**1. Introduction**

Angiogenesis is the formation of new blood vessels from the existing vasculature, and neo‐ vascularization is a prerequisite for the growth of solid tumors beyond 1-2 mm in diameter [1]. Because of this, during tumorigenesis, tumor growth reaches a growth-limiting step where oxygen and nutrient levels are insufficient to continue proliferation.

Tumors acquire blood vessels by co-option of neighboring vessels from sprouting or intus‐ suscepted microvascular growth and by vasculogenesis from endothelial precursor cells [2]. In most solid tumors the newly formed vessels are plagued by structural and functional ab‐ normalities due to the sustained and excessive exposure to angiogenic factors produced by the tumor [3]. As a result of this, the new tumor-associated vasculature is abnormal and in‐ efficient, but it is essential for tumor growth and metastasis. Despite being abnormal, these new vessels allow tumor growth at early stages of carcinogenesis and progression from in situ lesions to locally invasive, and eventually to metastatic tumors.

As a result, tumors tend to become hypoxic. The normal cellular response to hypoxia is to produce growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-α), and platelet derived growth factor (PDGF), by neoplastic, stro‐ mal cells or inflammatory cells [4], and may trigger an angiogenic switch to allow the tumor to induce the formation of microvessels from the surrounding host vasculature [5], that stimulate neoangiogenesis [6].

VEGF is the most potent and specific growth factor for endothelial cells, and is associat‐ ed with tumor vessel density, cancer metastasis, and prognosis [7-10]: high levels of cir‐ culating VEGF have been reported in patients with non-small cell lung cancer (NSCLC)

[7,10-18]. VEGF is continuously expressed throughout the development of many tumor types, and is the only angiogenic factor known to be present throughout the entire tu‐ mor life cycle [19]. The clinical significance of circulating levels of VEGF in patients with NSCLC is controversial.

poiesis, anaerobic metabolism, buffering of the intracellular compartment and induction of growth factors. HIF-1 activity *in vivo* promotes tumor growth in the most of the studies and resistance to several chemotherapy agents, as platinum compounds [22]. Carbonic anhy‐ drase (CA) IX and glucose transporter-1 are other transcriptional targets of HIF-1 and, along with HIF-1, have been identified as novel markers of hypoxia in different tumor types [27-31]. Up-regulation of CA IX in vivo in a perinecrotic pattern suggests this may be an im‐ portant pathway in hypoxia, possibly regulating pH to allow survival of cells under hypoxic

Angiogenesis and Lung Cancer http://dx.doi.org/10.5772/54309 5

Other study showed that HIF-1 is commonly expressed in NSCLC and is involved in the pathogenesis of NSCLC. HIF-1 expression seems associated with a poor prognosis and this was found to be as an independent factor. A similar observation has been made for the prognostic impact of the extent of TN, another marker for hypoxia in NSCLC, where although extensive TN predicts outcome in earlier stages of the disease, no such effect is seen in locally advanced disease. Thus, a number of other studies have included patients with locally advanced disease in different cancer types and reported an association be‐ tween HIF-1 expression and prognosis [22]. Although some other studies have reported

The associations between HIF-1, CA IX, TN and squamous NSCLC are coherent with the known pathways that regulate and are regulated by HIF-1. CA IX is regulated by HIF-1. TN

By other hand, glucose transporter GLUT-1 is a potential intrinsic marker of hypoxia in can‐ cer [29]. VEGF and GLUT-1 are similarly regulated in response to hypoxia [33]. They may functionally help each other to endure hypoxia. Therefore, an upregulated expression of GLUT-1 allows the cell to better use an inadequate source of glucose, while an upregulated expression of VEGF will improve the reserve of glucose and oxygen through the recruitment

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‐

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‐

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

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

cularization, that was conditioned by the diffusion of oxygen and nutrients [34].

and CA IX have been associated with a poor prognosis in NSCLC [22,31].

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

fore, an important role in tumor growth and metastasis development.

conditions [28].

different results [32].

of additional blood vessels [33].

has been the VEGF.

Since tumor growth and metastasis are angiogenesis-dependent, relying upon the genera‐ tion of new blood vessels to sustain proliferation, survival and spread of the malignant cells, therapeutic strategies aimed at inhibiting angiogenesis area theoretically attractive. Target‐ ing and damaging blood vessels can potentially kill thousands of tumor cells. The antiangio‐ genesis and vascular targeting strategies, therefore, may no result in whole tumor cell kill, but may maintain stable disease: this has given rise to the concept *cytostatic paradigm* [20].

The investigation and development of different anti-angiogenesis and vascular targeting strategies are of interest with respect to lung cancer.
