Genome-wide profile of pleural mesothelioma versus parietal and visceral pleura: the emerging gene portrait of the mesothelioma phenotype

Our plain-English summary of Genome-wide profile of pleural mesothelioma versus parietal and visceral pleura: the emerging gene portrait of the mesothelioma phenotype, by O.D. Røe, E. Anderssen, E. Helge, et al (PloS One, 2009).

The study

• Authors: O.D. Røe, E. Anderssen, E. Helge, C.H. Pettersen, K.S. Olsen, H. Sandeck, R. Haaverstad, S. Lundgren, E. Larsson
• Journal: PloS One
• Published: 2009;4(8):e6554
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma is considered an almost incurable tumour with increasing incidence worldwide. It usually develops in the parietal pleura, from mesothelial lining or submesothelial cells, subsequently invading the visceral pleura. Chromosomal and genomic aberrations of mesothelioma are diverse and heterogenous. Genome-wide profiling of mesothelioma versus parietal and visceral normal pleural tissue could thus reveal novel genes and pathways explaining its aggressive phenotype.

Methodology And Principal Findings: Well-characterised tissue from five mesothelioma patients and normal parietal and visceral pleural samples from six non-cancer patients were profiled by Affymetrix oligoarray of 38 500 genes. The lists of differentially expressed genes tested for overrepresentation in KEGG PATHWAYS (Kyoto Encyclopedia of Genes and Genomes) and GO (gene ontology) terms revealed large differences of expression between visceral and parietal pleura, and both tissues differed from mesothelioma. Cell growth and intrinsic resistance in tumour versus parietal pleura was reflected in highly overexpressed cell cycle, mitosis, replication, DNA repair and anti-apoptosis genes. Several genes of the "salvage pathway" that recycle nucleobases were overexpressed, among them TYMS, encoding thymidylate synthase, the main target of the antifolate drug pemetrexed that is active in mesothelioma. Circadian rhythm genes were expressed in favour of tumour growth. The local invasive, non-metastatic phenotype of mesothelioma, could partly be due to overexpression of the known metastasis suppressors NME1 and NME2. Down-regulation of several tumour suppressor genes could contribute to mesothelioma progression. Genes involved in cell communication were down-regulated, indicating that mesothelioma may shield itself from the immune system. Similarly, in non-cancer parietal versus visceral pleura signal transduction, soluble transporter and adhesion genes were down-regulated. This could represent a genetical platform of the parietal pleura propensity to develop mesothelioma.

Conclusions: Genome-wide microarray approach using complex human tissue samples revealed novel expression patterns, reflecting some important features of mesothelioma biology that should be further explored.

In plain English

This laboratory study from Norway compared gene activity in pleural mesothelioma tissue with normal pleura, using a microarray covering 38 500 genes. Six tumour samples came from five mesothelioma patients diagnosed between 2003 and 2005. Seven parietal and three visceral pleural samples came from six non-cancer patients (mean age 27, against 56 for the patients) operated on for recurrent pneumothorax. None of the controls was reportedly exposed to asbestos. Four of the five patients had various levels of exposure. Normal parietal and visceral pleura differed in 392 genes. Compared with parietal pleura, mesothelioma had 828 overexpressed and 1004 down-regulated genes. Cell cycle, DNA replication and DNA repair genes were overexpressed, including TYMS, the target of the drug pemetrexed. Cell communication, adhesion and defense genes, and several tumour suppressor genes, were down-regulated. Staining confirmed overexpression of five proteins. The authors concluded that the profile reflected the tumour's malignant, resistant but non-metastatic behaviour. They noted the small number of samples and that the results are relative values.

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 gene expression (genome-wide microarray) study comparing tumour tissue with normal pleural tissue, with immunohistochemistry checks of selected proteins
• Who was studied: Five pleural mesothelioma patients (diagnosed 2003–2005, mean age 56) giving six tumour samples. Six non-cancer controls (mean age 27) who had thoracoscopy for recurrent pneumothorax, giving seven parietal and three visceral pleural samples. All were treated at Norwegian hospitals (Trondheim, Bergen).
• Exposure: Asbestos exposure was recorded but was not the variable studied. No fiber types are given. Controls were reportedly never exposed. Four of five cases had various levels of exposure (listed in the table as, for example, 'possible ecological', a hair-dryer with asbestos elements, 'minimal', and 40 years).
• Main results:
  • Normal parietal pleura versus normal visceral pleura: 392 differentially expressed genes, with 341 down-regulated and 52 overexpressed in parietal pleura
  • Mesothelioma versus normal parietal pleura: 828 genes overexpressed and 1004 genes down-regulated in tumour tissue
  • In mesothelioma versus parietal pleura, cell cycle, DNA repair and microtubule cytoskeleton gene groups were highly overexpressed
  • TYMS, which encodes thymidylate synthase (the target of pemetrexed), was overexpressed in mesothelioma
  • The metastasis suppressor genes NME1 and NME2 were overexpressed; the authors suggested this could partly explain the locally invasive, non-metastatic pattern of mesothelioma
  • Gene groups for development, cell communication, defense and cell adhesion were down-regulated in mesothelioma, as were tumour suppressor genes DLC1, TNF, CAV1 and GSN
  • Cytokine-cytokine receptor interaction genes in mesothelioma: 19 of 21 down-regulated
  • Central circadian clock genes were differentially expressed in mesothelioma versus parietal pleura
  • Immunohistochemistry confirmed overexpression of thymidylate synthase, VG5Q, Chk1, NQO1 and RAD21 in tumour cells in most cases. Mesothelin (MSLN) mRNA was not differentially expressed.
• The authors' conclusion: The authors concluded that genome-wide profiling showed significant differences in gene expression between mesothelioma, visceral and parietal pleura, and that the profile reflected mesothelioma's highly malignant, resistant but non-metastatic behaviour. They also concluded that down-regulation of adhesion, solute transporter and signal transduction systems in normal parietal pleura could contribute to its susceptibility to transformation by asbestos.
• Limitations the authors state:
  • Mesothelial cells were not separated out and analysed on their own, so the results reflect the whole tissue, not mesothelial cells alone
  • Gene expression values are relative: apparent overexpression in tumour could instead reflect down-regulation in normal tissue
  • The authors described uncertainties about the visceral pleura comparison and noted the small number of visceral samples
  • Microscopic emphysema in the visceral pleural samples could influence the gene profile, although the authors judged this unlikely
  • Limited material from needle biopsies meant only a few genes could be checked at the protein level

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Visceral Pleura, Mesothelioma, Parietal Pleura, Apoptosis, Antifolate, Pemetrexed (Alimta), Metastasis.

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