journal article·2021-05-15Open access

Antitumor Effects in Gas Plasma-Treated Patient-Derived Microtissues—An Adjuvant Therapy for Ulcerating Breast Cancer?

Zahra Akbari, Fariba Saadati, Hamed Mahdikia, Eric Freund, Fereshteh Abbasvandi, Babak Shokri, Hakimeh Zali, Sander Bekeschus

Applied Sciences· Volume 11· Issue 10

Abstract

Despite global research and continuous improvement in therapy, cancer remains a challenging disease globally, substantiating the need for new treatment avenues. Medical gas plasma technology has emerged as a promising approach in oncology in the last years. Several investigations have provided evidence of an antitumor action in vitro and in vivo, including our recent work on plasma-mediated reduction of breast cancer in mice. However, studies of gas plasma exposure on patient-derived tumors with their distinct microenvironment (TME) are scarce. To this end, we here investigated patient-derived breast cancer tissue after gas plasma-treated ex vivo. The tissues were disjoint to pieces smaller than 100 µm, embedded in collagen, and incubated for several days. The viability of the breast cancer tissue clusters and their outgrowth into their gel microenvironment declined with plasma treatment. This was associated with caspase 3-dependent apoptotic cell death, paralleled by an increased expression of the anti-metastatic adhesion molecule epithelial (E)-cadherin. Multiplex chemokine/cytokine analysis revealed a marked decline in the release of the interleukins 6 and 8 (IL-6, IL-8) and monocyte-chemoattractant-protein 1 (MCP) known to promote a cancer-promoting milieu in the TME. In summary, we provide here, for the first time, evidence of a beneficial activity of gas plasma exposure on human patient-derived breast cancer tissue.
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Research context

OpenAlex topics: Plasma Applications and Diagnostics

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran

ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), 17489 Greifswald, Germany

Laser and Plasma Research Institute, Shahid Beheshti University, Tehran 19839-69411, Iran

Department of General, Vascular, Thoracic, and Visceral Surgery, Greifswald University Medical Center, 17475 Greifswald, Germany

Nano Electronic Center of Excellence, Nano Bio Electronic Devices Lab, School of Electrical and Computer Engineering, University of Tehran, Tehran 14174-66191, Iran

ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, Tehran 14155-6615, Iran

Physics Department, Shahid Beheshti University, Tehran 19839-63113, Iran

Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19857-17443, Iran

Funding

Bundesministerium für Bildung, Wissenschaft und Forschung

References (89)

