Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities

Antonova, Dina V.; Zinovyeva, Marina V.; Kondratyeva, Liya G.; Sass, Alexander V.; Alekseenko, Irina V.; Pleshkan, Victor V.

doi:10.3390/ijms22073298

Open AccessArticle

Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities

by

Dina V. Antonova

¹,

Marina V. Zinovyeva

¹,

Liya G. Kondratyeva

¹

,

Alexander V. Sass

¹,

Irina V. Alekseenko

^1,2,3 and

Victor V. Pleshkan

^1,2,*

¹

Department of Genomics and Postgenomic Technologies, Gene Immunooncotherapy Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia

²

Gene Oncotherapy Sector, Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia

³

Institute of Oncogynecology and Mammology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2021, 22(7), 3298; https://doi.org/10.3390/ijms22073298

Submission received: 28 February 2021 / Revised: 19 March 2021 / Accepted: 21 March 2021 / Published: 24 March 2021

(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)

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Abstract

Cancer-associated fibroblasts (CAF) are attractive therapeutic targets in the tumor microenvironment. The possibility of using CAFs as a source of therapeutic molecules is a challenging approach in gene therapy. This requires transcriptional targeting of transgene expression by cis-regulatory elements (CRE). Little is known about which CREs can provide selective transgene expression in CAFs. We hypothesized that the promoters of FAP, CXCL12, IGFBP2, CTGF, JAG1, SNAI1, and SPARC genes, the expression of whose is increased in CAFs, could be used for transcriptional targeting. Analysis of the transcription of the corresponding genes revealed that unique transcription in model CAFs was characteristic for the CXCL12 and FAP genes. However, none of the promoters in luciferase reporter constructs show selective activity in these fibroblasts. The CTGF, IGFBP2, JAG1, and SPARC promoters can provide higher transgene expression in fibroblasts than in cancer cells, but the nonspecific viral promoters CMV, SV40, and the recently studied universal PCNA promoter have the same features. The patterns of changes in activity of various promoters relative to each other observed for human cell lines were similar to the patterns of activity for the same promoters both in vivo and in vitro in mouse models. Our results reveal restrictions and features for CAF transcriptional targeting.

Keywords: transcriptional targeting; promoter; tumor microenvironment; fibroblasts; gene therapy

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MDPI and ACS Style

Antonova, D.V.; Zinovyeva, M.V.; Kondratyeva, L.G.; Sass, A.V.; Alekseenko, I.V.; Pleshkan, V.V. Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities. Int. J. Mol. Sci. 2021, 22, 3298. https://doi.org/10.3390/ijms22073298

AMA Style

Antonova DV, Zinovyeva MV, Kondratyeva LG, Sass AV, Alekseenko IV, Pleshkan VV. Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities. International Journal of Molecular Sciences. 2021; 22(7):3298. https://doi.org/10.3390/ijms22073298

Chicago/Turabian Style

Antonova, Dina V., Marina V. Zinovyeva, Liya G. Kondratyeva, Alexander V. Sass, Irina V. Alekseenko, and Victor V. Pleshkan. 2021. "Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities" International Journal of Molecular Sciences 22, no. 7: 3298. https://doi.org/10.3390/ijms22073298

APA Style

Antonova, D. V., Zinovyeva, M. V., Kondratyeva, L. G., Sass, A. V., Alekseenko, I. V., & Pleshkan, V. V. (2021). Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities. International Journal of Molecular Sciences, 22(7), 3298. https://doi.org/10.3390/ijms22073298

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Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities

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