Hedgehog Signaling in Malignant Pleural Mesothelioma

Our plain-English summary of Hedgehog Signaling in Malignant Pleural Mesothelioma, by E. Felley-Bosco, I. Opitz, M. Meerang (Genes, 2015).

The study

• Authors: E. Felley-Bosco, I. Opitz, M. Meerang
• Journal: Genes
• Published: 2015;6(3):500-11
• Type of article: Review
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a cancer associated with exposure to asbestos fibers, which accumulate in the pleural space, damage tissue and stimulate regeneration. Hedgehog signaling is a pathway important during embryonic mesothelium development and is inactivated in adult mesothelium. The pathway is reactivated in some MPM patients with poor clinical outcome, mainly mediated by the expression of the ligands. Nevertheless, mutations in components of the pathway have been observed in a few cases. Data from different MPM animal models and primary culture suggest that both autocrine and paracrine Hedgehog signaling are important to maintain tumor growth. Drugs inhibiting the pathway at the level of the smoothened receptor (Smo) or glioma-associated protein transcription factors (Gli) have been used mostly in experimental models. For clinical development, biomarkers are necessary for the selection of patients who can benefit from Hedgehog signaling inhibition.

In plain English

This review summarized published research and public data on Hedgehog signaling in malignant pleural mesothelioma (MPM), rather than reporting a new study. The pathway is essential for embryonic mesothelium development and inactive in most adult tissues. The authors described MPM as commonly associated with asbestos, but did not study asbestos exposure. In the authors' earlier study, high GLI1 gene expression was associated with shorter overall survival. In The Cancer Genome Atlas data on 85 tumors, one group overexpressed Hedgehog target genes. Among 39 patients with outcome data, it was one of the two groups with the worst overall survival (median 6.6 months). Another group found an SMO gene insertion in one of seven cell lines and one of 14 patients. In the authors' laboratory work, four of six patient-derived cell lines responded to a pathway-blocking drug. Three mesothelioma patients in an early trial of vismodegib showed no response, but that trial did not check whether the pathway was activated in their tumors. The authors concluded that the pathway is activated in a subgroup of MPM patients and is associated with the worst clinical outcome.

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: Review of published studies, the authors' own earlier work, and data from The Cancer Genome Atlas (TCGA)
• Who was studied: Published laboratory, animal and patient studies of malignant pleural mesothelioma, plus TCGA molecular data on tumor samples from 85 patients (clinical outcome available for 39)
• Exposure: No asbestos exposure was studied. Asbestos is mentioned only as background, citing other work. The subject of the review is activity of the Hedgehog signaling pathway in MPM.
• Main results:
  • In the authors' earlier study (reference 18), high GLI1 gene expression was associated with shorter overall survival in MPM patients.
  • In TCGA data, the 85 tumors clustered into four groups, one marked by overexpression of Hedgehog target genes. Among the 39 patients with clinical outcome data, this was one of the two groups with the worst overall survival (median 6.6 months).
  • A study of seven MPM cell lines by other researchers (reference 30) found a 3-base-pair insertion in the SMO gene in one cell line. The same insertion was found in one of 14 patients. The authors stated that this indicates mutations of the pathway rarely exist in MPM.
  • In the authors' primary cultures, four of six MPM cell lines responded to the pathway blocker cyclopamine. Another blocker, HhAntag, reduced the growth of tumors implanted under the skin of immunodeficient mice by approximately 40%.
  • In a rat mesothelioma model (data listed by the authors as unpublished), treatment with a Hedgehog antagonist downregulated the pathway mostly in the stromal part of the tumor. This was associated with reduced tumor volume.
  • Three mesothelioma patients enrolled in a phase 1 trial of the drug vismodegib showed no response. In that trial, activation of the Hedgehog pathway in the tumors was not investigated.
• The authors' conclusion: The authors concluded that Hedgehog signaling is activated in a subgroup of MPM patients and is associated with the worst clinical outcome. In a limited number of patients, they concluded, this activation may result from mutations, and in the others it seems to be ligand-driven. They stated that identifying biomarkers may be useful for exploring treatment combinations.
• Limitations the authors state:
  • The authors stated that the factors driving abnormal Hedgehog pathway activity in MPM are not known yet.
  • The authors stated that the functional impact of the SMO gene insertion remains to be investigated.
  • The authors noted that the vismodegib trial did not investigate whether the pathway was activated in the patients' tumors.
  • The authors stated that it is not known whether the gene signature used to select patients in medulloblastoma would be the same in mesothelioma.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelium, Biomarker.

Related studies

• Inhibition of hedgehog signaling reduces the side population in human malignant mesothelioma cell lines — H.A. Kim, M.C. Kim, et al. (2015)
• Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma — M. Meerang, K. Bérard, et al. (2016)
• PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy — B.K. Bitanihirwe, M. Meerang, et al. (2014)
• Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro — M. You, J. Varona-Santos, et al. (2014)
• Endogenous retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development — S. Sun, F. Frontini, et al. (2021)
• FAK signaling in human cancer as a target for therapeutics — B.Y. Lee, P. Timpson, et al. (2015)

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