Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Dec;115(6):308-317.
doi: 10.32074/1591-951X-920. Epub 2023 Oct 9.

Up-regulation by overexpression of c-MET in fibroblastic foci of usual interstitial pneumonia

Laura Melocchi  1 , Giulia Cervi  2 , Giuliana Sartori  3 , Laura Gandolfi  1 , Genny Jocollé  4 , Alberto Cavazza  3 , Giulio Rossi  1
Affiliations

Up-regulation by overexpression of c-MET in fibroblastic foci of usual interstitial pneumonia

Laura Melocchi et al. Pathologica. 2023 Dec.

Abstract

Background: Usual interstitial pneumonia (UIP) is the radiologic and histologic hallmark of idiopathic pulmonary fibrosis (IPF) and the commonest histologic pattern of other progressive fibrosing interstitial lung diseases (e.g., fibrotic hypersensitivity pneumonia). Analogous to lung cancer, activation of epithelial-to-mesenchymal transition (EMT) is one of the main molecular pathways recently identified by transcriptomic studies in IPF. Fibroblastic foci (FF) are considered the active/trigger component of UIP pattern. The proto-oncogene C-MET is a key gene among molecules promoting EMT against which several inhibitors are currently available or promising in ongoing studies on lung cancer.

Methods: Twenty surgical cases of diffuse fibrosing interstitial lung diseases (fILD) with UIP pattern and FF-rich (17 IPF and 3 patients with fibrotic hypersensitivity pneumonia, fHP) were retrospectively selected. FF were manually microdissected and analysed for c-MET gene alterations (FISH amplification and gene hot-spot mutations Sanger sequencing) and tested with a c-MET companion diagnostic antibody (clone SP44 metmab) by immunohistochemistry.

Results: FF are characterized by upregulation of c-MET as shown by overexpression of the protein in 80% of cases, while no gene amplification by FISH or mutations were detected. C-MET upregulation of FF was observed either in IPF and fHP, with a tropism for the epithelial cell component only.

Conclusion: Upregulation of c-MET in FF of ILD with UIP pattern further confirms the key role of the proto-oncogene c-MET in its pathogenesis, possibly representing an interesting and easily-detectable molecular target for selective therapy using specific inhibitors in future clinical trials, similar to lung cancer. It is reasonable to speculate that molecular alterations in FF can also be detected in FF by transbronchial cryobiopsy.

Keywords: IPF; PCR; UIP; c-MET; fibroblast foci; immunohistochemistry.

PubMed Disclaimer

Conflict of interest statement

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. All the material (text, tables and images) used for the current research article is entirely original and never published elsewhere.

Figures

Figure 1.
Figure 1.
A case of IPF with several fibroblastic foci (blue circles) characterized by a superficial layer of epithelial cells (blue arrows) covering the proliferation of fibro/myofibroblastic mesenchymal component (hematoxylin-eosin, magnification x 100).
Figure 2.
Figure 2.
A case of IPF with several fibroblastic foci before (orange circles) and after (blue circles) microdissection using an hematoxylin-eosin-stained slide without coverslide (hematoxylin-eosin, magnification x 100). Microdissection included all epithelial and mesenchymal components (sandwich) of fibroblastic foci.
Figure 3.
Figure 3.
Electropherogram of direct Sanger showing of the c-MET exon 14 evidencing a wild type gene.
Figure 4.
Figure 4.
FISH analysis using a MET/CEN7 dual color probe in epithelial and mesenchymal cells of fibroblastic foci showed a regular < 2 MET/CEN7 ratio.
Figure 5.
Figure 5.
A case of IPF with fibroblastic foci (A, hematoxylin-eosin staining, magnification x 200) showing overexpression of c-MET (clone SP44) in the epithelial component (indicated by blue hashtags) but not in mesenchymal part (red crosstrees) of fibroblastic foci (immunohistochemistry, magnification x 200) or other lung structures.
See this image and copyright information in PMC

References

    1. Travis WD, Costabel U, Hansell DM, et al. . An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:733-748. https://doi.org/10.1164/rccm.201308-1483ST 10.1164/rccm.201308-1483ST - DOI - PMC - PubMed
    1. Raghu G, Remy-Jardin M, Richeldi L, et al. . Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med 2022;205:e18-e47. https://doi.org/10.1164/rccm.202202-0399ST 10.1164/rccm.202202-0399ST - DOI - PMC - PubMed
    1. Spagnolo P, Kropski JA, Jones MG, et al. . Idiopathic pulmonary fibrosis: disease mechanisms and drug development. Pharmacol Ther 2021;222:107798. https://doi.org/10.1016/j.pharmthera.2020.107798 10.1016/j.pharmthera.2020.107798 - DOI - PMC - PubMed
    1. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol Mech Dis 2014;9:157-179. https://doi.org/10.1146/annurev-pathol-012513-104706 10.1146/annurev-pathol-012513-104706 - DOI - PMC - PubMed
    1. Raghu G, Remy-Jardin M, Ryerson CJ, et al. . Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med 2020;202:e36-e69. https://doi.org/10.1164/rccm.202005-2032ST 10.1164/rccm.202005-2032ST - DOI - PMC - PubMed

MeSH terms

Substances