Abstract
Simple SummaryCold atmospheric plasma (CAP) and plasma-activated medium (PAM) are known to selectively kill cancer cells, however the efficacy of CAP in cancer cells following epithelial-mesenchymal transition (EMT), a process which endows cancer cells with increased stemness, metastatic potential, and resistance to conventional therapies, has not been previously examined. We have used several established models of EMT to show that PAM is significantly more active in cancer cells exhibiting EMT than their epithelial counterparts. We further show that this enhancement correlated with increased levels of reactive oxygen species (ROS) in the mesenchymally-shifted cell lines. Cold atmospheric plasma (CAP) has emerged as a highly selective anticancer agent, most recently in the form of plasma-activated medium (PAM). Since epithelial–mesenchymal transition (EMT) has been implicated in resistance to various cancer therapies, we assessed whether EMT status is associated with PAM response. Mesenchymal breast cancer cell lines, as well as the mesenchymal variant in an isogenic EMT/MET human breast cancer cell system (PMC42-ET/LA), were more sensitive to PAM treatment than their epithelial counterparts, contrary to their responses to other therapies. The same trend was seen in luminal muscle-invasive bladder cancer model (TSU-Pr1/B1/B2) and the non-muscle-invasive basal 5637 bladder cancer cell line. Three-dimensional spheroid cultures of the bladder cancer cell lines were less sensitive to the PAM treatment compared to their two-dimensional counterparts; however, incrementally better responses were again seen in more mesenchymally-shifted cell lines. This study provides evidence that PAM preferentially inhibits mesenchymally-shifted carcinoma cells, which have been associated with resistance to other therapies. Thus, PAM may represent a novel treatment that can selectively inhibit triple-negative breast cancers and a subset of aggressive bladder cancers, which tend to be more mesenchymal. Our approach may potentially be utilized for other aggressive cancers exhibiting EMT and opens new opportunities for CAP and PAM as a promising new onco-therapy.
Highlights
Cold atmospheric plasma (CAP) represents an emerging onco-therapeutic approach offering a new opportunity to effectively manage aggressive cancers [1,2]
We tested the relationship between epithelial–mesenchymal transition (EMT) status and viability of cells in response to plasma-activated medium (PAM)
In human breast cancer cell lines, we observed incrementally greater responses of the cell lines to PAM treatment as they progressed from Luminal (MCF-7) to Basal A/BL1 (MDA-MB-468) and Basal B/M (MDA-MB-231)
Summary
Cold atmospheric plasma (CAP) represents an emerging onco-therapeutic approach offering a new opportunity to effectively manage aggressive cancers [1,2]. In addition to the direct CAP strategy, CAP activity can be transferred to liquids (i.e., plasma activated medium (PAM)), adding flexibility to the application of plasma therapy [4,5,6]. PAM, produced by activating culture medium with CAP, has been found to selectively cause a significant reduction in the viability of cancer cells, including breast cancer [7], bladder cancer [8], osteosarcoma [9], and skin cancer [10] cells. Epithelial-mesenchymal transition (EMT) is an important cellular process during organ development through which cells lose their epithelial features at the cellular and molecular levels, and acquire mesenchymal traits such as stellate morphology, reduced adhesion, and increased migration [11]. EMT processes are hijacked by malignant epithelial cells, leading to increased mobility and invasion, and in some cases, reduced proliferation [12]. Successful metastasis requires MET to revert the phenotype to an epithelial state [13]
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