Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells

Our plain-English summary of Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells, by X. He, L. Wang, H. Riedel, et al (Molecular Cancer, 2017).

The study

• Authors: X. He, L. Wang, H. Riedel, K. Wang, Y. Yang, C.Z. Dinu, Y. Rojanasakul
• Journal: Molecular Cancer
• Published: 2017;16(1):63
• Cited by: 97 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Lung cancer and pleural mesothelioma are two of the most deadly forms of cancer. The prognosis of lung cancer and mesothelioma is extremely poor due to limited treatment modalities and lack of understanding of the disease mechanisms. We have identified mesothelin as a potentially unique therapeutic target that as a specific advantage appears nonessential in most cell types. Mesothelin (MSLN), a plasma membrane differentiation antigen, is expressed at a high level in many human solid tumors, including 70% of lung cancer and nearly all mesotheliomas. However, the role of MSLN in the disease process and underlying mechanisms is largely unknown.

Methods: ShRNA knockdown and overexpression of MSLN were performed in human cancer cell lines and corresponding normal cells, respectively. Tumorigenic and metastatic effects of MSLN were examined by tumor sphere formation, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo. EMT and CSCs were detected by qPCR array, immunoblotting and flow cytometry.

Results: MSLN plays a key role in controlling epithelial-to-mesenchymal transition (EMT) and stem properties of human lung cancer and mesothelioma cells that control their tumorigenicity and metastatic potential. Firstly, MSLN was found to be highly upregulated in non-small cell lung cancer (NSCLC) patient tissues and in lung carcinoma and mesothelioma cell lines. Secondly, genetic knockdown of MSLN significantly reduced anchorage-independent cell growth, tumor sphere formation, cell adhesion, migration and invasion in vitro, as well as tumor formation and metastasis in vivo. Thirdly, ectopic overexpression of MSLN induced the malignant phenotype of non-cancerous cells, supporting its role as an oncogene. Finally, mechanistic studies revealed that knockdown of MSLN reversed EMT and attenuated stem cell properties, in addition to inhibiting tumor growth and metastasis.

Conclusions: These results indicate an essential role of MSLN in controlling EMT and stem cell properties of human lung cancer and mesothelioma cells. Since EMT is an important process in tumor progression and metastasis, and MSLN is nonessential in most normal tissue, our findings on MSLN may provide new insights into the disease mechanisms and may aid in the development of novel targeted therapy for lung cancer and mesothelioma.

In plain English

This was a laboratory study of mesothelin (MSLN) in human lung cancer and pleural mesothelioma cells, using cultured cell lines, patient tumour tissue and mice; asbestos is mentioned only in the background as a major cause of mesothelioma. Ten pairs of human lung tumour and adjacent normal tissue were tested by Western blot: MSLN was undetectable in all normal tissues and clearly present in 5 of 10 tumours, with increases of 2-10 fold over matched controls. MSLN was also higher in the cancer lines (A549, H460, H2052) than in non-cancer BEAS-2B and MeT5A cells. Knocking MSLN down with shRNA in H460 and H2052 cells slowed proliferation and reduced soft agar colonies, tumour spheres, migration and invasion, while raising adhesion. In NSG mice (6 per group) knockdown cells formed smaller tumours and fewer metastatic nodules; liver and lung nodules occurred in all control mice but in only one of six knockdown mice. Knockdown raised CDH1 (28.5 fold), MITF (26 fold) and CAV2 (9 fold) and lowered TWIST (13 fold), and reduced ALDH activity. Overexpressing MSLN in non-cancerous MeT5A cells increased colony formation, migration and invasion. The authors concluded MSLN controls epithelial-to-mesenchymal transition and stem cell properties in these cells.

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 study: human cell line experiments (shRNA knockdown and plasmid overexpression), patient tumour tissue analysis, and mouse xenograft experiment
• Who was studied: Ten paired human lung tumour and adjacent normal tissue specimens from the Lung Cancer Biospecimen Resource Network; human cell lines BEAS-2B, A549, H460, MeT5A and H2052; immunodeficient NSG mice, 6 per group
• Exposure: Genetic manipulation of mesothelin (MSLN): stable shRNA knockdown in H460 lung carcinoma and H2052 pleural mesothelioma cells, and MSLN plasmid overexpression in non-cancerous MeT5A mesothelial cells; no asbestos or fibre exposure was tested
• Main results:
  • In the 10 patient tissue pairs, MSLN was undetectable in all normal tissues and clearly present in 5 of 10 lung tumour tissues
  • The rise in MSLN in the tumour samples ranged from 2-10 fold over the matched normal tissue controls
  • MSLN knockdown clones of H460 and H2052 proliferated more slowly than their scrambled-shRNA vector controls, and formed fewer tumour spheres
  • Knockdown cells formed smaller and fewer tumour spheres than control cells
  • Knockdown cells adhered more tightly to the substrate than control cells (about 2-3 fold more attached cells after rinsing) and showed about 20% more surface area when attached
  • In the xenograft mice, metastatic nodules were found in liver and lungs of all control (shC) mice but in only one of six mice in the knockdown group
  • EMT gene array in knockdown versus control cells: CDH1 (E-cadherin) was upregulated 28.5 fold
  • CAV2 (caveolin-2) was upregulated 9 fold in the MSLN knockdown cells
  • MITF was upregulated 26 fold in the MSLN knockdown cells
  • TWIST was downregulated 13 fold, and EGF, FN1 and snail1 were reduced by 3-7 fold, in the knockdown cells
  • MSLN knockdown reduced ALDH activity in H460 lung carcinoma and H2052 mesothelioma cells
  • Overexpressing MSLN in non-cancerous MeT5A mesothelial cells produced multiple large soft agar colonies, whereas control MeT5A cells formed no or very few small colonies
  • The authors reported that MSLN overexpression in MeT5A cells also increased migration and invasion
• The authors' conclusion: The authors concluded that MSLN has a role in EMT regulation, tumorigenesis and metastasis of lung carcinoma and mesothelioma cells, and could be a potential therapeutic target
• Limitations the authors state:
  • The authors stated that the effect of MSLN on EMT may depend on the cell line used, citing a different result in the H2373 mesothelioma line
  • The authors stated the physiological role of MSLN and its pathological mechanism in cancer are not well defined

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Lung Cancer, Mesothelioma, Pleural Mesothelioma, Prognosis, STEM, Non-Small Cell Lung Cancer, Carcinoma.

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• Multi-walled carbon nanotubes directly induce epithelial-mesenchymal transition in human bronchial epithelial cells via the TGF-β-mediated Akt/GSK-3β/SNAIL-1 signalling pathway — M. Polimeni, G.R. Gulino, et al. (2016)
• Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event — S. Turini, L. Bergandi, et al. (2019)
• Epithelial-mesenchymal transition involved in pulmonary fibrosis induced by multi-walled carbon nanotubes via TGF-beta/Smad signaling pathway — T. Chen, H. Nie, et al. (2014)
• FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal — K. Schelch, C. Wagner, et al. (2018)

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