Tumor-Treating Fields Induce RAW264.7 Macrophage Activation Via NK-?B/MAPK Signaling Pathways

Park, Jeong-In; Song, Kyung-Hee; Jung, Seung-Youn; Ahn, Jiyeon; Hwang, Sang-Gu; Kim, Joon; Kim, Eun Ho; Song, Jie-Young

Tumor-treating fields (TTFs) therapy, in which small electric fields are pulsed through the skin to disturb mitosis, represents a noninvasive, regional treatment modality that was recently approved for the therapy of recurrent glioblastoma (GBM) by the US Food and Drug Administration and gained a CE mark in Europe. [1] [2] [3] The clinical concept is that TTFs therapy delivers low-intensity (0.9-3 V/cm), intermediate-frequency (100-300 kHz), and alternating electric fields to the tumor using transducer arrays placed on the skin around the tumor site. 4 The proposed mechanisms of action involve disruption of the metaphase of tumor cells by interfering with mitotic spindle formation and disruption of anaphase by the dielectrophoretic dislocation of intracellular constituents, resulting in an overall effect of apoptosis. 3 The antimitotic effect of TTFs treatment has been showed in various cell lines as well as in GBM by tuning the appropriate frequency to specific cancer cell types. [5] [6] [7] A phase III trial of TTFs combined with temozolomide established that this treatment protocol led to minimal toxicity, increased the overall survival rate, and improved patient quality of life with equivalent therapeutic efficacy to chemotherapy. Moreover, in addition to its combination with chemotherapy, synergistic enhancement of the cellular response was reported when TTFs were administered in combination with radiation therapy. Thus, with these merits, ongoing and future trials will evaluate TTFs to treat various cancer types, including newly diagnosed GBM, solid tumor brain metastases, nonsmall cell lung cancer, ovarian cancer, and pancreatic cancer.