Changes in VEGF expression and in the vasculature during the growth of early-stage ethylnitrosourea-induced malignant astrocytomas in rats

Abstract

Vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, may be important as a mediator of brain tumour progression. However, it is still not clear whether VEGF plays a causative role in the early stage of glioma development. We investigated the relationship between VEGF protein expression (as assayed by immunohistochemistry) and different morphological parameters reflecting tumour progression (tumour diameter, vascular density and vascular diameter) in tumours at various stages. As a tumour model, ethylnitrosourea (ENU)-induced rat malignant astrocytoma was used. Tumours were classified by size and level of vascularity estimated by the von Willebrand factor (vWF) staining. Tumours less than 10 mm in diameter were designated early stage neoplastic lesions. All 34 early astroglial tumours were found to be VEGF positive. Increase in the VEGF immunopositive rate of tumour cells correlated significantly with increase in vascular density and vascular diameter. We suggest that VEGF induces angiogenesis and growth of microvessels, promoting growth of the early stage malignant astrocytoma.

VEGF Immunopositivity Related to Malignancy Degree, Proliferative Activity and Angiogenesis in ENU-Induced Gliomas

“…ENU-induced glial tumors have been diagnosed as oligodendrogliomas (Vaquero et al 1994), astrocitomas (Yoshimura et al 1998), mixed gliomas, and ependimomas (Zook et al 2000). Histological and immunohistochemical data reported in the present work showed that oligodendrocytes were the major cellular lineage.…”

“…Chemical induction of brain tumors by ethylnitrosourea has allowed the study of several aspects of neoplasm behavior, such as microvascular organization (Yoshimura et al 1998;Schlageter et al 1999), dedifferentiation (Jang et al 2004), gene mutations (O'Neill 2000Bielas and Heddle 2000), or experimental therapeutic agents (Kish et al 2001). However, aspects such as microcirculation and angiogenesis have scarcely been studied using this chemical model.…”

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“…No significant increase (Wilcoxon log rank test, P = 0.18) in survival due to RP treatment was detected. tumors induced by ENU [48,49]. Increases in vascular permeability are thought to be associated with the angiogenic process and this is further supported by the size of the tumor (∼1-2 mm), which is within the range postulated for the development of vascular elements (the angiogenic switch [50][51][52]).…”

“…However, many of the chemopreventative agents are gaining recognition as potentially having anti-angiogenic properties. As described above, VEGF has been shown to be expressed very early in the brain tumors induced by ENU [48,49]. All-trans retinoic acid (RA), 13-cis RA and all-trans retinol reduced VEGF secretion by human keratinocytes in primary cultures [57].…”

T 1 ‐W DCE‐MRI: T 1 ‐Weighted Dynamic Contrast‐Enhanced MRI

“…The causes of BBB breakdown in tumours are complex and partly related to the secretion of angiogenic stimulator molecules. Certainly, vascular endothelial growth factor (VEGF) has been implicated in the glial tumour angiogenesis (Yoshimura et al, 1998;Varlet et al, 2000;Chaudhry et al, 2001), but is also a potent vascular permeability factor Nagy et al, 1995). Angiogenesis in itself does not explain BBB breakdown because angiogenesis and increased vascular density are commonly observed with an intact BBB (e.g.…”