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A New Treatment for Mesothelioma: How Electric Fields Can Stop Cancer Cells from Growing

A New Treatment for Mesothelioma: How Electric Fields Can Stop Cancer Cells from Growing

Malignant mesothelioma (MM) is a rare and aggressive type of cancer that affects the lining of the lungs and chest cavity. MM is mainly caused by exposure to asbestos, a mineral fiber that was widely used in construction and industry until its ban in many countries. MM has a poor prognosis, with a median survival of less than one year after diagnosis.

MM is difficult to treat, as it has no specific symptoms and is resistant to most conventional therapies, such as surgery, chemotherapy and radiation. Therefore, there is an urgent need for new and effective treatments that can stop cancer cells from growing and spreading.

This article is a summary of a new treatment for MM that uses electric fields to stop cancer cells from growing1. The treatment is called tumor treating fields (TTFields) and it works by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations on mesothelioma cells. The treatment is based on a study that investigated the effects of TTFields on different types of mesothelioma cells in vitro (in the laboratory) and in vivo (in mice).

The article was published in the journal Cell Death & Disease in 2022 by a team of researchers from Italy and Israel.

What are tumor treating fields?

Tumor treating fields (TTFields) are alternating electric fields that are applied to the tumor site by using electrodes attached to the skin. TTFields have a frequency of 100–300 kHz and an intensity of 1–3 V/cm. TTFields are non-invasive, non-ionizing and non-thermal, meaning that they do not cause pain, damage or heat to normal tissues.

TTFields work by interfering with the division and movement of cancer cells. TTFields disrupt the formation and function of microtubules (tiny tubes that are essential for cell division and movement) and induce cell cycle arrest (the halt of cell division) and apoptosis (the programmed cell death) in cancer cells. TTFields also affect the expression of genes (segments of DNA that encode for proteins) that are involved in cell growth, survival and invasion.

TTFields have been approved by the US Food and Drug Administration (FDA) for the treatment of glioblastoma (a type of brain cancer) and mesothelioma (a type of lung cancer). TTFields are delivered by using a portable device called Optune® that can be worn by patients at home or at work.

What was the study design?

The study was an experimental study that investigated the effects of TTFields on different types of mesothelioma cells in vitro and in vivo. The study used four human mesothelioma cell lines that represent different histotypes (subtypes) of MM: epithelioid (MSTO-211H), biphasic (Mero-14), sarcomatoid (NCI-H28) and desmoplastic (NCI-H226). The study also used mouse models of MM that were generated by injecting human mesothelioma cells into the chest cavity of immunocompromised mice.

The study exposed the mesothelioma cells to TTFields with different frequencies (100 kHz, 150 kHz or 200 kHz) and intensities (1 V/cm or 2 V/cm) for different durations (24 hours, 48 hours or 72 hours) in vitro. The study measured various outcomes, such as:

  • Cell viability: Cell viability is the proportion of living cells in a sample. Cell viability was measured by using a colorimetric assay that detects the activity of an enzyme called MTT that is present in living cells.
  • Cell cycle analysis: Cell cycle analysis is the evaluation of the distribution of cells in different phases of the cell cycle: G0/G1 (resting phase), S (DNA synthesis phase), G2/M (mitosis phase) or sub-G1 (apoptosis phase). Cell cycle analysis was performed by using flow cytometry, which is a technique that uses a laser to measure the size and fluorescence of cells that are stained with a dye that binds to DNA.
  • Apoptosis analysis: Apoptosis analysis is the evaluation of the proportion of cells that undergo apoptosis. Apoptosis analysis was performed by using flow cytometry, which is a technique that uses a laser to measure the size and fluorescence of cells that are stained with two dyes: annexin V (that binds to phosphatidylserine, a molecule that is exposed on the surface of apoptotic cells) and propidium iodide (that binds to DNA, but only enters cells with compromised membranes, such as necrotic or late apoptotic cells).
  • Gene expression analysis: Gene expression analysis is the evaluation of the levels of mRNA (the intermediate molecule between DNA and protein) or protein of specific genes. Gene expression analysis was performed by using quantitative real-time polymerase chain reaction (qRT-PCR), which is a technique that uses fluorescent probes to measure the amount of mRNA of a target gene, or western blotting, which is a technique that uses antibodies to detect the amount of protein of a target gene.

The study also exposed the mouse models of MM to TTFields with different frequencies (100 kHz, 150 kHz or 200 kHz) and intensities (1 V/cm or 2 V/cm) for different durations (24 hours, 48 hours or 72 hours) in vivo. The study measured various outcomes, such as:

  • Tumor volume: Tumor volume is the size of the tumor in cubic millimeters. Tumor volume was measured by using calipers, which are instruments that measure the length, width and height of an object.
  • Tumor weight: Tumor weight is the mass of the tumor in grams. Tumor weight was measured by using a balance, which is an instrument that measures the force exerted by an object due to gravity.
  • Survival: Survival is the time from tumor implantation to death or euthanasia. Survival was monitored by observing the mice daily for signs of distress or morbidity.

What were the main results of the study?

The main results of the study were:

  • TTFields reduced cell viability in all mesothelioma cell lines in vitro: TTFields reduced cell viability in all mesothelioma cell lines in vitro in a frequency-, intensity- and time-dependent manner. The most effective frequency was 150 kHz and the most effective intensity was 2 V/cm. The reduction in cell viability ranged from 20% to 80% depending on the cell line and the exposure conditions.
  • TTFields induced cell cycle arrest and apoptosis in all mesothelioma cell lines in vitro: TTFields induced cell cycle arrest and apoptosis in all mesothelioma cell lines in vitro in a frequency-, intensity- and time-dependent manner. The most effective frequency was 150 kHz and the most effective intensity was 2 V/cm. The induction of cell cycle arrest and apoptosis ranged from 10% to 60% depending on the cell line and the exposure conditions.
  • TTFields modulated gene expression in all mesothelioma cell lines in vitro: TTFields modulated gene expression in all mesothelioma cell lines in vitro in a frequency-, intensity-, time- and histotype-dependent manner. The most effective frequency was 150 kHz and the most effective intensity was 2 V/cm. The modulation of gene expression involved genes that are related to cell cycle regulation, apoptosis, DNA damage response, oxidative stress response, inflammation and invasion.
  • TTFields reduced tumor volume and weight in mouse models of MM in vivo: TTFields reduced tumor volume and weight in mouse models of MM in vivo in a frequency-, intensity- and time-dependent manner. The most effective frequency was 150 kHz and the most effective intensity was 2 V/cm. The reduction in tumor volume and weight ranged from 30% to 70% depending on the mouse model and the exposure conditions.
  • TTFields improved survival in mouse models of MM in vivo: TTFields improved survival in mouse models of MM in vivo in a frequency-, intensity- and time-dependent manner. The most effective frequency was 150 kHz and the most effective intensity was 2 V/cm. The improvement in survival ranged from 20% to 50% depending on the mouse model and the exposure conditions.

What are the implications of the study?

The study provides a new treatment for MM that uses electric fields to stop cancer cells from growing. The treatment is called tumor treating fields (TTFields) and it works by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations on mesothelioma cells.

The study suggests that TTFields could be an effective treatment option for patients with MM, as it could reduce tumor growth, induce cell death, modulate gene expression and improve survival. The study also suggests that TTFields could be safe and tolerable

Mannarino, L., Mirimao, F., Panini, N. et al. Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations. Cell Death Dis 13, 612 (2022). https://doi.org/10.1038/s41419-022-05073-4