Tumor cell death after electrotransfer of plasmid DNA is associated with cytosolic DNA sensor upregulation

Žnidar, Katarina; Bošnjak, Maša; Semenova, Nina; Pakhomova, Olga N.; Heller, Loree C.; Čemažar, Maja

doi:10.18632/oncotarget.24816

Cited by 21 publications

(18 citation statements)

References 99 publications

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“…Our recent in vivo study demonstrated the antitumor and antivascular effects of intratumoral GET with plasmid DNA-encoding shRNA against MCAM in melanoma B16F10, which resulted in significant tumor growth delay and 17% of tumor cures [15]. Furthermore, in that and in other studies from our group, we showed that the gene electrotransfer of control plasmid DNA, without the therapeutic gene, activated cytosolic DNA sensors that led to the release of inflammatory cytokines and consequently antitumor effectiveness [15,[26][27][28][29]. Furthermore, in our previous studies, exploring the silencing of endoglin (CD105), which is involved in alternative angiogenic pathways in tumors, together with irradiation of tumors, we pointed out also the importance of immunogenicity of tumors to obtain a pronounced antitumor effect [26].In the current study, we explore the potential of the combined treatment utilizing the irradiation of tumors with local GET with plasmid DNA-encoding shRNA against MCAM in two radioresistant tumor models.…”

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confidence: 58%

“…The antitumor effectiveness of nontherapeutic plasmids after GET was demonstrated also in many other studies in different tumor models, such as in melanomas, mammary carcinomas, fibrosarcomas, colorectal carcinomas, lung carcinomas, and pancreatic carcinomas [26,27,29,36,[40][41][42][43][44][45][46][47]. A possible mechanism for this antitumor effect is the activation and upregulation of several cytosolic DNA sensors as a response to foreign DNA in the cells, acting as DAMPs (damage-associated molecular patterns) [28,29,48], inducing also the translation of several proinflammatory cytokines, such as type 1 interferons, TNF-α, and other cytokines [49]. This can enhance the non-specific killing of tumor cells by the innate immune system, enhance the presentation of tumor antigens, recruit cells of the adaptive immune system, and generate long-term memory against recurring tumor cells [50][51][52][53][54].…”

Section: Discussionmentioning

confidence: 70%

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Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response

Kranjc

Mrak²,

Bošnjak

et al. 2020

Vaccines

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In this study, radiotherapy was combined with the gene electrotransfer (GET) of plasmid encoding shRNA against melanoma cell adhesion molecule (pMCAM) with dual action, which was a vascular-targeted effect mediated by the silencing of MCAM and an immunological effect mediated by the presence of plasmid DNA in the cytosol-activating DNA sensors. The effects and underlying mechanisms of therapy were evaluated in more immunogenic B16F10 melanoma and less immunogenic TS/A carcinoma. The silencing of MCAM potentiated the effect of irradiation (IR) in both tumor models. Combined therapy resulted in 81% complete responses (CR) in melanoma and 27% CR in carcinoma. Moreover, after the secondary challenge of cured mice, 59% of mice were resistant to challenge with melanoma cells, and none were resistant to carcinoma. Combined therapy reduced the number of blood vessels; induced hypoxia, apoptosis, and necrosis; and reduced cell proliferation in both tumor models. In addition, the significant increase of infiltrating immune cells was observed in both tumor models but more so in melanoma, where the expression of IL-12 and TNF-α was determined as well. Our results indicate that the combined therapy exerts both antiangiogenic and immune responses that contribute to the antitumor effect. However, tumor immunological status is crucial for a sufficient immune system contribution to the overall antitumor effect. and functionally different from that expressed in normal cells. Therefore, it would be reasonable to specifically target the MCAM expressed on tumor cells, which has already been performed by the development of antibodies recognizing only MCAM expressed in tumor cells [3,7]. Furthermore, the in vitro targeting MCAM using antibodies altered the biological properties of endothelial, melanoma, breast, ovarian, adenoid cystic carcinoma, and osteosarcoma cells, such as the proliferation or survival, migration, and invasion [3,[15][16][17][18][19][20][21][22][23]. In particular, treating cells with antibodies against MCAM reduced proliferation for approximately 60%, migration for 75%, and tube formation in human umbilical vein endothelial cells (HUVEC), and invasion in melanoma and osteosarcoma cells, while the proliferation of melanoma, hepatocarcinoma, osteosarcoma, ovary, and cervix tumor cells was not affected [21][22][23][24]. In vivo, intratumoral treatment with antibodies against MCAM in melanoma, hepatocarcinoma, osteosarcoma, leiomyosarcoma, and pancreatic tumors reduced tumor growth and the formation of metastases in melanoma and osteosarcoma [21,23]. Specifically, peritumoral treatment of C81-61 melanoma xenograft for 46 days with a monoclonal antibody specific for tumor MCAM (TsCD146 mAb) significantly reduced tumor growth [3].Another possibility is the direct local tumor targeting, either using siRNA molecules against MCAM or plasmid DNA encoding shRNA against MCAM [15][16][17][18]23,25]. These therapeutic approaches, utilizing siRNA or plasmid DNA encoding shRNA against MCAM delivered by electroporation (gene elect...

