Abstract
Hypoxia is one of the most important features of the tumor microenvironment, exerting an adverse effect on tumor aggressiveness and patient prognosis. Two types of hypoxia may occur within the tumor mass, chronic (prolonged) and cycling (transient, intermittent) hypoxia. Cycling hypoxia has been shown to induce aggressive tumor cell phenotype and radioresistance more significantly than chronic hypoxia, though little is known about the molecular mechanisms underlying this phenomenon. The aim of this study was to delineate the molecular response to both types of hypoxia induced experimentally in tumor cells, with a focus on cycling hypoxia. We analyzed in vitro gene expression profile in three human cancer cell lines (melanoma, ovarian cancer, and prostate cancer) exposed to experimental chronic or transient hypoxia conditions. As expected, the cell-type specific variability in response to hypoxia was significant. However, the expression of 240 probe sets was altered in all 3 cell lines. We found that gene expression profiles induced by both types of hypoxia were qualitatively similar and strongly depend on the cell type. Cycling hypoxia altered the expression of fewer genes than chronic hypoxia (6,132 vs. 8,635 probe sets, FDR adjusted p<0.05), and with lower fold changes. However, the expression of some of these genes was significantly more affected by cycling hypoxia than by prolonged hypoxia, such as IL8, PLAU, and epidermal growth factor (EGF) pathway-related genes (AREG, HBEGF, and EPHA2). These transcripts were, in most cases, validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our results indicate that experimental cycling hypoxia exerts similar, although less intense effects, on the examined cancer cell lines than its chronic counterpart. Nonetheless, we identified genes and molecular pathways that seem to be preferentially regulated by cyclic hypoxia.
Highlights
In the tumor microenvironment, hypoxia is one of the crucial factors, which promote an aggressive phenotype of tumor cells and decrease the effectiveness of standard treatment
The analysis indicated that cycling hypoxia exerts a similar, weaker, influence on gene expression in cancer cells than chronic hypoxia
Cycling vs. chronic hypoxia In this study, we present a report on global gene expression analysis in three tumor cell lines subjected to experimental cycling and chronic hypoxia
Summary
Hypoxia is one of the crucial factors, which promote an aggressive phenotype of tumor cells and decrease the effectiveness of standard treatment. The existence of acutely hypoxic cells in tumors was first observed several decades ago [2] and was attributed to transient changes in blood perfusion [3]. These preliminary observations were subsequently confirmed in spontaneous animal tumors [4], experimental tumors [5,6,7], and in naturally occurring human tumors [8]. It was estimated that tumor areas exposed to cycling hypoxia can range from 12 to 43%, (20% [3]; 35% [7]; 12% and 43% [10]), and can even be greater than the areas of chronic hypoxia in some tumors [10]
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