Modeling Epidermal Growth Factor Inhibitor-mediated Enhancement of Photodynamic Therapy Efficacy Using 3D Mesothelioma Cell Culture

Our plain-English summary of Modeling Epidermal Growth Factor Inhibitor-mediated Enhancement of Photodynamic Therapy Efficacy Using 3D Mesothelioma Cell Culture, by G. Cramer, M. Shin, S. Hagan, et al (Photochemistry and Photobiology, 2019).

The study

• Authors: G. Cramer, M. Shin, S. Hagan, S.I. Katz, C.B. Simone, T.M. Busch, K.A. Cengel
• Journal: Photochemistry and Photobiology
• Published: 2019;95(1):397-405
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We have demonstrated that lung-sparing surgery with intraoperative photodynamic therapy (PDT) achieves remarkably extended survival for patients with malignant pleural mesothelioma (MPM). Nevertheless, most patients treated using this approach experience local recurrence, so it is essential to identify ways to enhance tumor response. We previously reported that PDT transiently activates EGFR/STAT3 in lung and ovarian cancer cells and inhibiting EGFR via erlotinib can increase PDT sensitivity. Additionally, we have seen higher EGFR expression associating with worse outcomes after Photofrin-mediated PDT for MPM, and the extensive desmoplastic reaction associated with MPM influences tumor phenotype and therapeutic response. Since extracellular matrix (ECM) proteins accrued during stroma development can alter EGF signaling within tumors, we have characterized novel 3D models of MPM to determine their response to erlotinib combined with Photofrin-PDT. Our MPM cell lines formed a range of acinar phenotypes when grown on ECM gels, recapitulating the locally invasive phenotype of MPM in pleura and endothoracic fascia. Using these models, we confirmed that EGFR inhibition increases PDT cytotoxicity. Together with emerging evidence that EGFR inhibition may improve survival of lung cancer patients through immunologic and direct cell killing mechanisms, these results suggest erlotinib-enhanced PDT may significantly improve outcomes for MPM patients.

© 2018 The American Society of Photobiology.

In plain English

This was a laboratory study of cancer cell lines grown in dishes. It did not study asbestos exposure or patients. The authors grew malignant pleural mesothelioma (MPM) cell lines in three-dimensional (3D) cultures. They tested whether erlotinib, a drug that blocks a growth-signal receptor called EGFR, made photodynamic therapy (PDT) with the light-activated drug Photofrin kill more cells. Of the culture methods tried, a gel called Matrigel worked best. Two cell lines did not grow well in it. PDT increased activated EGFR in every gel mixture tested. In nodules of the EMP cell line, erlotinib plus PDT produced more dead-cell staining than PDT alone. A marker of programmed cell death appeared at a PDT dose that showed none without erlotinib. In one measurement, 27.0% of cells were dying after the combination, compared with 15.8% after PDT alone, 6.99% after erlotinib alone and 1.19% in untreated cells. The authors called this only slightly more than additive. Erlotinib did not change Photofrin uptake. The authors concluded that the results lend support to erlotinib's potential to improve PDT response clinically.

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) experiment using 3D cell culture of mesothelioma cell lines
• Who was studied: Malignant pleural mesothelioma cell lines AB12 (mouse), M30, OK6, EMP, EMP-GFP, EMM, REN and MSTO-211H (human). Treatment experiments mainly used EMP cells grown on Matrigel.
• Exposure: No asbestos exposure was studied. Cells were treated with erlotinib (an EGFR inhibitor, 8 micromolar in the cell-death analyses) and/or Photofrin (10 micrograms per ml) followed by 632 nm laser light (photodynamic therapy).
• Main results:
  • Matrigel was the most effective 3D culture method. REN and EMP formed consistent acini (rounded cell clusters) around day 7, other cell lines showed a range of growth patterns, and OK6 and M30 did not proliferate well.
  • In EMP cells grown on different Matrigel and collagen I combinations, PDT increased activated (phosphorylated) EGFR in all conditions.
  • In EMP nodules, erlotinib plus PDT increased dead-cell (ethidium homodimer) staining compared with PDT alone. Cleavage of PARP, a marker of programmed cell death, was seen at 4 J/cm2 PDT with erlotinib but not without it.
  • By flow cytometry, the share of apoptotic (sub-G1) EMP cells was 1.19% in untreated cells, 6.99% with erlotinib, 15.8% with PDT and 27.0% with erlotinib plus PDT. The authors described the combination effect as only slightly more than additive.
  • Erlotinib did not alter Photofrin levels in EMP acini.
• The authors' conclusion: The authors concluded that erlotinib increased the direct cytotoxicity of Photofrin-mediated PDT without altering Photofrin uptake. They stated that this lends support to the potential of drugs like erlotinib to improve PDT response clinically.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, EGFR, Ovarian Cancer, Desmoplastic Mesothelioma, Acinar, Pleura, Endothoracic Fascia.

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• Photodynamic therapy for lung cancer and malignant pleural mesothelioma — C.B. Simone, K.A. Cengel (2014)
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