Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network

Our plain-English summary of Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network, by Q. Li, W. Wang, T. Yamada, et al (The American Journal of Pathology, 2011).

The study

• Authors: Q. Li, W. Wang, T. Yamada, K. Matsumoto, K. Sakai, Y. Bando, H. Uehara, Y. Nishioka, S. Sone, S. Iwakiri, K. Itoi, T. Utsugi, K. Yasumoto, S. Yano
• Journal: The American Journal of Pathology
• Published: 2011;179(3):1483-93
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The tumor microenvironment is crucial to the progression of various malignancies. Malignant pleural mesothelioma (MPM), which originates from the pleura, grows aggressively in the thoracic cavity. Here we describe an orthotopic implantation SCID mouse model of MPM and demonstrate that α-SMA-positive fibroblast-like cells accumulate in the tumors produced by the human MPM cell lines MSTO-211H and Y-Meso-14. We assessed the interaction between MPM cells and their microenvironments, focusing on tumor-associated fibroblasts. MSTO-211H and Y-Meso-14 cells produced fibroblast growth factor-2 (FGF-2) and/or platelet-derived growth factor-AA (PDGF-AA); they also enhanced growth, migration, and production of hepatocyte growth factor (HGF) by human lung fibroblast MRC-5 cells. MRC-5 cells stimulated HGF-mediated growth and migration of MSTO-211H and Y-Meso-14 cells in an in vitro coculture system. In the orthotopic model, tumor formation by MSTO-211H and Y-Meso-14 cells was significantly inhibited by TSU-68, an inhibitor of FGF, VEGF, and PDGF receptors; imatinib, an inhibitor of PDGF receptors; and NK4, an antagonist of HGF. Histological analyses of clinical specimens from 51 MPM patients revealed considerable tumor-associated fibroblasts infiltration and expression of HGF, together with FGF-2 or PDGF-AA, in tumors. These findings indicate that MPM instigates tumor-associated fibroblasts, promoting tumor progression via a malignant cytokine network. Regulation of this cytokine network may be therapeutically useful for controlling MPM.

Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

In plain English

This was a laboratory study of malignant pleural mesothelioma (MPM). It used human MPM cell lines, mice injected with those cells into the chest cavity, and tumor samples from 51 patients from Hyogo Prefectural Amagasaki Hospital in Japan. Patients' asbestos exposure was recorded as yes for 18 (35%), no for 13 (25%) and unknown for 20 (39%), but the study did not analyze whether exposure was related to its findings. In cell experiments, two MPM cell lines (MSTO-211H and Y-Meso-14) released the growth factors FGF-2 and/or PDGF-AA. These stimulated fibroblasts (supporting connective-tissue cells) to grow and to make another factor, HGF. HGF in turn increased the growth and movement of those two MPM cell lines, but not a third line, EHMES-10. In mice, the drugs TSU-68 and imatinib, and the HGF blocker NK4 at 9 mg/kg, significantly reduced chest tumor growth. In patient samples, 46 of 51 tumors stained positive for FGF-2, 40 for PDGF-AA and 50 for HGF. The authors concluded that blocking these three molecules together may be clinically beneficial. That idea was not tested in patients in this study.

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 combining cell-culture experiments, an orthotopic (chest-cavity) implantation mouse model, and staining of tumor specimens from patients
• Who was studied: Human MPM cell lines (MSTO-211H, EHMES-10, Y-Meso-14), human and mouse fibroblast cell lines, SCID mice, and tumor biopsy specimens from 51 MPM patients from Hyogo Prefectural Amagasaki Hospital, Japan (42 men, 9 women; median age 67, range 38 to 80). Dates of specimen collection are not given.
• Exposure: The study recorded patients' asbestos-exposure status: yes for 18 (35%), no for 13 (25%) and unknown for 20 (39%) of the 51 patients. It did not experimentally investigate asbestos, name any fiber types, or analyze whether exposure was related to the findings. The experimental treatments in mice were TSU-68 (200 mg/kg), imatinib (25 or 50 mg/kg) and NK4 (3 or 9 mg/kg).
• Main results:
  • In cell culture, MSTO-211H and Y-Meso-14 MPM cells secreted high concentrations of PDGF-AA, and MSTO-211H cells contained large amounts of FGF-2.
  • Fibroblast cells (MRC-5), but not the MPM cell lines, produced high levels of HGF. FGF-2 and PDGF-AA stimulated HGF production by the fibroblasts.
  • HGF enhanced the growth of MSTO-211H cells, and an anti-HGF antibody blocked this effect. HGF also stimulated Y-Meso-14 cells, but it stimulated neither the growth nor the motility of EHMES-10 cells.
  • When grown together with MPM cells, fibroblasts stimulated the growth of MSTO-211H cells. TSU-68 and combined antibodies against FGF-2 and PDGF blocked this effect.
  • In mice with MSTO-211H tumors, median thoracic tumor weight was 164 mg with TSU-68 versus 378 mg in controls. It was 83 mg with imatinib 25 mg/kg and 76 mg with imatinib 50 mg/kg, versus 187 mg in controls. It was 40 mg with NK4 9 mg/kg versus 356 mg in controls. In mice with Y-Meso-14 tumors, median tumor weight was 140 mg with TSU-68, 60 mg with imatinib and 140 mg with NK4, versus 320 mg in controls. All of these differences were marked as statistically significant.
  • In mice with Y-Meso-14 tumors, TSU-68 and imatinib (and NK4) significantly reduced pleural effusion.
  • In NK4-treated mouse tumors, the number of tumor-associated fibroblasts tended to be lower, but the difference was not statistically significant.
  • Of the 51 patient tumors, 46 (90%) stained positive for FGF-2, 40 (78%) for PDGF-AA and 50 (98%) for HGF. All 51 (100%) were positive for MET.
  • Of the 51 patient tumors, 27 (53%) were highly positive for the fibroblast marker alpha-SMA. The amount of tumor-associated fibroblasts did not correlate with the histological type of MPM.
• The authors' conclusion: The authors concluded that a cytokine network between MPM and tumor-associated fibroblasts, involving FGF-2, PDGF-AA and HGF, exists in a population of MPM patients. They concluded that inhibiting these three molecules together may be clinically beneficial.
• Limitations the authors state:
  • The cytokine antibody array used did not include PDGF-AA, and its results did not match the ELISA results. The authors attributed this mismatch to the array's relatively lower specificity.

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, Fibroblast, Cytokine, Tumor Microenvironment, Pleura, Platelet-Derived Growth Factor (PDGF).

Related studies

• Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation — S. Takeuchi, K. Fukuda, et al. (2017)
• SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model — T.T. Van, M. Hanibuchi, et al. (2012)
• Conditioned medium from asbestos-exposed fibroblasts affects proliferation and invasion of lung cancer cell lines — S. Yu, H.H. Choi, et al. (2019)
• Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophages — J.C. Bonner, A.R. Osornio-Vargas, et al. (1991)
• Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor — E. Nakataki, S. Yano, et al. (2006)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)

Browse more research in The American Journal of Pathology, or return to medical research.