# Cold Atmospheric Pressure Plasma in Wound Healing and Cancer Treatment
## 4 Properties of CAP Stimulate Tissue Regeneration but May also Induce Cell Death
RONS play an important role in initiating CAP induced apoptosis by directly oxidizing cellular proteins, lipids, or nucleic acids and causing general damage and dysfunction. Death receptors, such as tumor necrosis factor (TNF) receptor-I, enhance the generation of RONS via the mitochondria, leading to the activation of caspases and cell death. However, TNF-induced oxidative stress also activates anti-apoptotic signaling by increasing the expression levels of MnSOD and catalase by nuclear factor-\(\kappa\)B (NF-\(\kappa\)B) [86]. NF-\(\kappa\)B, in turn, activates the transcription of various genes, such as the uPA and different matrix metalloproteinases [87; 88; 89]. These proteases increase motility of different cell types, such as endothelial cells [90; 91] and mesenchymal stem/stromal cells [92; 93], which is necessary for the reorganization processes in both wound healing and tumor development [94; 95]. Taken together, these examples demonstrate that CAP generated RONS may trigger a variety of mechanisms leading to growth arrest or cell death via apoptosis or necrosis. Besides typically elevated levels of RONS in cancer, there are further common differences between cancer cells and their non-malignant counterparts that render these cells more vulnerable to extrinsic oxidative stress than normal cells. While minimal amounts of RONS may diffuse through the cell membrane, it has been suggested that the transition of reactive species into the cytosol is facilitated by aquaporins, which are often increased in membranes of cancer cells [96]. Diffusion of RONS into the cell may also be facilitated by lipid peroxidation caused by reactive species, which then leads to pore formation in the membrane. This effect may be enhanced in cancer cells, due to lower levels of cholesterol in cancer cells [97]. Cholesterol is a lipid important for providing membrane stability and fluidity. These distinct properties of many cancer cells render them especially sensitive and may promote the selective killing of cancer cells through CAP treatment. Lipid peroxidation was, however, only a minor contributor in a recent study that investigated plasma-induced cell death mechanisms [98]. The fact that CAP may enhance proliferation and angiogenesis in wound healing, sparks the question if CAP used for cancer treatment may pose a risk for carcinogenesis and have tumor-promoting effects. In studies assessing treatment modalities used for wound healing, no apparent side effects, including mutagenicity, tumor formation, or chronic inflammation even one year after CAP treatment, have been observed in mice and humans [14; 99; 100]. Nonetheless, it is a concern that with increased treatment times or intensities for cancer treatment also cancer-promoting effects may be achieved. Therefore, the concern of carcinogenesis or tumor-promoting side effects needs to be addressed in future studies and is already being addressed by existing consortia assessing CAP as a potential cancer therapy in vitro and in vivo. In summary, research elucidating the molecular mechanisms for the efficacy of CAP in wound healing, and cancer treatment revealed that RONS plays a major role in both applications. Treatment duration and intensities determine the concentration of RONS and hence its effect on treated cells regarding stimulation or inhibition of growth.