Global gene expression profiling of human pleural mesotheliomas: identification of matrix metalloproteinase 14 (MMP-14) as potential tumour target

Our plain-English summary of Global gene expression profiling of human pleural mesotheliomas: identification of matrix metalloproteinase 14 (MMP-14) as potential tumour target, by S. Crispi, R.A. Calogero, M. Santini, et al (PloS One, 2009).

The study

• Authors: S. Crispi, R.A. Calogero, M. Santini, P. Mellone, B. Vincenzi, G. Citro, G. Vicidomini, S. Fasano, R. Meccariello, G. Cobellis, S. Menegozzo, R. Pierantoni, F. Facciolo, A. Baldi, M. Menegozzo
• Journal: PloS One
• Published: 2009;4(9):e7016
• Cited by: 72 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The goal of our study was to molecularly dissect mesothelioma tumour pathways by mean of microarray technologies in order to identify new tumour biomarkers that could be used as early diagnostic markers and possibly as specific molecular therapeutic targets.

Methodology: We performed Affymetrix HGU133A plus 2.0 microarray analysis, containing probes for about 39,000 human transcripts, comparing 9 human pleural mesotheliomas with 4 normal pleural specimens. Stringent statistical feature selection detected a set of differentially expressed genes that have been further evaluated to identify potential biomarkers to be used in early diagnostics. Selected genes were confirmed by RT-PCR. As reported by other mesothelioma profiling studies, most of genes are involved in G2/M transition. Our list contains several genes previously described as prognostic classifier. Furthermore, we found novel genes, never associated before to mesotheliom that could be involved in tumour progression. Notable is the identification of MMP-14, a member of matrix metalloproteinase family. In a cohort of 70 mesothelioma patients, we found by a multivariate Cox regression analysis, that the only parameter influencing overall survival was expression of MMP14. The calculated relative risk of death in MM patients with low MMP14 expression was significantly lower than patients with high MMp14 expression (P = 0.002).

Conclusions: Based on the results provided, this molecule could be viewed as a new and effective therapeutic target to test for the cure of mesothelioma.

In plain English

This laboratory study looked for genes that behave differently in pleural mesothelioma. The authors used gene microarrays to compare tumour tissue from 9 patients treated in Naples in 2004 to 2005 with 4 samples of normal pleura. Seven of the 9 patients had some history of asbestos exposure. The authors identified 386 genes with different activity in tumours, and a second test confirmed 6 selected genes. They focused on one gene, MMP14. In tumour samples from 70 mesothelioma patients treated in Naples and Rome between 2001 and 2006, MMP14 protein was always present, at varying levels. The text reports median survival of 24 months with low MMP14 versus 5 months with high MMP14 (a table lists 26 months for the low group). In an analysis adjusting for other factors, MMP14 level remained linked to survival (P = 0.002), as did tumour (T) stage. The authors concluded that MMP-14 has prognostic value and could be a therapy target. They also called their gene data not conclusive because few patients were analyzed.

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 (microarray) comparison of pleural mesothelioma tissue with normal pleura, plus a retrospective analysis of MMP14 protein staining (immunohistochemistry) and survival in a separate group of mesothelioma patients
• Who was studied: Microarray part: 9 patients with pleural mesothelioma treated at the Second University of Naples from 2004 to 2005, plus 4 normal pleural specimens from patients having surgery for non-cancer disease. Survival part: 70 mesothelioma patients (45 epithelioid, 14 mixed, 11 sarcomatoid) treated at the Second University of Naples and Regina Elena Cancer Institute between 2001 and 2006
• Exposure: Asbestos exposure was not measured or analysed. Seven of the 9 microarray patients had some history of asbestos exposure. No fiber types, sources or doses are given. The factor studied for survival was the level of MMP14 protein in the tumour (low, medium or high).
• Main results:
  • In the 9 tumours compared with 4 normal pleural samples, 386 genes (470 probe sets) showed different activity.
  • A second laboratory test (qRT-PCR) on 6 selected genes, including MMP14, confirmed the microarray differences in all cases.
  • In the 70-patient group, MMP14 protein was found in every mesothelioma sample, at different levels.
  • In the unadjusted analysis of the 70 patients, survival differed by MMP14 level (p less than 0.0001). The text gives median survival of 24 months for low MMP14 versus 5 months for high MMP14. Table 4 lists 26 months for low, 14 months for medium and 5 months for high.
  • In the analysis adjusted for T stage, N stage and histology, MMP14 level was associated with overall survival (P = 0.002). The risk of death was lower in patients with low MMP14 than in those with high MMP14.
  • Compared with low MMP14, the hazard ratio for death in that adjusted analysis was 1.56 (95% CI 1.03–2.34) for medium MMP14 and 3.56 (95% CI 2.48–5.90) for high MMP14.
  • In the adjusted analysis, T status was also associated with survival (P = 0.01), while histological type was borderline (p = 0.079).
  • Cytoreductive surgery was not associated with overall survival in these patients (P = 0.398 in the unadjusted analysis).
• The authors' conclusion: The authors concluded that MMP-14 expression had prognostic value in their group of mesothelioma patients, with high expression significantly correlated with poor survival. They suggested MMP14 could be a target for mesothelioma therapy, pending further study.
• Limitations the authors state:
  • Because few patients were analyzed, the authors said the gene expression data must be considered not conclusive.
  • The authors said prospective studies are needed to know whether MMP14 inside tumour cells reflects the amount secreted, before MMP-14 could be considered a biomarker.
  • The authors said further molecular and clinical studies are needed to confirm the observations before proposing MMP14 as a therapy target.

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, Mesothelioma, Biomarker, Overall Survival, Relative Risk.

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• Identification of intelectin overexpression in malignant pleural mesothelioma by serial analysis of gene expression (SAGE) — A. Wali, P.J. Morin, et al. (2005)
• Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells — T.N. Perkins, P.M. Peeters, et al. (2015)

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