Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma

Our plain-English summary of Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma, by F.E. Lennon, G.C. Cianci, R. Kanteti, et al (Scientific Reports, 2016).

The study

• Authors: F.E. Lennon, G.C. Cianci, R. Kanteti, J.J. Riehm, Q. Arif, V.A. Poroyko, E. Lupovitch, W. Vigneswaran, A. Husain, P. Chen, J.K. Liao, M. Sattler, H.L. Kindler, R. Salgia
• Journal: Scientific Reports
• Published: 2016;6:24578
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM), is an intractable disease with limited therapeutic options and grim survival rates. Altered metabolic and mitochondrial functions are hallmarks of MM and most other cancers. Mitochondria exist as a dynamic network, playing a central role in cellular metabolism. MM cell lines display a spectrum of altered mitochondrial morphologies and function compared to control mesothelial cells. Fractal dimension and lacunarity measurements are a sensitive and objective method to quantify mitochondrial morphology and most importantly are a promising predictor of response to mitochondrial inhibition. Control cells have high fractal dimension and low lacunarity and are relatively insensitive to mitochondrial inhibition. MM cells exhibit a spectrum of sensitivities to mitochondrial inhibitors. Low mitochondrial fractal dimension and high lacunarity correlates with increased sensitivity to the mitochondrial inhibitor metformin. Lacunarity also correlates with sensitivity to Mdivi-1, a mitochondrial fission inhibitor. MM and control cells have similar sensitivities to cisplatin, a chemotherapeutic agent used in the treatment of MM. Neither oxidative phosphorylation nor glycolytic activity, correlated with sensitivity to either metformin or mdivi-1. Our results suggest that mitochondrial inhibition may be an effective and selective therapeutic strategy in mesothelioma, and identifies mitochondrial morphology as a possible predictor of response to targeted mitochondrial inhibition.

In plain English

This was a laboratory study of mesothelioma tissue and cell lines. It did not examine asbestos exposure. The authors measured two image-based shape measures, fractal dimension and lacunarity, in stained samples from 36 epithelioid and 20 biphasic mesothelioma tumors and 12 benign hyperplastic controls. Both mesothelioma types had significantly higher fractal dimension and lower lacunarity than benign tissue (p less than 0.0001). Biphasic and epithelioid samples did not differ significantly. The authors then applied these measures to mitochondria, the cell's energy-producing structures, in seven mesothelioma cell lines and one control line, MeT-5A. Every mesothelioma line had significantly lower mitochondrial fractal dimension than the control. In 72-hour drug tests, MeT-5A was the most resistant to metformin (EC50 67.28 mM). Higher lacunarity correlated with greater sensitivity to metformin (r = -0.8974, p = 0.0025) and to mdivi-1 (r = -0.7342, p = 0.0381). Neither measure correlated with sensitivity to cisplatin. The authors wrote that they believe mitochondria are a viable target in mesothelioma, and that mitochondrial shape may indicate sensitivity to drugs targeting mitochondria. They added that larger tissue studies, including sarcomatoid tumors, are needed.

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: image analysis of a tissue microarray of human tumor samples, plus in vitro experiments on mesothelioma and control cell lines
• Who was studied: Tissue: 36 epithelioid and 20 biphasic mesothelioma tumors and 12 hyperplastic/benign controls analyzed, under a University of Chicago review-board-approved protocol. Cell lines: MeT-5A (control, transformed non-tumorigenic mesothelial cells) and seven mesothelioma cell lines, H28, H513, H2052, H2461 (epithelioid), H2373, H2596 (sarcomatoid) and H2452 (biphasic)
• Exposure: No asbestos exposure was studied. Cell lines were exposed to the drugs metformin (described as a complex I inhibitor), mdivi-1 (a DRP-1, mitochondrial fission, inhibitor) and cisplatin (a standard chemotherapy) for 72 hours
• Main results:
  • In tumor tissue, biphasic and epithelioid mesothelioma samples had significantly higher fractal dimension and lower lacunarity than hyperplastic/benign tissue (p less than 0.0001). The difference between biphasic and epithelioid was not statistically significant
  • In ROC analysis distinguishing mesothelioma from benign hyperplasia, the area under the curve for fractal dimension was 96.97% (biphasic) and 91.84% (epithelioid). For lacunarity it was 97.06% (biphasic) and 90.00% (epithelioid)
  • All mesothelioma cell lines had significantly decreased mitochondrial fractal dimension compared with control MeT-5A cells. H513 and H2596 showed the largest changes
  • Basal oxygen consumption rate, a measure of oxidative phosphorylation, was significantly lower in H28, H2052, H2452 and H2596 than in control MeT-5A cells
  • For metformin, control MeT-5A cells were the most resistant of all cell lines (EC50 67.28 mM). H513 and H2596 were the most sensitive (EC50 4.762 mM and 15.8 mM), described as 14 and 4 times more sensitive than MeT-5A
  • For mdivi-1, H28 and MeT-5A were the most resistant (EC50 51.11 μM and 46.0 μM) and H2596 was the most sensitive (EC50 8.722 μM)
  • For cisplatin, H2452 and H28 were the most resistant (EC50 80.13 μM and 66.63 μM) and H513 and H2596 were the most sensitive (EC50 5.5 μM and 6.769 μM)
  • Mitochondrial fractal dimension correlated significantly with metformin EC50 (r = 0.8315, p = 0.0105). Its correlation with mdivi-1 was not significant (r = 0.5726, p = 0.138)
  • Mitochondrial lacunarity was significantly inversely correlated with EC50 for metformin (r = -0.8974, p = 0.0025) and mdivi-1 (r = -0.7342, p = 0.0381), but not with cisplatin (r = -0.4793, p = 0.2294)
  • Oxygen consumption rate did not correlate with sensitivity to any of the drugs tested
• The authors' conclusion: The authors wrote that classifying mitochondria by fractal dimension and lacunarity may be a useful indicator of sensitivity to mitochondrial-targeted inhibition. They also wrote that they believe mitochondria are a viable target in mesothelioma
• Limitations the authors state:
  • Larger numbers of tissue samples, including sarcomatoid tumors, are needed to assess whether the measures can distinguish between mesothelioma subtypes
  • Some tissue samples were missing or damaged, which reduced the number analyzed

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, Mesothelial Cells, Cisplatin.

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