**2. Hypoxia and lung cancer, HIF-1α, carbonic anhydrase IX and glucose transporter glut**

Hypoxia is one of the most important challenges for tumor growth and survival. The angio‐ genesis is a fundamental to avoid tumor necrosis (TN); every cell in a tissue is forced to be within 100μm capillary blood vessel [5].

Hypoxia inducible factor-1 (HIF-1) is a regulator of VEGF under hypoxia conditions [21].

HIF-1 is a heterodimer consisting of 2 subunits, HIF-1α and HIF-1β (otherwise known as the aryl hydrocarbon receptor nuclear translocator), which is stabilized by hypoxia. The expres‐ sion of these subunits is different; HIF-1β is constitutively expressed, unlike HIF-1α, which is rapidly degraded under normoxic conditions [22]. In the presence of oxygen, HIF-1α is hydroxylated on conserved prolyl residues within the oxygen-dependent degradation do‐ main by prolylhydroxylases and binds to von Hippel-Lindau protein (pVHL), which in turn targets it for degradation through the ubiquitin-proteasome pathway [23-26]. Hypoxia in‐ hibits hydroxylation of prolyl residues 402 and 564 in the oxygen-dependent degradation domain that avoid binding of the pVHL. Similar hypoxia-dependent inhibition of hydroxy‐ lation of asparagines residues within the C-terminal activation domain increases HIF-1α transcriptional activity. Oxygen-dependent degradation of HIF-1α is inhibited by *src* and *ras* oncogenes [22-25].

The HIF-1 complex recognizes hypoxia response elements on the promoter of several genes, including VEGF, PDGF, and TGF-α [26].

Growth factors, cytokines and oncogenes, which stimulate p42/p44 mitogen-associated pro‐ tein kinase (MAPK) and/or phosphoinositidyl-3 kinase (PI-3K) pathways, may enhance HIF-1 activity. HIF-1 binds to a conserved sequence (5-CGTG-3) known as the hypoxic re‐ sponse element in the promoter region of its target genes. These target genes are involved in processes that promote cellular survival, angiogenesis, blood vessel vasodilatation, erythro‐ 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 conditions [28].

[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

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

**2. Hypoxia and lung cancer, HIF-1α, carbonic anhydrase IX and glucose**

Hypoxia is one of the most important challenges for tumor growth and survival. The angio‐ genesis is a fundamental to avoid tumor necrosis (TN); every cell in a tissue is forced to be

Hypoxia inducible factor-1 (HIF-1) is a regulator of VEGF under hypoxia conditions [21].

HIF-1 is a heterodimer consisting of 2 subunits, HIF-1α and HIF-1β (otherwise known as the aryl hydrocarbon receptor nuclear translocator), which is stabilized by hypoxia. The expres‐ sion of these subunits is different; HIF-1β is constitutively expressed, unlike HIF-1α, which is rapidly degraded under normoxic conditions [22]. In the presence of oxygen, HIF-1α is hydroxylated on conserved prolyl residues within the oxygen-dependent degradation do‐ main by prolylhydroxylases and binds to von Hippel-Lindau protein (pVHL), which in turn targets it for degradation through the ubiquitin-proteasome pathway [23-26]. Hypoxia in‐ hibits hydroxylation of prolyl residues 402 and 564 in the oxygen-dependent degradation domain that avoid binding of the pVHL. Similar hypoxia-dependent inhibition of hydroxy‐ lation of asparagines residues within the C-terminal activation domain increases HIF-1α transcriptional activity. Oxygen-dependent degradation of HIF-1α is inhibited by *src* and *ras*

The HIF-1 complex recognizes hypoxia response elements on the promoter of several genes,

Growth factors, cytokines and oncogenes, which stimulate p42/p44 mitogen-associated pro‐ tein kinase (MAPK) and/or phosphoinositidyl-3 kinase (PI-3K) pathways, may enhance HIF-1 activity. HIF-1 binds to a conserved sequence (5-CGTG-3) known as the hypoxic re‐ sponse element in the promoter region of its target genes. These target genes are involved in processes that promote cellular survival, angiogenesis, blood vessel vasodilatation, erythro‐

NSCLC is controversial.

**transporter glut**

oncogenes [22-25].

strategies are of interest with respect to lung cancer.

4 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

within 100μm capillary blood vessel [5].

including VEGF, PDGF, and TGF-α [26].

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 different results [32].

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

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 of additional blood vessels [33].
