FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal

Our plain-English summary of FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal, by K. Schelch, C. Wagner, S. Hager, et al (Carcinogenesis, 2018).

The study

• Authors: K. Schelch, C. Wagner, S. Hager, C. Pirker, K. Siess, E. Lang, R. Lin, M.B. Kirschner, T. Mohr, L. Brcic, B. Marian, K. Holzmann, B. Grasl-Kraupp, G. Krupitza, V. Laszlo, T. Klikovits, B. Dome, B. Hegedus, T. Garay, G. Reid, N. van Zandwijk, W. Klepetko, W. Berger, M. Grusch, M.A. Hoda
• Journal: Carcinogenesis
• Published: 2018;39(4):534-545
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.

In plain English

This laboratory study of mesothelioma cells grown in dishes did not study asbestos exposure. The authors treated cell lines mainly from biphasic malignant pleural mesothelioma and compared them with epithelioid and sarcomatoid lines. They studied what makes cells switch from a compact epithelioid shape to a spread-out, fibroblast-like shape. FGF2 and EGF caused this switch in several biphasic lines; other lines did not change shape with FGF2. Treated cells also attached less firmly, invaded more and grew more in soft agar. In the two main lines, other factors, including TGF beta, did not cause comparable changes; two epithelioid lines responded moderately to TGF beta. Blocking the MAP-kinase pathway prevented the scattering and shape changes; blocking PI3K/AKT did not. Blocking MMP1 prevented FGF2-induced scattering, and blocking FGF receptors made sarcomatoid-looking lines look more epithelioid. Staining of 13 tumor specimens showed no significant difference between subtypes. Endocan (ESM1), measured in 32 serum samples, was not raised in any subtype. The authors concluded that their findings suggest a critical role of the MAP-kinase axis in these changes of shape and behavior.

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 (in vitro) study of mesothelioma cell lines, with additional analysis of tumor tissue specimens and serum samples
• Who was studied: Malignant pleural mesothelioma cell lines. The growth-factor experiments used mainly M38K and SPC212, which come from biphasic MPM. Other lines included VMC58 (biphasic) and Meso84, Meso62 and Meso80 (sarcomatoid). For comparison, expression data came from 15 epithelioid and 3 sarcomatoid cell lines. The study also used 13 MPM tissue specimens, two normal pleura controls and 32 serum samples. The article does not state where or when the patients were recruited.
• Exposure: Cells were treated with the growth factors FGF2 and EGF, and with other cytokines for comparison. Some treatments were combined with drugs that block specific signaling pathways. Asbestos exposure was not studied.
• Main results:
  • Of the cytokines tested in M38K and SPC212 cells, only FGF2 and EGF induced scattering and fibroblast-like shape changes. FGF18, HGF, PDGF, TGF beta and BMP2 did not.
  • Two epithelioid cell lines in the panel showed a moderate EMT-like response to TGF beta.
  • The other MPM cell lines in the panel did not show EMT-like shape changes after FGF2 treatment.
  • Inhibitors of the MAPK pathway prevented the scattering and shape changes caused by FGF2 or EGF. Inhibitors of the PI3K/AKT pathway did not.
  • In the treated cell lines, FGF2 and EGF decreased adhesion and increased both invasion and growth in soft agar.
  • In M38K and SPC212 cells, FGF2 changed the expression of 39 genes by more than 3-fold, and EGF changed 33.
  • The gene expression pattern of growth factor-treated cells grouped with that of sarcomatoid cell lines (n = 3). The untreated controls grouped with epithelioid cell lines (n = 15).
  • In M38K cells, an MMP inhibitor and MMP1-targeting siRNA both prevented FGF2-induced shape changes and scattering. Blocking Ets-family factors or ESM1 had no effect.
  • Blocking FGF receptors shifted VMC58 (biphasic) and Meso84 (sarcomatoid) cells toward an epithelioid-like shape.
  • In the 13 tissue specimens, staining for pERK and MMP1 showed no significant difference between histological subtypes.
  • In the four biphasic tumors, there was a trend toward higher ERK phosphorylation and MMP1 in the sarcomatoid parts of the tumor than in the epithelioid parts.
  • ESM1 (endocan) was measured in 32 serum samples. It was not upregulated in the blood of MPM patients, regardless of subtype.
• The authors' conclusion: The authors concluded that their findings suggest a critical role of the MAP-kinase axis in the changes of shape and behavior of mesothelioma cells.
• Limitations the authors state:
  • The authors stated that it is currently impossible to trace which part of a biphasic tumor a given cell line came from.
  • The authors noted that the cytokine concentrations that induce EMT in cultured cells usually exceed those found in human plasma.
  • The authors attributed the lack of a significant difference between subtypes in tissue staining to high variability between samples.

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: Pleural Mesothelioma, Histological Subtype, Epithelioid, Sarcomatoid, Biphasic Mesothelioma, Prognosis, Mesothelioma.

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