Abstract
BackgroundHypoxia is a hallmark of the solid tumor microenvironment and is associated with poor outcomes in cancer patients. The present study was performed to investigate mechanisms underlying the hypoxia-induced phenotypic changes using human malignant mesothelioma (HMM) cells.MethodsHypoxic conditions were achieved by incubating HMM cells in the air chamber. The effect of hypoxia on phenotype changes in HMM cells was investigated by performing in vitro clonogenicity, drug resistance, migration, and invasion assays. Signaling pathways and molecules involved in the more aggressive behaviors of HMM cells under hypoxia were investigated. A two-tailed unpaired Student’s t-test or one-way ANOVA with Bonferroni post-test correction was used in this study.ResultsHypoxic conditions upregulated hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α in parallel with the upregulation of its target, Glut-1, in HMM cells. In vitro clonogenicity of HMM cells was significantly increased in hypoxic conditions, but the proliferation of cells at a high density in hypoxia was lower than that in normoxic conditions. The expression levels of HIF-2α and Oct4 were increased in hypoxic HMM cells. The percentage of cells with high CD44 expression was significantly higher in HMM cells cultured in hypoxia than those cultured in normoxia. Hypoxia significantly enhanced the resistance of HMM cells to cisplatin, which occurred through cytoprotection against cisplatin-induced apoptosis. While cisplatin treatment decreased the ratio of Bcl-2 to Bax in normoxic condition, hypoxia conversely increased the ratio in HMM cells treated with cisplatin. Hypoxia increased the mobility and invasiveness of HMM cells. Epithelial to mesenchymal transition was promoted, which was indicated by the repression of E-cadherin and the concomitant increase of vimentin in HMM cells.ConclusionsThe data illustrated that hypoxic conditions augmented the aggressive phenotypes of HMM cells at the biological and molecular levels. The present study provides valuable background information beginning to understand aggressiveness of HMM in tumor microenvironments, suggesting that a control measure for tumor hypoxia may be an effective therapeutic strategy to reduce the aggressiveness of cancer cells in HMM patients.
Highlights
Hypoxia is a hallmark of the solid tumor microenvironment and is associated with poor outcomes in cancer patients
Experimental induction of hypoxia in vitro Experimental establishment of hypoxia was verified by Hypoxia-inducible factor alpha (HIFα) induction in human malignant mesothelioma (HMM) cells
Western blot analysis confirmed the upregulation of Hypoxia-inducible factor 1 alpha (HIF-1α) and the de novo synthesis of Hypoxia-inducible factor 2 alpha (HIF-2α) under hypoxia (Fig. 1a)
Summary
Hypoxia is a hallmark of the solid tumor microenvironment and is associated with poor outcomes in cancer patients. There are two types of hypoxia in solid tumors, intermittent hypoxia and chronic hypoxia. Chronic hypoxia arises due to the inability of the vascular system to supply the growing tumor mass with adequate amounts of oxygen [3]. Both types of tumor hypoxia have been reported to be correlated with poor outcomes in many cancer patients [4]. Hypoxia enhances cancer cell survival, metastasis, and drug resistance in multiple tumor types [1, 4]
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