The impact of O2 availability on human cancer

Abstract

During the last century, it has been established that regions within solid tumors experience mild to severe oxygen deprivation, due to aberrant vascular function. These hypoxic regions are associated with altered cellular metabolism, as well as increased resistance to radiation and chemotherapy. As discussed in this Timeline, over the past decade, work from many laboratories has elucidated the mechanisms by which hypoxia-inducible factors (HIFs) modulate tumor cell metabolism, angiogenesis, growth, and metastasis. The central role played by intra-tumoral hypoxia and HTF in these processes has made them attractive therapeutic targets in the treatment of multiple human malignancies.Oxygen (O 2 ) is required for aerobic metabolism to maintain intracellular bioenergetics and serve as an electron acceptor in many organic and inorganic reactions. Hypoxia, defined as reduced O 2 levels, occurs in a variety of pathological conditions, including stroke, tissue ischemia, inflammation, and the growth of solid tumors. The beginnings of hypoxia research in tumor biology can be traced back to observations made in the early 20 th century by Otto Warburg who demonstrated that, unlike normal cells, tumor cells favor glycolysis, independent of cellular oxygenation levels. He postulated that tumor growth is caused by mitochondrial dysfunction in neoplastic cells, forcing them to generate energy through glycolysis (reviewed in 1 ). This hypothesis appears to be incorrect, but a number of other molecular mechanisms promoting "aerobic glycolysis" have been proposed including mutations and epigenetic changes in genes encoding tumor suppressors (e.g. p53), oncogene activation (e.g. c-Myc), and hypoxic adaptations {Denko, 2008 #6606; Gatenby, 2004 #6608; Deberardinis, 2008 #6609.

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

“…Finally, the inhibition of HIF1a expression markedly suppressed synthesis of vascular endothelial growth factor (VEGF) as determined in EIA with the ALK þ TCL cell culture supernatants (Figure 4d). Our findings indicate that ALK þ TCL cells express HIF1a, an important oncogenic protein found in other types of malignancy to be involved in tumor angiogenesis, growth, invasive properties, metastasis formation and resistance to therapy (Semenza, 2003;Bertout et al, 2008). Although the expression of HIF1a mRNA is persistent and independent of cell oxygenation status, HIF1a is strongly expressed in response to hypoxia.…”

“…Although the phosphoinositide 3-kinase/AKT and MEK/ERK pathways have also been implicated in HIF1a synthesis, they seem to impact primarily, if not exclusively, the translation, rather than the transcription of HIF1a, by activating the mTORC1 complex - (Semenza, 2003). It is well established that HIF1a promotes carcinogenesis by various mechanisms, including the enhancement of tumor angiogenesis, invasion, metastasis and resistance to therapy (Semenza, 2003;Bertout et al, 2008). Our observation that HIF1a inhibits ALK þ TCL cell proliferation by partially inhibiting mTORC1 activation is in agreement with the previous finding that HIF1a inhibits TOR in Drosophila by activating the REDD analog protein (Brugarolas et al, 2004).…”

“…Hypoxia-inducible factor 1 (HIF1) has an important role in carcinogenesis by fostering tumor angiogenesis, invasive properties, metastasis formation and resistance to therapy (Semenza, 2003;Bertout et al, 2008). This heterodimeric transcription factor is composed of a-and b-subunits, with expression of the former being tightly controlled by the degree of cell oxygenation.…”

Induction of strand breaks in DNA films by low energy electrons and soft X-ray under nitrous oxide atmosphere

“…In addition, some N 2 O molecules can react with electronically excited oxygen atoms via N 2 O + O( 1 D) → 2NO and N 2 O + O( 1 D) → N 2 + O 2 that the latter is a source of formation of molecular oxygen which can induce significant damage of DNA due to oxygen fixation hypothesis (Burtt and Kircher, 1958). According to this hypothesis, oxygen sensitizes the DNA because the short-lived free radicals in DNA arising from the direct interaction of soft X-rays and LEEs, react with available oxygen molecules to change the chemical composition of DNA and generate 'non-restorable' lesions in the DNA molecule, i.e., peroxy radical (DNA-O 2 • ) (Bertout et al, 2008).…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…In vitro studies support this conclusion as tumor cells established as cell lines can survive for several days at as low concentrations as 0.1% oxygen. Another interesting aspect of tumor hypoxia is the well-documented association between oxygen shortage and tumor aggressiveness (reviewed in Bertout et al 2008) . The mechanistic background is probably very complex, but involves cytotoxic resistance, insensitivity to radiation, decreased DNA repair capacity, increased vascularization and increased metastatic potential (reviewed in Semenza 2003;Erler et al 2006;Löfstedt et al 2007) and, as will be discussed in more detail below, dedifferentiation or loss of a differentiated tumor phenotype.…”