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supporting

confidence: 58%

Section: Discussionmentioning

confidence: 70%

Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response

Kranjc

Mrak²,

Bošnjak

et al. 2020

Vaccines

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“…The expression of murine ErbB2 in TS/A cells was exploited to provide experimental evidence of the oncosuppressor role of FoxP3 in mammary cancers, that downmodulated the expression of the ErbB2 oncogene [44]. TS/A cells was also used as a model to study optimization of parameters of gene electrotransfer [50].…”

Section: Gene Therapy Studiesmentioning

confidence: 99%

Bioprofiling TS/A Murine Mammary Cancer for a Functional Precision Experimental Model

Giovanni

Nicoletti

Landuzzi

et al. 2019

Cancers

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The TS/A cell line was established in 1983 from a spontaneous mammary tumor arisen in an inbred BALB/c female mouse. Its features (heterogeneity, low immunogenicity and metastatic ability) rendered the TS/A cell line suitable as a preclinical model for studies on tumor–host interactions and for gene therapy approaches. The integrated biological profile of TS/A resulting from the review of the literature could be a path towards the description of a precision experimental model of mammary cancer.

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“…Another application of electroporation is the clinical trials that have been achieved, where electroporation is used for transfection of cells within tissues with plasmid DNA, for the purpose of cancer therapy. (49,50,51) 3.CONCLUSIONS As a result, we discussed the effects of electricity on cell in general with new treatment methods. The effects of electricity on cells are very important for medicine .…”

Section: Gene Electrotransferencementioning

confidence: 99%

The Literature Review of Electricity Effects on Cell Physiology and Related New Electrical Treatment Modalities

Simdi¹,

Ozcan²

2019

Preprint

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This paper is a mini literature review about electromagnetic field’s effects on cells, tissues and new treatment modalities. We have reviewed a papers which have been published in high quality journals in the last 5 years as two authors. This review’s aim is to be a resource for experimental studies about electricity’s effects on cell biology and pathophysiology. As a result of this literature review, we found that especially extremely low electric frequency and intermediate frequency fields have very important pathophysiological effects. We have mentioned four important expressions on this subject; electroporation, electrofusion, electrochemotherapy, gene electrotransference. Two different new treatment approaches have been developed by use of these two important electrical waves. First is tumor treating fields and the other is pulsed electric fields. Most studies in literature have been done with extremely low frequency and pulsed electric fields. In terms of diseases, most studies are about glioblastoma multiforme and malign melanoma.Most studies in literature have been done with extremely low frequency and pulsed electric fields. In terms of diseases, most studies are about glioblastoma and melanoma.

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Tumor cell death after electrotransfer of plasmid DNA is associated with cytosolic DNA sensor upregulation

Cited by 21 publications

References 99 publications

Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response

Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response

Bioprofiling TS/A Murine Mammary Cancer for a Functional Precision Experimental Model

The Literature Review of Electricity Effects on Cell Physiology and Related New Electrical Treatment Modalities

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