**2. Overview and significance**

## **2.1. Classification of gliomas**

CNS neoplasms are diverse and demonstrate a great deal of variability in terms of clinical presentation, aggressiveness, and response to therapy, with distinctions in histology and cellular and molecular composition being primarily responsible for these variations (Brat and Mapstone 2003; Omuro and DeAngelis 2013). Gliomas are the most frequent primary brain tumors in adults and, of this group, anaplastic astrocytomas and glioblastoma (GBM) are the two highest-grade astrocytic neoplasms (Brat and Mapstone 2003; Ricard, Idbaih et al. 2012). The World Health Organization (WHO) system classifies astrocytomas into four grades. These histological grades are defined by increasing degrees of undifferentiation, anaplasia, and aggressiveness (Louis, Ohgaki et al. 2007; Omuro and DeAngelis 2013). Grade I and II tumors, the lower grade tumors, are well-differentiated with limited cell density. The characteristic features of grade III astrocytomas (anaplastic) are increased vessel and cell density, cellular atypias, and high mitotic activity. Grade IV astrocytoma (GBM) is characterized by vascular proliferation or necrosis (Westphal and Lamszus 2011; Omuro and DeAngelis 2013). Glioblas‐ toma and other malignant gliomas are highly infiltrative tumors. Of note, there is also a WHO grading system for oligodendrogliomas and oligoastrocytomas, but they will not be discussed in this chapter (Omuro and DeAngelis 2013).

**3.2. Summary of angiogenesis**

**3.3. Molecular signals of angiogenesis**

**3.4. Angiogenesis in tumors**

et al. 2004).

Angiogenesis is the process by which the vascular system is formed through growth of new capillaries from pre-existing vessels (Plate, Scholz et al. 2012). Angiogenesis plays a critical role in key physiologic and formative processes such as embryogenesis, regeneration, and wound healing. Angiogenesis is also involved in various pathologic processes including age-related macular degeneration, rheumatoid arthritis, and tumor growth and development (Wang, Fei

Anti-Angiogenesis, Gene Therapy, and Immunotherapy in Malignant Gliomas

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The process of angiogenesis can be briefly summarized as follows. First, there is vasodilation, in response to nitric oxide, and increased permeability of the existing vessels. This is followed by degradation of the existing vessel's basement membrane. Next, endothelial precursor cells migrate to the area and begin to proliferate and mature into capillaries via a balance of both growth and inhibition. The final steps involve recruitment of vascular smooth muscle cells and

Although there are numerous factors and signals that contribute to angiogenesis, the chemical signal that seems to play the most critical role in the process is Vascular Endothelial Growth Factor (VEGF). VEGF is a pro-angiogenic growth factor, which is secreted by many cells, including mesenchymal, stromal, and especially tumor cells. VEGF induces the migration of the endothelial precursor cells to sites of angiogenesis and is responsible for their proliferation and differentiation. The VEGF gene is located on chromosome 6p12 and the gene family is composed of five members, namely VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placentalderived growth factor (PlGF). Of these, VEGF-A, B, and PIGF are involved in the development of the vascular system and VEGF-C and D are involved in the development of the lymphatic system (Ahluwalia and Gladson 2010). VEGF primarily signals through its receptor VEGFR2 which is a tyrosine kinase receptor that is expressed by many cells, including endothelial cells, endothelial cell precursors, and tumor cells (Jain, di Tomaso et al. 2007). Other chemical signals that play an important role in angiogenesis are fibroblast growth factor, hepatocyte growth factor (HGF), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), angiopoietins, and platelet derived growth factor (PDGF). Their various roles include involve‐ ment in extracellular matrix degradation, endothelial proliferation and migration, and neovessel stabilization and maturation (Martin and Jiang 2010; Ucuzian, Gassman et al. 2010).

Seven different cellular mechanisms appear to contribute to tumor angiogenesis: (1) classical sprouting angiogenesis, (2) vascular co-option, (3) myeloid cell-driven angiogenesis, (4) vessel intussusception, (5) vasculogenic mimicry, (6) bone marrow derived vasculogenesis, and (7) cancer stem-like cell derived vasculogenesis (Carmeliet and Jain 2011; Plate, Scholz et al. 2012). Of the above-listed mechanisms, the first three seem to have a clear role in glioma

**1.** *Classical sprouting angiogenesis*. This is believed to be the primary modulator of neovascu‐ larization of the brain during development and in pathological conditions (Plate, Breier

vascularization, as supported by pre-clinical tumor models (Plate, Scholz et al. 2012).

pericytes that form a new network of mature vessels (Shinkaruk, Bayle et al. 2003).

#### **2.2. Significance of malignant gliomas**

The annual incidence of malignant glioma is 5.26 per 100 thousand and this group accounts for approximately 80% of the total number of new cases of malignant primary brain tumors diagnosed in the United States each year (Omuro and DeAngelis 2013). The overall incidence of gliomas is highest among Caucasians, as compared to other ethnic groups, and is higher among males as compared to females (7.2 versus 5.0 per 100,000 persons-years) (Peak and Levin 2010). Malignant gliomas can occur in any age group; however, the incidence increases in the fifth decade of life and peaks at about 65 years of age (Brat and Mapstone 2003). GBM is the most aggressive glioma. Stupp and colleagues reported that 27.2 and 9.8 percent of GBM patients treated by concomitant and adjuvant Temozolamide and radiotherapy remained alive at 2 years and 5 years, respectively (Stupp, Mason et al. 2005; Stupp, Hegi et al. 2009). For patients diagnosed with anaplastic astrocytoma, the median survival time is higher at approximately 2 to 5 years (Wen and Kesari 2008).
