**3. Pathophysiology and clinical implications of VEGF**

The role of angiogenesis in cancer biology was defended by Folkman in 1971, who first postulated that solid tumors remained latent at a specific size due to the absence of neovas‐ cularization, that was conditioned by the diffusion of oxygen and nutrients [34].

Subsequent studies have shown that angiogenesis is involved in tumor development from the initial stages to the most advanced stages of the disease [35]. Angiogenesis plays there‐ fore, an important role in tumor growth and metastasis development.

Since then, one of the most important questions has been the identification of proangio‐ genic factors and the mechanisms in order to block its action. One of the most studied has been the VEGF.

VEGF is a potent mediator of angiogenesis. It is a growth factor that stimulates the prolifera‐ tion and migration, promotes survival, inhibits apoptosis and regulates the permeability of vascular endothelial cells. It belongs to the growth factors family, which includes four ho‐ mologues VEGF-A (commonly referred to as VEGF)-B, -C, -D, -E and placental growth fac‐ tor (PIGF). The biological activity of VEGF is mediated by binding to receptors with tyrosine kinase activity VEGFR-1 (also known as fms-like tyrosine kinase 1, ftl-1), VEGFR-2 (also known as kinase-insert domain receptor, KDR) and VEGFR-3 (ftl4).

**4. Pathophysiology and clinical implications of EGF/PDGF/VEG**

tor Insulin-like type I (IGF-I) and Platelet Derived Growth Factor platelet (PDGF).

contributions to a complicated signaling network.

proteins and molecules (Fig 2).

**4.1. EGF**

(NRGs).

It is known that other several growth factors regulate developmental processes, among which are the Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), growth fac‐

Angiogenesis and Lung Cancer http://dx.doi.org/10.5772/54309 7

Members of the EGF family of peptide growth factors serve as agonists for ErbB family re‐ ceptors. They include EGF, TGFα, amphiregulin (AR), betacellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF), epiregulin (EPR), epigen (EPG), and the neuregulins

EGF is a polypeptide of 53 amino acids (6 Kda) that appears as a product of proteolytic proc‐ essing of a large protein integral membrane (1207aa). This precursor protein is consisting of 8 domains called EGF-like, of which only one is active. The gene corresponding to this growth factor is located on chromosome 4q25 and stimulates epithelial cell proliferation, on‐ cogenesis and is involved in wound healing. Its three-dimensional structure is characterized by the presence of common domain to other family ligands. This protein shows a strong se‐ quential and functional homology with TGFα, which is a competitor for EGF receptor sites. Collectively, these agonists regulate the activity of the four ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) family receptors, each of which appears to make a unique set of

EGF binds to a specific receptor on the surface of responsive cells known as EGFR (Epider‐ mal growth factor receptor). EGFR is a member of the ErbB family receptors, a subfamily of four closely related to tyrosine kinase receptors: EGFR (ErbB1), Her2/c-neu (ErbB2), Her3 (ErbB3) and Her4 (ErbB4) (Fig.1). The EGF family ligands exhibits a complex pattern of in‐ teractions with the four ErbB family receptors; for example, EGFR can bind eight different EGF family members and Neuregulin 2beta (NRG2β) binds EGFR, ErbB3 and ErbB4. Given that ErbB2 lacks an EGF family ligand, ErbB3 lacks kinase activity, and the four ErbB recep‐ tor display distinct coupling patterns to different signaling effectors in the affinity of a given

In response to toxic environmental stimuli, such as ultraviolet irradiation, or to receptor occupation by EGF, the EGFR forms Homo- or Heterodimers with other family mem‐ bers. Binding of EGF to the extracellular domain of EGFR leads to receptor dimerization, activation of the intrinsic PTK (Protein Tyrosine Kinase), tyrosine autophosphorylation, and recruitment of various signaling proteins to these autophosphorylation sites located primarily in the C-terminal tail of the receptor. Tyrosine phosphorylation of the EGFR leads to the recruitment of diverse signaling proteins, including the Adaptor proteins GRB2 (Growth Factor Receptor-Bound Protein-2) and Nck (Nck Adaptor Protein), PLC- &γ; (Phospholipase-C-γ), SHC (Src Homology-2 Domain Containing Transforming Pro‐ tein), STATs (Signal Transducer and Activator of Transcription), and several other

EGF family member as a key determinant of specificity for the ligand [49].

When VEGF binds to its receptors it causes receptor dimerization, autophosphorylation, and downstream signaling of different pathways, as v-src sarcoma viral oncogene homolog (Src), phosphoinositol (PI)-3 kinase (PI3K) and phospholipase-C γ (PLCγ) which activate proliferation and angiogenesis.

In animal tumor models, VEGF is produced both by tumor cells and also by stromal tissues [4].

VEGF and its receptor are expressed in tumor cells in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) [36,37]. It is involved in tumor growth by neoangio‐ genesis, lymphangiogenesis and lymph nodal dissemination [38]. High levels of VEGF have been correlated with poor prognosis [39]. But there are several questions about the role of VEGF levels and its various isoforms plays as a potential biomarker, which may be useful in the use and selection of therapies against it. VEGF levels are elevated in lung cancer patients when compared to controls [40]. There is also a correlation between VEGF levels and the clinical stage in NSCLC patients [7,10,13,15] and an inverse correlation between the VEGF serum levels and survival [41]. Low levels of VEGF have shown to be correlated with a good response to chemotherapy [12]. Moreover, a study showed that low levels of VEGF were correlated with a good response to anti-EGFR. Furthermore, levels of VEGF in responders were not significantly different from volunteers, but were different from non-responders [42]. However, it remains unclear whether the clinical effects of anti-EGFR in patients with NSCLC are correlated with reductions in the levels of angiogenic growth factors. Further‐ more, it is unclear whether these factors are correlated with response to anti-EGFR treat‐ ment, blocking EGFR autophosphorylation [43] and the subsequent signal transduction pathways implicated in proliferation, metastasis and inhibition of apoptosis, as well as an‐ giogenesis [44,45]. The inhibition of EGFR has been shown to reduce production of angio‐ genic growth factors in various types of cancer cells [45,46].

Antiangiogenic drugs have demonstrated efficacy in the treatment of NSCLC in the last years. The more tested antiangiogenic drug in lung cancer is bevacizumab, a monoclonal an‐ tibody directed against VEGF, which is the first antiangiogenic approved for treatment of metastatic NSCLC in combination with chemotherapy. Two phase III studies have assessed the efficacy of chemotherapy combinations associated with bevacizumab. The AVAiL study [47] analyzed the combination of cisplatin and gemcitabine with or without bevacizumab in first line treatment for NSCLC. The primary endpoint was reached, showing a benefit in progression-free survival in the bevacizumab arm. The second study [48] compared the ad‐ dition of bevacizumab with carboplatin and paclitaxel regimen, aiming differences in over‐ all survival, progression-free survival and response rate.

These detailed studies further in subsequent chapters, show that bevacizumab is an effective and safe drug in the treatment of advanced NSCLC.