Show source-provided references
1. Breast cancer in the world: Incidence and mortality
2. Breast cancer in developing countries: Opportunities for improved survival10.1155/2010/595167 ↗
3. Cancer incidence and mortality worldwide: Sources, methods and major patterns in globocan 201210.1002/ijc.29210 ↗
4. Research needs in breast cancer10.1093/annonc/mdw571 ↗
5. Thioredoxin-mediated redox regulation of resistance to endocrine therapy in breast cancer
6. Hypoxia-inducible factors: Coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype10.15252/embj.201695204 ↗
7. Direct (1)o2 optical excitation: A tool for redox biology10.1016/j.redox.2017.05.011 ↗
8. Redox potential and ros-mediated nanomedicines for improving cancer therapy10.1089/ars.2017.7370 ↗
9. New combination treatment from ros-induced sensitized radiotherapy with nanophototherapeutics to fully eradicate orthotopic breast cancer and inhibit metastasis10.1016/j.biomaterials.2020.120229 ↗
10. Ros from physical plasmas: Redox chemistry for biomedical therapy
11. Perspective: The physics, diagnostics, and applications of atmospheric pressure low temperature plasma sources used in plasma medicine10.1063/1.4993710 ↗
12. Adil, B.H., Al-Shammari, A.M., and Murbat, H.H. (2020). Breast cancer treatment using cold atmospheric plasma generated by the fe-dbd scheme. Clin. Plasma Med., 19–20.10.1016/j.cpme.2020.100103 ↗
13. Boisvert, J.-S., Lafontaine, J., Glory, A., Coulombe, S., and Wong, P. (2020). Comparison of three radio-frequency discharge modes on the treatment of breast cancer cells in vitro. IEEE Trans. Radiat. Plasma Med. Sci., 644–654.10.1109/TRPMS.2020.2994870 ↗
14. Combination of cold atmospheric plasma and iron nanoparticles in breast cancer: Gene expression and apoptosis study10.2147/OTT.S95644 ↗
15. Jezeh, M.A., Tayebi, T., Khani, M.R., Niknejad, H., and Shokri, B. (2020). Direct cold atmospheric plasma and plasma-activated medium effects on breast and cervix cancer cells. Plasma Process. Polym.10.1002/ppap.201900241 ↗
16. Lafontaine, J., Boisvert, J.S., Glory, A., Coulombe, S., and Wong, P. (2020). Synergy between non-thermal plasma with radiation therapy and olaparib in a panel of breast cancer cell lines. Cancers, 12.10.3390/cancers12020348 ↗
17. Cold atmospheric plasma restores tamoxifen sensitivity in resistant mcf-7 breast cancer cell10.1016/j.freeradbiomed.2017.06.017 ↗
18. Selective effects of non-thermal atmospheric plasma on triple-negative breast normal and carcinoma cells through different cell signaling pathways10.1038/s41598-017-08792-3 ↗
19. Park, S., Kim, H., Ji, H.W., Kim, H.W., Yun, S.H., Choi, E.H., and Kim, S.J. (2019). Cold atmospheric plasma restores paclitaxel sensitivity to paclitaxel-resistant breast cancer cells by reversing expression of resistance-related genes. Cancers, 11.10.3390/cancers11122011 ↗
20. Wang, M., Holmes, B., Cheng, X., Zhu, W., Keidar, M., and Zhang, L.G. (2013). Cold atmospheric plasma for selectively ablating metastatic breast cancer cells. PLoS ONE, 8.10.1371/journal.pone.0073741 ↗
21. Synergistic effect of cold atmospheric plasma and drug loaded core-shell nanoparticles on inhibiting breast cancer cell growth10.1038/srep21974 ↗
22. Elucidation of in vitro cellular steps induced by antitumor treatment with plasma-activated medium10.1038/s41598-019-41408-6 ↗
23. Physical plasma-treated saline promotes an immunogenic phenotype in ct26 colon cancer cells in vitro and in vivo10.1038/s41598-018-37169-3 ↗
24. Tumor cytotoxicity and immunogenicity of a novel v-jet neon plasma source compared to the kinpen10.1038/s41598-020-80512-w ↗
25. Low-temperature plasma-induced antiproliferative effects on multi-cellular tumor spheroids10.1088/1367-2630/16/4/043027 ↗
26. Hasse, S., Meder, T., Freund, E., von Woedtke, T., and Bekeschus, S. (2020). Plasma treatment limits human melanoma spheroid growth and metastasis independent of the ambient gas composition. Cancers, 12.10.3390/cancers12092570 ↗
27. Freund, E., Spadola, C., Schmidt, A., Privat-Maldonado, A., Bogaerts, A., von Woedtke, T., Weltmann, K.D., Heidecke, C.D., Partecke, L.I., and Kading, A. (2020). Risk evaluation of emt and inflammation in metastatic pancreatic cancer cells following plasma treatment. Front. Phys., 8.10.3389/fphy.2020.569618 ↗
28. Gas plasma irradiation of breast cancers promotes immunogenicity, tumor reduction, and an abscopal effect in vivo10.1080/2162402X.2020.1859731 ↗
29. Plasma-induced suppression of recurrent and reinoculated melanoma tumors in mice
30. Medical gas plasma jet technology targets murine melanoma in an immunogenic fashion10.1002/advs.201903438 ↗
31. Three-dimensional cell culture: A breakthrough in vivo10.3390/ijms16035517 ↗
32. 2d and 3d cell cultures–a comparison of different types of cancer cell cultures
33. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors10.1089/adt.2014.573 ↗
34. Dynamic cell–matrix interactions modulate microbial biofilm and tissue 3d microenvironments10.1016/j.ceb.2016.05.005 ↗
35. Microenvironment complexity and matrix stiffness regulate breast cancer cell activity in a 3d in vitro model10.1038/srep35367 ↗
36. 3d extracellular matrix mimics: Fundamental concepts and role of materials chemistry to influence stem cell fate10.1021/acs.biomac.0c00045 ↗
37. 3d microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade10.1039/C8LC00322J ↗
38. Synergistic effect of h2o2 and no2 in cell death induced by cold atmospheric he plasma10.1038/srep29098 ↗
39. Freund, E., Miebach, L., Clemen, R., Schmidt, S., Heidecke, A., von Woedtke, T., Weltmann, K., Kersting, S., and Bekeschus, S. (2021). Large volume spark discharge and plasma jet-technology for generating plasma-oxidized saline targeting colon cancer in vitro and in vivo. J. Phys. D Appl. Phys., 129.10.1063/5.0033406 ↗
40. The transcription factor zeb1 (deltaef1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity10.1038/sj.onc.1210508 ↗
41. E-cadherin expression in primary carcinomas of the breast and its distant metastases10.1186/bcr651 ↗
42. Cold atmospheric plasma in cancer therapy10.1063/1.4801516 ↗
43. The lingering mysteries of metastatic recurrence in breast cancer10.1038/s41416-020-01161-4 ↗
44. Cell adhesion molecules10.1126/science.6823544 ↗
45. Oxidative damage to hyaluronan–cd44 interactions as an underlying mechanism of action of oxidative stress-inducing cancer therapy10.1016/j.redox.2021.101968 ↗
46. E-cadherin–integrin crosstalk in cancer invasion and metastasis10.1242/jcs.100115 ↗
47. Bekeschus, S., Freund, E., Spadola, C., Privat-Maldonado, A., Hackbarth, C., Bogaerts, A., Schmidt, A., Wende, K., Weltmann, K.D., and von Woedtke, T. (2019). Risk assessment of kinpen plasma treatment of four human pancreatic cancer cell lines with respect to metastasis. Cancers, 11.10.3390/cancers11091237 ↗
48. Evaluation of non-thermal plasma-induced anticancer effects on human colon cancer cells10.1364/BOE.8.002649 ↗
49. Antitumorigenic effect of atmospheric-pressure dielectric barrier discharge on human colorectal cancer cells via regulation of sp1 transcription factor10.1038/srep43081 ↗
50. Non-thermal gas plasma-induced endoplasmic reticulum stress mediates apoptosis in human colon cancer cells10.3892/or.2016.5038 ↗
51. Effectiveness of plasma treatment on pancreatic cancer cells10.3892/ijo.2015.3149 ↗
52. Effect of plasma-activated lactated ringer’s solution on pancreatic cancer cells in vitro and in vivo10.1245/s10434-017-6239-y ↗
53. Non-thermal plasma-activated medium induces apoptosis of aspc1 cells through the ros-dependent autophagy pathway10.21873/invivo.11755 ↗
54. Welz, C., Emmert, S., Canis, M., Becker, S., Baumeister, P., Shimizu, T., Morfill, G.E., Harreus, U., and Zimmermann, J.L. (2015). Cold atmospheric plasma: A promising complementary therapy for squamous head and neck cancer. PLoS ONE, 10.10.1371/journal.pone.0141827 ↗
55. Non-thermal atmospheric pressure plasma induces apoptosis in oral cavity squamous cell carcinoma: Involvement of DNA-damage-triggering sub-g(1) arrest via the atm/p53 pathway10.1016/j.abb.2014.01.022 ↗
56. Clemen, R., Heirman, P., Lin, A., Bogaerts, A., and Bekeschus, S. (2020). Physical plasma-treated skin cancer cells amplify tumor cytotoxicity of human natural killer (nk) cells. Cancers, 12.10.3390/cancers12123575 ↗
57. Effects of low temperature plasmas on cancer cells10.1002/ppap.201300083 ↗
58. Roles of intracellular and extracellular ros formation in apoptosis induced by cold atmospheric helium plasma and x-irradiation in the presence of sulfasalazine10.1016/j.freeradbiomed.2018.10.434 ↗
59. Redox-regulation of activator protein 1 family members in blood cancer cell lines exposed to cold physical plasma-treated medium10.1002/ppap.201600090 ↗
60. Akter, M., Jangra, A., Choi, S.A., Choi, E.H., and Han, I. (2020). Non-thermal atmospheric pressure bio-compatible plasma stimulates apoptosis via p38/mapk mechanism in u87 malignant glioblastoma. Cancers, 12.10.3390/cancers12010245 ↗
61. The effect of tuning cold plasma composition on glioblastoma cell viability10.1371/journal.pone.0098652 ↗
62. Cold atmospheric plasma treatment of melanoma and glioblastoma cancer cells10.1002/ppap.201600116 ↗
63. Cold atmospheric plasma and silymarin nanoemulsion synergistically inhibits human melanoma tumorigenesis via targeting hgf/c-met downstream pathway10.1186/s12964-019-0360-4 ↗
64. Pro-apoptotic noxa is implicated in atmospheric-pressure plasma-induced melanoma cell death10.1088/0022-3727/48/46/464002 ↗
