Blockade of aquaporin 1 inhibits proliferation, motility, and metastatic potential of mesothelioma in vitro but not in an in vivo model

Our plain-English summary of Blockade of aquaporin 1 inhibits proliferation, motility, and metastatic potential of mesothelioma in vitro but not in an in vivo model, by S. Klebe, K. Griggs, Y. Cheng, et al (Disease Markers, 2015).

The study

• Authors: S. Klebe, K. Griggs, Y. Cheng, J. Driml, D.W. Henderson, G. Reid
• Journal: Disease Markers
• Published: 2015;2015:286719
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is an aggressive tumor of the serosal membranes, mostly the pleura. It is related to asbestos exposure and has a poor prognosis. MM has a long latency period, and incidence is predicted to remain stable or increase until 2020. Currently, no biomarkers for a specific targeted therapy are available. Previously, we observed that expression of aquaporin 1 (AQP1) was an indicator of prognosis in two independent cohorts. Here we determine whether AQP1 inhibition has therapeutic potential in the treatment of MM.

Methods: Functional studies were performed with H226 cells and primary MM cells harvested from pleural effusions. AQP1 expression and mesothelial phenotype was determined by immunohistochemistry. AQP1 function was inhibited by a pharmacological blocker (AqB050) or AQP1-specific siRNA. Cell proliferation, migration, and anchorage-independent cell growth were assessed. A nude mouse heterotopic xenograft model of MM was utilised for the in vivo studies.

Results: Inhibition of AQP1 significantly decreases cell proliferation, metastatic potential, and motility without inducing nonspecific cytotoxicity or increasing apoptosis. In vivo blockade of AQP1 had no biologically significant effect on growth of established tumours.

Conclusions: Targeted blockade of AQP1 restricts MM growth and migration in vitro. Further work is warranted to fully evaluate treatment potential in vivo.

In plain English

This was a laboratory study of mesothelioma cells and mice. It did not study asbestos exposure. The authors tested whether blocking aquaporin 1 (AQP1), a water-channel protein, affects malignant mesothelioma cells. They used a commercial cell line (H226) and cells collected from 15 pleural effusions from 13 patients aged 65 to 94. AQP1 function was blocked with a drug (AqB050), and AQP1 levels were lowered with siRNA. In patient cells, higher AQP1 expression was associated with faster growth (R2 = 0.485, P = 0.026). The blocker significantly reduced growth of H226 cells at 80 micromolar (P = 0.021) and of patient cells with high AQP1 (P less than 0.001). It did not significantly change growth of patient cells with low AQP1 (P = 0.397). Lowering AQP1 with siRNA also reduced growth. The blocker reduced cell movement and colony formation, a test of metastatic potential. In mice with H226 tumours under the skin, the blocker had no significant effect on tumour growth. The authors concluded that AQP1 blockade may be a useful strategy but that further in vivo work is required.

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) experiments on mesothelioma cells plus an animal experiment (subcutaneous xenograft in nude mice)
• Who was studied: The commercial H226 mesothelioma cell line; primary malignant mesothelioma cells from 15 pleural effusions from 13 patients (12 male, 1 female) aged 65 to 94, with epithelioid (12) and biphasic (3) tumours; BALB/c nude mice injected with H226 cells (first experiment: 5, 6 and 6 mice per group; follow-up: 6, 5 and 7 mice per group). The work was approved by Adelaide ethics committees; dates are not given.
• Exposure: Not an asbestos exposure. AQP1 function was inhibited in cells with the pharmacological blocker AqB050 (20, 40 or 80 micromolar), and AQP1 expression was reduced with AQP1-specific siRNA. Mice received daily injections of AqB050 at 20 or 80 micromolar directly into the tumour, compared with DMSO vehicle or no treatment.
• Main results:
  • In primary mesothelioma cells (n = 14 in the figure), higher AQP1 expression was associated with higher cell proliferation (R2 = 0.485; P = 0.026)
  • In H226 cells, AqB050 produced a dose-dependent decrease in proliferation, statistically significant at 80 micromolar compared with control (P = 0.021)
  • Primary cells with high AQP1 (at least 20% of cells expressing it; n = 8) showed a significant dose-dependent decrease in proliferation (P less than 0.001). Low-AQP1 primary cells (n = 3) showed no statistically significant difference (P = 0.397)
  • AQP1 siRNA significantly decreased proliferation in H226 cells (P = 0.021) and primary cells (P = 0.008). AQP1 mRNA was knocked down to 6 to 17% of vehicle control levels
  • No toxicity of AqB050 was identified at the tested concentrations
  • In H226 cells, AqB050 reduced cell movement in a scratch assay in a dose-dependent manner (P less than or equal to 0.001)
  • In H226 cells, AqB050 reduced colony formation in an anchorage-independent assay in all treatment groups compared with vehicle control (P = 0.001). Colonies were smaller at 80 micromolar (P = 0.039)
  • In mice, there was no significant effect of 20 or 80 micromolar AqB050 on tumour size after six days (P = 0.334). In the follow-up experiment there was no significant effect on tumour growth after 15 days (P = 0.761)
• The authors' conclusion: The authors concluded that their in vitro results suggest AQP1 blockade may be a useful strategy to limit mesothelioma tumour growth, but that further in vivo work is required to evaluate its potential for therapy.
• Limitations the authors state:
  • The subcutaneous mouse model may not reproduce the 'sliding' growth of mesothelioma tumour cells in the pleural space
  • The drug may have interacted with blood proteins, limiting how much was available
  • The drug was given locally rather than systemically, and a relatively small dose was used
  • The in vivo half-life of AqB050 has not been characterised, so local drug levels may not have stayed at therapeutic levels long enough
  • Some of the drug may have bound to AQP1 on blood components and vascular endothelium instead of reaching tumour cells

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, Pleura, Asbestos Exposure, Prognosis, Latency, Biomarker, Targeted Therapy, Pleural Effusion.

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