In fact, many clinical and experimental observations indicate tha

In fact, many clinical and experimental observations indicate that hypoxia is associated with

the aggressiveness of tumor cells, leading to poor prognosis and metastasis in a variety of human cancers. Within tumor tissues, oxygen concentrations fluctuate both spatially and temporally. Hypoxic tumor cells may be re-exposed by a higher concentration of oxygen (re-oxygenation), which can alter the cancer genome and contribute to tumor progression. In this review, mechanisms by which hypoxia and re-oxygenation induce genetic alterations in sporadic cancer will be considered. Toward this goal, literature relating to tumor hypoxia, cellular pathways affected by hypoxia, types of genetic alterations and DNA repair systems affected by hypoxia and re-oxygenation has been compiled. The impact of hypoxia on human cancer in medicine was first recognized by radiologists. In the 1930s, the presence of hypoxia in solid tumor tissues was first hypothesized based on the observation that low levels of oxygen (hypoxia) protect a cell from the lethal effects of ionizing radiation and that some solid tumors are resistant to radiation.13 In 1955, Thomlinson and Gray reported histological observations

of tumor cords with and without central necrosis in human lung tumors, suggesting the presence of an oxygen gradient within a tumor cord. They found that: (i) all of the tumor cords surrounded by the stroma and >200 µm in

radius contained central necrosis; (ii) none of the tumor cords <160 µm Pictilisib supplier in radius contained central necrosis; and (iii) no intact tumor cells were found at a distant of 180 µm from the stroma. Based on these results and the calculated distance of oxygen diffusion (150 µm), they proposed the presence of radio-resistant hypoxic cells at the edge of the necrotic area.14 Until the late 1980s when polarographic electrodes were used to directly measure levels Buspirone HCl of oxygen in human cancer tissues, the presence of tumor hypoxia was speculative.15,16 During the 1990s, several key findings were made using various methods for directly detecting tumor hypoxia in human tumor tissues.9,15 These findings are as follows: (i) hypoxic and anoxic areas exist in most solid tumors (areas with <2.5 mmHg of oxygen pressure); (ii) there is no predictable association between tumor hypoxia and other clinical factors, including size, stage, grade and site; (iii) tumor hypoxia may be an adverse prognostic factor;9,17 and (iv) tumor hypoxia not only induces radiation-resistance, but it may also induce resistance to chemotherapeutic agents.9,18 Using DNA-binding chemical Hoechst 33 432, cell sorting and radiation, Chaplin et al. first demonstrated that two types of hypoxia exist in solid tumor tissues.

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