Endogenous experimental glioma model, links between glioma stem cells and angiogenesis.

Glioblastomas (GBM) are the most malignant solid tumours (grade IV) of CNS. They are glial lineage neoplasias with a high proliferative and invasive capacity, reaching to occupy an entire lobe of the brain (Kleihues et al., 2007). According with their genesis, they can be differentiated between primary and secondary glioblastoma.
The primary is the most common glioblastoma.This is a new generated tumour after a brief medical history (three months), with no evidence of a less malignant lesion. On the other hand, secondary glioblastoma develops from diffuse astrocytoma, anaplastic astrocytoma or oligodendroglioma and malignant progression. Its development time is about five years. It is thought that both types of glioblastomas may be generated from neoplastic cells with characteristic of stem cells (Ohgaki & Kleihues, 2009). In addition, these cancer stem cells called “glioma stem cells” (GSCs) may be the responsible for glioma recurrences due to chemo-and radio resistance (Bao et al., 2006; Rich, 2007). Glioma stem cells (GSCs) are a subpopulation of neoplastic cells identified in glioma sharing properties with neural stem cells (self-renewal, high proliferation rate, undifferentiating, and neurospheres conformation) and the capacity for leading the tumourigenesis and tumour malignancy. The proliferation and the invasion into adjacent normal parenchyma have been attributed to glioma stem cells as well. Indeed, they were related to the angiogenesis process needed for the growth and survival of the neoplasia.
The microvascular network in gliomas has to get adapt to metabolic tissue requirements (Folkman, 2000). When the vascular network cannot satisfy cell requirements (Oxygen pressure of 5-10 mm Hg) tissue hypoxia occurs. This situation triggers the synthesis of proangiogenic factors as matrix metalloprotease (MMP-2), angiopoietin-1, phosphoglycerate kinase (PGK), erythropoietin (EPO), and vascular endothelial growth factor (VEGF)-A (Fong, 2008).
Vascular endothelial growth factor (VEGF) is a major regulator of tumour angiogenesis (Bulnes & Lafuente, 2007; Lafuente et al., 1999; Machein & Plate, 2004; Marti et al., 2000). VEGF acts as mitogen, survival, antiapoptotic and vascular permeability factor (VPF) for the endothelial cells (Dvorak, 2006). The increase of this pro-angiogenic factor, secreted either by neoplastic cells or by cells of the tumour microenvironment, induces the start of angiogenesis, the called “angiogenic switch” (Bergers & Benjamin, 2003). This event results in the transition from avascularised hyperplasia to outgrowing vascularised tumour and eventually to malignant progression. It has been shown in human glioma biopsies that VEGF overexpression correlates directly to proliferation, vascularization and degree of malignancy, and therefore inversely to prognosis (Ke et al., 2000; Lafuente et al., 1999; Plate, 1999). The synthesis of VEGF is mediated by the Hypoxia-Inducible Factor (HIF-1), a critical step for the formation of new blood vessels and for the adaptation of microenvironment to the growth of gliomas (Jin et al., 2000; Marti et al., 2000; Semenza, 2003). Recent researches have reported that glioma stem cells play a pivotal role inducing the angiogenesis via HIF-1/VEGF (Bao et al., 2006). By the other hand, hypoxia has been related to clones selection of tumour cells. These clones adapted to the tumour microenvironment have acquired the phenotype of tumour stem cell with increased proliferative and infiltrative capacity (Heddleston et al., 2009; Li et al., 2009). Invasion of adjacent normal parenchyma has been attributed to glioma stem cells as well.
Due to these evidences, GSCs are currently being considered as a potential therapeutic target of the tumours. Recent studies have been focused on the identification of GSCs. In human glioblastomas they have been identified using CD133 marker (Ignatova et al., 2002).
However, little is known about their genesis during glioma progression, especially during the early stages. Some authors have previously reported the induction of glial tumour in rats by
transplacentary administration of the carcinogen ethylnitrosourea (ENU) as a suitable method for studying the natural development of glioma (Bulnes-Sesma et al., 2006; Zook et al., 2000). In addition to this, it has been reported that ENU glioma model is a representative model for human glioma due to its location and also to its similar cellular, molecular and genetic alterations (Kokkinakis et al., 2004). Our experience with this model has proven to be useful to study many aspects of tumourigenesis and neoangiogenesis. In previous researches we reported the progression of tumour malignancy associated with vascular structural alterations and blood brain barrier (BBB) disturbances (Bulnes & Lafuente, 2007; Bulnes et al., 2009). ENU induced glioma permitted us to identify tumour developmentstages following microvascular changes. In addition, it was possible to study the angiogenesis process. Recently, we have used this model to study the relationship between glioma stem cells and angiogenesis process during the neoplasia development.
Many evidences corroborate the hypothesis that “glioma stem cells” have a close relationship with angiogenesis process, intratumour hypoxia and neoplastic microvascular network.
SOURCE: Susana Bulnes, Harkaitz Bengoetxea, Naiara Ortuzar, Enrike.G. Argandoña and José Vicente Lafuente (2011). Endogenous experimental glioma model, links between glioma stem cells and angiogenesis.