Abstract
The requirements for new technologies to serve as anticancer agents go far beyond their toxicity potential. Novel applications also need to be safe on a molecular and patient level. In a broader sense, this also relates to cancer metastasis and inflammation. In a previous study, the toxicity of an atmospheric pressure argon plasma jet in four human pancreatic cancer cell lines was confirmed and plasma treatment did not promote metastasis in vitro and in ovo. Here, these results are extended by additional types of analysis and new models to validate and define on a molecular level the changes related to metastatic processes in pancreatic cancer cells following plasma treatment in vitro and in ovo. In solid tumors that were grown on the chorion-allantois membrane of fertilized chicken eggs (TUM-CAM), plasma treatment induced modest to profound apoptosis in the tissues. This, however, was not associated with a change in the expression levels of adhesion molecules, as shown using immunofluorescence of ultrathin tissue sections. Culturing of the cells detached from these solid tumors for 6d revealed a similar or smaller total growth area and expression of ZEB1, a transcription factor associated with cancer metastasis, in the plasma-treated pancreatic cancer tissues. Analysis of in vitro and in ovo supernatants of 13 different cytokines and chemokines revealed cell line-specific effects of the plasma treatment but a noticeable increase of, e.g., growth-promoting interleukin 10 was not observed. Moreover, markers of epithelial-to-mesenchymal transition (EMT), a metastasis-promoting cellular program, were investigated. Plasma-treated pancreatic cancer cells did not present an EMT-profile. Finally, a realistic 3D tumor spheroid co-culture model with pancreatic stellate cells was employed, and the invasive properties in a gel-like cellular matrix were investigated. Tumor outgrowth and spread was similar or decreased in the plasma conditions. Altogether, these results provide valuable insights into the effect of plasma treatment on metastasis-related properties of cancer cells and did not suggest EMT-promoting effects of this novel cancer therapy.
Highlights
Cancer is the second leading cause of death worldwide after cardiovascular diseases [1]
This study extends on the previous investigations of four different pancreatic cancer cell lines (MiaPaCa2, PaTuS, PaTuT, and Panc01) and tissue from in ovo-grown tumors, to a more detailed analysis of factors that can mediate an altered cell detachment and outgrowth
Plasma Treatment Partly Elicited Apoptosis of Pancreatic Cancer Cells Grown in ovo To test the anticancer efficacy of cold physical plasma generated via the kINPen, different pancreatic cancer cell lines (MiaPaCa2, PaTuS, PaTuT, and Panc01) were seeded on the chorion-allantois membrane of fertilized chicken eggs (TUM-CAM model) to grow solid tumors before these were plasma-treated twice for 60 s on two consecutive days (Figure 1A)
Summary
Cancer is the second leading cause of death worldwide after cardiovascular diseases [1]. New concepts of cancer therapies are under investigation This includes immunotherapies [2], target-specific drugs [3, 4], or technological innovations such as photodynamic [5, 6] and cold physical plasma therapy [7]. Cold physical plasmas are partially ionized gases generating a plethora of reactive species (ROS) besides other components such as electric fields, temperature, light of different wavelengths, and charged particles [8, 9]. At sufficient concentrations, these species mediate oxidation-induced damage and death in tumor cells [7]. First patients with tumors of the head and neck benefited from this new therapeutic approach and experienced a reduced tumor burden [10, 11]
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