Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo

Our plain-English summary of Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo, by C. Li, V. Rezov, E. Joensuu, et al (Scientific Reports, 2018).

The study

• Authors: C. Li, V. Rezov, E. Joensuu, V. Vartiainen, M. Rönty, M. Yin, M. Myllärniemi, K. Koli
• Journal: Scientific Reports
• Published: 2018;8(1):10070
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive cancer with poor prognosis. It is characterized by prominent extracellular matrix, mesenchymal tumor cell phenotypes and chemoresistance. In this study, the ability of pirfenidone to alter mesothelioma cell proliferation and migration as well as mesothelioma tumor microenvironment was evaluated. Pirfenidone is an anti-fibrotic drug used in the treatment of idiopathic pulmonary fibrosis and has also anti-proliferative activities. Mesothelioma cell proliferation was decreased by pirfenidone alone or in combination with cisplatin. Pirfenidone also decreased significantly Transwell migration/invasion and 3D collagen invasion. This was associated with increased BMP pathway activity, decreased GREM1 expression and downregulation of MAPK/ERK and AKT/mTOR signaling. The canonical Smad-mediated TGF-β signaling was not affected by pirfenidone. However, pirfenidone blocked TGF-β induced upregulation of ERK and AKT pathways. Treatment of mice harboring mesothelioma xenografts with pirfenidone alone did not reduce tumor proliferation in vivo. However, pirfenidone modified the tumor microenvironment by reducing the expression of extracellular matrix associated genes. In addition, GREM1 expression was downregulated by pirfenidone in vivo. By reducing two major upregulated pathways in mesothelioma and by targeting tumor cells and the microenvironment pirfenidone may present a novel anti-fibrotic and anti-cancer adjuvant therapy for mesothelioma.

In plain English

This laboratory study tested pirfenidone, an idiopathic pulmonary fibrosis drug, in mesothelioma cells and mice; asbestos exposure was not studied. The authors treated human mesothelioma cells (JL-1 and H2052 lines and patient-derived JP5 cells) and mouse AB12 cells with pirfenidone for 48 hours; proliferation fell significantly in all. At 750 μg/ml, H2052 proliferation was about 50% of untreated; other cells showed about 70% reduction. Cisplatin had at least an additive effect; pemetrexed added none. Pirfenidone also reduced migration and invasion, raised BMP pathway activity, lowered GREM1 and reduced ERK and AKT signaling, but not canonical Smad-mediated TGF-beta signaling. In mice with JP5 tumors, oral pirfenidone (200 mg/kg/day) produced no detectable difference in tumor luciferase signal and no significant difference in proliferation (mean Ki67-positive area 12.1 percent, SD 1.7, controls; 12.2 percent, SD 2.1, treated; n = 8). It did lower extracellular matrix gene expression. The authors concluded that pirfenidone may present a novel adjuvant therapy for mesothelioma. They noted a higher dose might have been effective and that benefit with chemotherapy remains to be demonstrated.

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: cell culture experiments on mesothelioma cells plus an animal experiment using mesothelioma xenografts in nude mice
• Who was studied: Human mesothelioma cell lines JL-1 and H2052, human JP5 mesothelioma cells obtained from the pleural effusion of a patient with malignant mesothelioma, and the mouse mesothelioma cell line AB12. For the animal experiment, female 6-week-old Balb/c nu/nu mice were randomly divided into two groups (reported as n = 8) at the University of Helsinki Laboratory Animal Center.
• Exposure: No asbestos exposure was studied. Cells were treated with the anti-fibrotic drug pirfenidone (100–750 μg/ml), alone or combined with cisplatin (10 μM) or pemetrexed. Mice received oral pirfenidone at 200 mg/kg/day or PBS (control) for 60 days.
• Main results:
  • All four types of mesothelioma cells tested (human JL-1, H2052 and JP5; mouse AB12) showed significantly reduced proliferation after 48 hours of pirfenidone treatment.
  • At 750 μg/ml, pirfenidone reduced H2052 cell proliferation to about 50% of the untreated level; the other cells showed about a 70% reduction.
  • Cisplatin combined with pirfenidone had at least an additive effect on reducing proliferation in JL-1 and H2052 cells; pemetrexed showed no additional effect.
  • Pirfenidone significantly reduced JL-1 and H2052 cell migration/invasion through collagen-coated inserts in a concentration-dependent manner.
  • In pirfenidone-treated cells, GREM1 expression was significantly reduced and BMP pathway activity increased, but canonical TGF-beta (Smad) signaling was not reduced.
  • Pirfenidone reduced ERK activation induced by TGF-beta and reduced P-AKT levels in TGF-beta-treated cells.
  • In mice, no difference in tumor luciferase signal was detected between control and pirfenidone-treated groups. Mean percent Ki67-positive area (a proliferation measure) was 12.1 (SD 1.7) in controls and 12.2 (SD 2.1) in the pirfenidone group (n = 8), with no significant difference.
  • In tumor tissue, most differentially expressed genes were downregulated by pirfenidone (101 of 127), including an extracellular matrix organization signature of over 30 genes.
  • In treated tumors, MMP2 expression was significantly decreased; FBN1 showed only a trend toward decreased expression (p = 0.073).
• The authors' conclusion: The authors concluded that pirfenidone reduced two major upregulated pathways in mesothelioma and targeted both tumor cells and the microenvironment, and that it may present a novel anti-fibrosis and anti-cancer adjuvant therapy for mesothelioma.
• Limitations the authors state:
  • Effects on metastasis could not be analyzed in the mouse model because a much longer follow-up would have been needed.
  • Only one dose (200 mg/kg/day) was tested in mice; a higher dose may have been effective.
  • Pirfenidone combined with chemotherapy was not tested in mice; the authors' hypothesis of a therapeutic effect remains to be demonstrated.
  • The phospho-kinase screening array was performed only twice.

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: Mesothelioma, Tumor Microenvironment, Prognosis, Mesenchymal Tumor, Idiopathic, Pulmonary Fibrosis, Cisplatin, Collagen.

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