Autotaxin signaling governs phenotypic heterogeneity in visceral and parietal mesothelia

Our plain-English summary of Autotaxin signaling governs phenotypic heterogeneity in visceral and parietal mesothelia, by E.L. Shelton, C.L. Galindo, C.H. Williams, et al (PloS One, 2013).

The study

• Authors: E.L. Shelton, C.L. Galindo, C.H. Williams, E. Pfaltzgraff, C.C. Hong, D.M. Bader
• Journal: PloS One
• Published: 2013;8(7):e69712
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelia, which cover all coelomic organs and body cavities in vertebrates, perform diverse functions in embryonic and adult life. Yet, mesothelia are traditionally viewed as simple, uniform epithelia. Here we demonstrate distinct differences between visceral and parietal mesothelia, the most basic subdivision of this tissue type, in terms of gene expression, adhesion, migration, and invasion. Gene profiling determined that autotaxin, a secreted lysophospholipase D originally discovered as a tumor cell-motility-stimulating factor, was expressed exclusively in the more motile and invasive visceral mesothelia and at abnormally high levels in mesotheliomas. Gain and loss of function studies demonstrate that autotaxin signaling is indeed a critical factor responsible for phenotypic differences within mesothelia. Furthermore, we demonstrate that known and novel small molecule inhibitors of the autotaxin signaling pathway dramatically blunt migratory and invasive behaviors of aggressive mesotheliomas. Taken together, this study reveals distinct phenotypes within the mesothelial cell lineage, demonstrates that differential autotaxin expression is the molecular underpinning for these differences, and provides a novel target and lead compounds to intervene in invasive mesotheliomas.

In plain English

This was a laboratory study of cells and tissues. It did not study people or asbestos exposure. The authors compared two kinds of mesothelium, the lining tissue that mesothelioma arises from, taken from adult mice: visceral (from the omentum) and parietal (from the body wall). They also studied two human mesothelioma cell lines, MSTO-211H (pleural) and ROB (peritoneal).

Gene testing found 796 transcripts more highly expressed in visceral mesothelium and 633 genes more highly expressed in parietal mesothelium. The largest difference was autotaxin, an enzyme that makes the signaling molecule LPA, at 48.4-fold higher expression in visceral mesothelium. Visceral cells attached, moved and invaded more than parietal cells. The autotaxin blocker S32826 cut visceral cell displacement by 90%. Adding autotaxin raised parietal cell invasion to visceral levels.

Both mesothelioma cell lines showed very high autotaxin activity. In culture, S32826 reduced their displacement by 68% (MSTO) and 87% (ROB). S32826 and two new compounds targeting the LPA receptor Lpar1 reduced their invasion. The authors concluded that the autotaxin pathway is a promising therapeutic target in mesotheliomas.

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 and animal tissue) study: gene profiling, protein staining and cell-behavior assays on mouse mesothelial cells and human mesothelioma cell lines, with autotaxin added or blocked
• Who was studied: Visceral (omental) and parietal (body wall) mesothelium from adult Wt1-cre; Rosa26ReYFP mice (number of mice not stated; two microarray replicates per tissue type), plus two human mesothelioma cell lines: MSTO-211H (pleural) and ROB (peritoneal). Small intestine tissue was also stained for autotaxin.
• Exposure: No asbestos or fiber exposure was studied. The experimental treatments were added autotaxin, the autotaxin inhibitor S32826, and two Lpar1 inhibitors (2440 and 8437) applied to cultured cells.
• Main results:
  • In mouse mesothelium, 796 transcripts were more highly expressed in visceral mesothelium and 633 genes were more highly expressed in parietal mesothelium.
  • Autotaxin was the most differentially expressed gene, with 48.4-fold higher expression in visceral mesothelium. By staining it was undetectable in parietal mesothelium, and by quantitative RT-PCR it was 82% higher in visceral mesothelium.
  • After 2 hours on fibronectin, 57% more visceral cells than parietal cells attached (n = 6).
  • Visceral cells were far more invasive than parietal cells. Adding autotaxin to parietal cells raised their invasion to visceral levels.
  • In visceral mesothelial cells, the autotaxin inhibitor S32826 decreased displacement (movement) by 90%.
  • The human pleural (MSTO) and peritoneal (ROB) mesothelioma cells showed exceedingly high autotaxin activity.
  • In the mesothelioma cells, S32826 reduced displacement by 68% in MSTO cells and by 87% in ROB cells.
  • Both mesothelioma cell lines were more invasive than the non-cancerous cells. S32826 and the Lpar1 inhibitors 2440 and 8437 reduced their invasion.
  • Autotaxin and Lpar1 inhibitors blocked smooth muscle differentiation from mesothelial cells.
• The authors' conclusion: The authors concluded that autotaxin signaling regulates the differences between visceral and parietal mesothelia, and that the autotaxin pathway, including its downstream mediator LPA1, is a promising therapeutic target to reduce the aggressive characteristics of mesotheliomas.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelial Cells.

Related studies

• Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma — K. Donaldson, F.A. Murphy, et al. (2010)
• Genome-wide profile of pleural mesothelioma versus parietal and visceral pleura: the emerging gene portrait of the mesothelioma phenotype — O.D. Røe, E. Anderssen, et al. (2009)
• Fibronectin expression and organization in mesothelial and mesothelioma cells — P.C. Ferriola, W. Stewart (1996)
• Length-dependent retention of carbon nanotubes in the pleural space of mice initiates sustained inflammation and progressive fibrosis on the parietal pleura — F.A. Murphy, C.A. Poland, et al. (2011)
• Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling — F. Qi, G. Okimoto, et al. (2013)
• Fra-1 governs cell migration via modulation of CD44 expression in human mesotheliomas — M.E. Ramos-Nino, S.R. Blumen, et al. (2007)

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