Oxytocin receptor is a promising therapeutic target of malignant mesothelioma

Our plain-English summary of Oxytocin receptor is a promising therapeutic target of malignant mesothelioma, by Y. Kodama, I. Tanaka, T. Sato, et al (Cancer Science, 2021).

The study

• Authors: Y. Kodama, I. Tanaka, T. Sato, K. Hori, S. Gen, M. Morise, D. Matsubara, M. Sato, Y. Sekido, N. Hashimoto
• Journal: Cancer Science
• Published: 2021;112(9):3520-3532
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (OXTR), which is a G-protein-coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of OXTR and its clinical relevance in MM. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and OXTR mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of OXTR and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, OXTR mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high OXTR expression showed poor overall survival. Moreover, OXTR knockdown dramatically decreased MM cell proliferation in cells with high OXTR expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. OXTR antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high OXTR expression, and oral administration of the OXTR antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that OXTR plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM.

© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a laboratory study of the oxytocin receptor gene (OXTR) in malignant mesothelioma. It did not study asbestos exposure. The authors used public databases, 14 mesothelioma cell lines (nine established in their laboratory, five purchased), and mice. OXTR mRNA levels were higher in 11 mesothelioma cell lines than in 1008 other cancer cell lines. In 85 tumor cases from The Cancer Genome Atlas, higher OXTR mRNA expression was associated with worse overall survival. Adjusted for sex, age, histology and stage, the hazard ratio for death was 2.2 (95% confidence interval 1.60 to 3.07) per tenfold increase in OXTR mRNA. Reducing OXTR expression (knockdown) slowed growth of high-OXTR cell lines, and knockdown cells formed smaller tumors in mice. Mice given the receptor-blocking drug cligosiban by mouth had tumors weighing 29.0 mg, against 56.8 mg in control mice. Each group had four mice. The authors concluded that OXTR could be a promising treatment target and prognostic marker. They noted the drug concentrations needed in cell experiments were relatively high and the cause of high OXTR levels was not fully identified.

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 study: analysis of public gene-expression databases (CCLE cell lines, TCGA tumor cases with survival analysis), cell-culture experiments, and mouse xenograft experiments
• Who was studied: The CCLE database (11 malignant mesothelioma cell lines versus 1008 other cancer cell lines). TCGA data on 87 malignant mesothelioma cases, 85 of them with survival information (two with unknown prognosis were excluded). 14 malignant mesothelioma cell lines (9 Japanese lines established in the authors' laboratory, 5 purchased from the American Type Culture Collection) plus an immortalized mesothelial cell line, MeT-5A. Female BALB/c nude mice, 4 per group.
• Exposure: No asbestos exposure was studied. The factors examined were OXTR mRNA expression, reducing OXTR expression (knockdown), oxytocin treatment, and four OXTR-blocking drugs including atosiban and cligosiban. In mice, cligosiban was given at 60 mg/kg by mouth every other day, 10 doses in total.
• Main results:
  • OXTR mRNA expression was significantly higher in the 11 malignant mesothelioma cell lines than in the 1008 other cancer cell lines (P less than .001)
  • In TCGA mesothelioma cases, high OXTR mRNA expression was significantly associated with worse overall survival (P less than .001, log-rank test)
  • In the multivariable analysis of 85 TCGA cases, OXTR mRNA expression was the strongest independent predictor of overall survival: hazard ratio for death 2.2, 95% confidence interval 1.60 to 3.07, P less than .001
  • In the survival model, OXTR mRNA was log10-converted and analyzed as a continuous variable, so the hazard ratio of 2.2 applies to each tenfold increase in expression, not to a high-versus-low group comparison
  • OXTR expression was more than 30 times higher in 7 of the 14 mesothelioma cell lines than in MeT-5A cells
  • Oxytocin treatment moderately increased proliferation of three mesothelioma cell lines with high OXTR expression
  • OXTR knockdown significantly reduced proliferation in three mesothelioma cell lines with high OXTR expression. No significant difference was seen in MeT-5A or NCI-H2452 cells.
  • In mice injected with NCI-H2052 cells, tumor weights were 37.0 mg in the control group versus 14.0 mg in the OXTR knockdown group (P = .001)
  • In mice injected with NCI-H2373 cells, tumor weights were 63.3 mg in the control group versus 14.3 mg in the OXTR knockdown group (P = .004)
  • The average cligosiban IC50 (the concentration that halves cell growth) was 30.2 micromolar for five high-OXTR mesothelioma cell lines versus 63.1 micromolar for five low-OXTR lines (P = .008)
  • In the mouse xenograft model, tumors weighed 29.0 mg after 10 oral doses of cligosiban versus 56.8 mg in the control group (P = .021), with 4 mice per group
• The authors' conclusion: The authors concluded that OXTR could be a promising therapeutic target and a prognostic biomarker for malignant mesothelioma, enabling a personalized approach to treatment
• Limitations the authors state:
  • The molecular mechanisms that increase OXTR expression in mesothelioma were not completely identified
  • The IC50 values of the OXTR-blocking drugs were relatively high
  • Further studies are needed to identify how OXTR knockdown lowers the four cell-cycle genes
  • Methods for selecting patients with high OXTR expression still need to be established

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Overall Survival, Biomarker.

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