Cell Biological Effects of Tumor Treating Fields

Abstract

Like many approaches to cancer therapy, Tumor Treating Fields (TTFields) target rapidly dividing cells. During mitosis, TTField-exposed cells progress normally through metaphase but exhibit uncontrolled membrane blebbing at the onset of anaphase, resulting in aberrant mitotic exit. The ability of TTFields to affect mitosis is likely dependent on their interactions with proteins possessing high dipole moments whose function is critical to mitosis. At least two proteins complexes have been proposed as molecular targets based on these criteria, α/β-tubulin and the Septin 2, 6, 7 heterotrimer. α/β-Tubulin heterodimer is the monomeric subunit of microtubules, which are essential for aligning and segregating mitotic chromosomes as well as the proper placement and regulation of the cytokinetic cleavage furrow. The Septin complex organizes and helps to coordinate the force generating actinomycin structures within the cytokinetic cleavage furrow and crosslinks actin bundles in the submembranous cytoskeleton which restrains the hydrostatic pressure produced by furrow ingression. TTFields perturb Septin localization to the anaphase spindle midline and cytokinetic furrow. TTField exposure leads to aberrant mitotic exit and cells exhibit abnormal nuclear architecture, signs of cellular stress, decreased proliferation, and apoptosis that might be influenced by the cell’s p53 mutational status. Thus, TTFields are able to disrupt cell proliferation by specifically perturbing key proteins involved in cell division, leading to mitotic catastrophe and subsequent cell death. Cells dying due to TTField exposure may also exhibit the hallmarks of immunogenic cell death, raising the likelihood that TTField treatment induces an anti-tumor immune response.