, Sanath; Iskander, Asm; Varma, Nadimpalli R S; Janic, Branislava; deCarvalho, Ana; Mikkelsen, Tom; Frank, Joseph A.; Ali, Meser M.; Knight, Robert A.; Brown, Stephen; Arbab, Ali Syed.

In: Chinese Journal of Cancer, Vol. 33, No. 3, 01.01.2014, p. 148-158.

Research output: Contribution to journalArticle

Shankar, A, Kumar, S, Iskander, A, Varma, NRS, Janic, B, deCarvalho, A, Mikkelsen, T, Frank, JA, Ali, MM, Knight, RA, Brown, S & Arbab, AS 2014, 'Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo', Chinese Journal of Cancer, vol. 33, no. 3, pp. 148-158. https://doi.org/10.5732/cjc.013.10095
Shankar, Adarsh ; Kumar, Sanath ; Iskander, Asm ; Varma, Nadimpalli R S ; Janic, Branislava ; deCarvalho, Ana ; Mikkelsen, Tom ; Frank, Joseph A. ; Ali, Meser M. ; Knight, Robert A. ; Brown, Stephen ; Arbab, Ali Syed. / Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo. In: Chinese Journal of Cancer. 2014 ; Vol. 33, No. 3. pp. 148-158.
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AU - Mikkelsen, Tom

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N2 - 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.

AB - 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.

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