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Glioblastomas, angiogenesis, and VEGF

Glioblastoma is characterized by high proliferation of tumor cells, increased cellularity, necrosis, and proliferation of capillary endothelial cells (neoangiogenesis).¹ Angiogenesis (the formation of new blood vessels from existing ones) is a vital process in the progression of gliomas to glioblastoma. Angiogenesis is responsible for the growth of small, localized neoplasms into larger, growing, and potentially metastatic tumors. Although glioblastoma rarely metastasizes, it almost always recurs locally due to diffuse infiltration resulting from angiogenesis.² Angiogenesis is regulated by growth factors that bind to their specific receptors on endothelial cells, thereby inducing the proliferation and migration of endothelial cells.¹

A large number of pro- and anti-angiogenic cellular factors regulate angiogenesis in glioblastoma. Among them, VEGF has been implicated as a major paracrine mediator in the pathogenesis of glioblastoma.^2-4

In a study by Takano et al, VEGF concentrations were measured in the sera and tumor extracts, as well as tumor cyst fluid, of brain tumor patients. Significantly higher concentrations of VEGF were found in the tissue of glioblastoma compared with other tumors and normal brain. Although VEGF concentration in the serum was not correlated with that of tumor tissue, VEGF concentration of the glioblastoma cyst fluid was 200 - to 300-fold higher than those in serum and normal brain.⁵

GBM: glioblastoma multiforme; AA: anaplastic astrocytoma; LGA: low-grade astrocytoma; MEN: meningioma; LYM: malignant lymphomas; META: metastatic brain tumor.⁵

Adapted with permission from American Association for Cancer Research.

Additionally, vascular density in the tumors was significantly correlated with VEGF concentration when measured by counting vessels positive for von Willebrand factor, an endothelial cell marker (r=0.76).⁵

Correlation of VEGF concentration in the tumor with tumor vascular density.⁵

Adapted with permission from American Association for Cancer Research.

Takano et al also demonstrated that glioma cells released VEGF in the culture medium in a time-dependent manner, and this correlated with the induction of endothelial cell migration (r=0.96).⁵

VEGF concentration was time-dependently increased in the serum-free conditioned medium of various glioma cells.⁵

Adapted with permission from American Association for Cancer Research.

Additionally, human glioblastoma cells endogeneously express 3 different VEGF variants or isoforms, VEGF₁₂₁, VEGF₁₆₅, and VEGF₁₈₉. Cheng et al conducted a study to determine whether there are biologically functional differences among these isoforms by highly expressing these isoforms individually in glioblastoma cells implanted in mouse brains. VEGF₁₂₁ and VEGF₁₆₅ were the predominant forms of VEGF expressed in glioblastoma cells. In contrast to mice that received VEGF₁₈₉, mice that received VEGF₁₂₁ and VEGF₁₆₅ highly expressing cells developed intracranial hemorrhage after 60 to 90 hours. VEGF₁₈₉ highly expressing cells had only slightly larger tumors soon after implantation; however, after longer periods of growth, enhanced angiogenicity and tumorigenicity were apparent. In VEGF₁₂₁ and VEGF₁₆₅ cells, rapid blood vessel growth and breakdown around the tumor vasculature was noted, whereas in VEGF₁₈₉ rapid vessel growth, but not breakdown, was seen.⁶

References:

1.

Steiner H, Karcher S, Mueller M, et al. J NeuroOnc. 2004;66:129-138.

2.

Maity A, Pore N, Lee J, et al. Cancer Res. 2000;60:5879-5886.

3.

Oka N, Soeda A, Inagaki A, et al. Biochem Biophys Res Commun. 2007;360:553-559.

4.

Nam D, Park K, Suh Y, Kim J. Oncol Rep. 2004;11:863-869.

5.

Takano S, Yoshii Y, Kondo S, et al. Cancer Res. 1996;56:2185-2190.

6.

Cheng S, Nagane M, Huang HJ, Cavenee W. Proc Natl Acad Sci.1997;94:12081-12087.