Hypoxia promotes acquisition of aggressive phenotypes in human malignant mesothelioma

Our plain-English summary of Hypoxia promotes acquisition of aggressive phenotypes in human malignant mesothelioma, by M.C. Kim, S.H. Hwang, N.Y. Kim, et al (BMC Cancer, 2018).

The study

• Authors: M.C. Kim, S.H. Hwang, N.Y. Kim, H.S. Lee, S. Ji, Y. Yang, Y. Kim
• Journal: BMC Cancer
• Published: 2018;18(1):819
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Hypoxia 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.

Methods: Hypoxic 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.

Results: Hypoxic 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.

Conclusions: The 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.

In plain English

This was a laboratory study of two human malignant mesothelioma cell lines, MS1 and H513, grown in dishes. It did not study asbestos exposure or patients. The authors compared cells kept in low oxygen (hypoxia: an air mixture with 2.2% oxygen) with cells kept in normal oxygen, with and without the chemotherapy drug cisplatin. Under hypoxia, the oxygen-sensing proteins HIF-1α and HIF-2α increased. Hypoxia raised the surviving fraction of single cells forming colonies by 34% in MS1 cells and 37% in H513 cells. It also raised Oct4 and the share of cells with high CD44, which the authors link to stem-like cancer cells. Cells grown at high density, however, multiplied less under hypoxia. Hypoxic cells were less sensitive to cisplatin and showed less cisplatin-induced cell death. Hypoxic cells left smaller gaps in a scratch test, and H513 cells invaded a gel barrier more. Vimentin rose and E-cadherin fell; E-cadherin was not detected in MS1 cells. The authors concluded that hypoxia promoted aggressive behavior in these mesothelioma cells.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on human malignant mesothelioma cell lines grown in culture
• Who was studied: Two human malignant mesothelioma cell lines, MS1 and H513 (no patients or animals)
• Exposure: Low oxygen (hypoxia) created with an air mixture of 2.2% oxygen, 5% carbon dioxide and 92.8% nitrogen, compared with normal oxygen; some cells were also treated with cisplatin (10 μM in the apoptosis assay). Asbestos was not an exposure in this study.
• Main results:
  • Under hypoxia, HIF-1α increased and HIF-2α was newly produced in the mesothelioma cells.
  • Hypoxia increased the surviving fraction in the colony-forming assay by 34% in MS1 cells and 37% in H513 cells, compared with cells in normal oxygen.
  • Oct4 gene expression increased significantly in the mesothelioma cells under hypoxia.
  • Hypoxia significantly increased the percentage of mesothelioma cells with high CD44 expression, described by the authors as a putative marker of cancer stemness.
  • Hypoxia did not increase the cells' growth; at higher cell densities it reduced proliferation.
  • Hypoxia significantly reduced the sensitivity of the mesothelioma cells to cisplatin.
  • Hypoxia reduced cell death (apoptosis) in untreated cells and significantly inhibited cisplatin-induced apoptosis.
  • In cisplatin-treated cells, the ratio of Bcl-2 to Bax fell under normal oxygen but rose under hypoxia.
  • In the scratch (wound healing) test, cells under hypoxia showed a smaller gap than cells in normal oxygen.
  • H513 cells showed increased invasiveness under hypoxia.
  • Hypoxia increased vimentin. E-cadherin decreased under hypoxia, but in MS1 cells E-cadherin was not detected at all.
• The authors' conclusion: The authors concluded that hypoxia caused the mesothelioma cells to behave more aggressively. They suggested that targeting the signaling pathways affected by hypoxia may help overcome the low effectiveness of traditional anticancer therapy for mesothelioma patients.
• Limitations the authors state:
  • The authors stated that the relationship between the HIFα proteins and stem cell factors, including Oct4, needs further study.
  • The authors reported only a weak correlation between Oct4 mRNA and Oct4 protein levels.
  • The authors stated that the role of Bcl-xL in drug resistance under hypoxia is unclear.
  • The authors noted that a published study in another mesothelioma cell line found the opposite shift under hypoxia. They said cell types and experimental conditions may explain the different responses.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Hypoxia, Mesothelioma, Tumor Microenvironment, Cisplatin, Apoptosis.

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