65. Preferential induction of apoptotic cell death in melanoma cells as compared with normal keratinocytes using a non-thermal plasma torch10.4161/cbt.21787 ↗
66. Bekeschus, S., Moritz, J., Helfrich, I., Boeckmann, L., Weltmann, K.D., Emmert, S., Metelmann, H.R., Stoffels, I., and von Woedtke, T. (2020). Ex vivo exposure of human melanoma tissue to cold physical plasma elicits apoptosis and modulates inflammation. Appl. Sci., 10.10.3390/app10061971 ↗
67. Mechanisms of plasma medicine: Coupling plasma physics, biochemistry, and biology10.1109/TRPMS.2017.2710880 ↗
68. Bekeschus, S., Liebelt, G., Menz, J., Berner, J., Sagwal, S.K., Wende, K., Weltmann, K.D., Boeckmann, L., von Woedtke, T., and Metelmann, H.R. (2021). Tumor cell metabolism correlates with resistance to gas plasma treatment: The evaluation of three dogmas. Free Radic. Biol. Med.10.1016/j.freeradbiomed.2021.02.035 ↗
69. Tanaka, H., Bekeschus, S., Yan, D., Hori, M., Keidar, M., and Laroussi, M. (2021). Plasma-treated solutions (pts) in cancer therapy. Cancers, 13.10.3390/cancers13071737 ↗
70. Freund, E., and Bekeschus, S. (2020). Gas plasma-oxidized liquids for cancer treatment: Pre-clinical relevance, immuno-oncology, and clinical obstacles. IEEE Trans. Radiat. Plasma Med. Sci., 1.10.1109/TRPMS.2020.3029982 ↗
71. Cold atmospheric plasma-induced acidification of tissue surface: Visualization and quantification using agarose gel models10.1088/1361-6463/ab1119 ↗
72. Two-dimensional concentration distribution of reactive oxygen species transported through a tissue phantom by atmospheric-pressure plasma-jet irradiation10.7567/APEX.9.076202 ↗
73. Slow molecular transport of plasma-generated reactive oxygen and nitrogen species and o2 through agarose as a surrogate for tissue10.1615/PlasmaMed.2016015740 ↗
74. An il6-adenosine positive feedback loop between cd73(+) gammadeltatregs and cafs promotes tumor progression in human breast cancer10.1158/2326-6066.CIR-19-0923 ↗
75. Prospective identification of tumorigenic breast cancer cells10.1073/pnas.0530291100 ↗
76. Neutralization of il-8 decreases tumor pmn-mdscs and reduces mesenchymalization of claudin-low triple-negative breast cancer10.1172/jci.insight.94296 ↗
77. Targeting cxcr1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting her2 via her2-dependent and -independent mechanisms10.1158/1078-0432.CCR-12-1063 ↗
78. The plasma-induced leukemia cell death is dictated by the ros chemistry and the ho-1/cxcl8 axis10.1109/TRPMS.2020.3020686 ↗
79. Ccl2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells10.1158/0008-5472.CAN-11-3567 ↗
80. Pasqual-Melo, G., Sagwal, S.K., Freund, E., Gandhirajan, R.K., Frey, B., von Woedtke, T., Gaipl, U., and Bekeschus, S. (2020). Combination of gas plasma and radiotherapy has immunostimulatory potential and additive toxicity in murine melanoma cells in vitro. Int. J. Mol. Sci., 21.10.3390/ijms21041379 ↗
81. Electrochemotherapy in the treatment of cutaneous metastases from breast cancer: A multicenter cohort analysis10.1245/s10434-015-4779-6 ↗
82. Chung, T.H., Stancampiano, A., Sklias, K., Gazeli, K., Andre, F.M., Dozias, S., Douat, C., Pouvesle, J.M., Santos Sousa, J., and Robert, E. (2020). Cell electropermeabilisation enhancement by non-thermal-plasma-treated pbs. Cancers, 12.10.3390/cancers12010219 ↗
83. Wolff, C.M., Kolb, J.F., Weltmann, K.D., von Woedtke, T., and Bekeschus, S. (2020). Combination treatment with cold physical plasma and pulsed electric fields augments ros production and cytotoxicity in lymphoma. Cancers, 12.10.3390/cancers12040845 ↗
84. Alimohammadi, M., Golpur, M., Sohbatzadeh, F., Hadavi, S., Bekeschus, S., Niaki, H.A., Valadan, R., and Rafiei, A. (2020). Cold atmospheric plasma is a potent tool to improve chemotherapy in melanoma in vitro and in vivo. Biomolecules, 10.10.3390/biom10071011 ↗
85. Effects of a non thermal plasma treatment alone or in combination with gemcitabine in a mia paca2-luc orthotopic pancreatic carcinoma model10.1371/journal.pone.0052653 ↗
86. Liedtke, K.R., Freund, E., Hermes, M., Oswald, S., Heidecke, C.D., Partecke, L.I., and Bekeschus, S. (2020). Gas plasma-conditioned ringer’s lactate enhances the cytotoxic activity of cisplatin and gemcitabine in pancreatic cancer in vitro and in ovo. Cancers, 12.10.3390/cancers12010123 ↗
87. Non-thermal atmospheric plasma induces ros-independent cell death in u373mg glioma cells and augments the cytotoxicity of temozolomide10.1038/bjc.2016.12 ↗
88. Combination of chemotherapy and physical plasma elicits melanoma cell death via upregulation of slc22a1610.1038/s41419-018-1221-6 ↗
89. Enhanced anticancer efficacy by drug chemotherapy and cold atmospheric plasma against melanoma and glioblastoma cell lines in vitro10.1109/TRPMS.2018.2789659 ↗