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Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts-Limitations and Opportunities.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Mar 24; Vol. 22 (7). Date of Electronic Publication: 2021 Mar 24. - Publication Year :
- 2021
-
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.
- Subjects :
- Animals
Cell Line, Tumor
Chemokine CXCL12 genetics
Connective Tissue Growth Factor genetics
Endopeptidases
Gelatinases genetics
Human Umbilical Vein Endothelial Cells metabolism
Humans
Insulin-Like Growth Factor Binding Protein 2 genetics
Jagged-1 Protein genetics
Membrane Proteins genetics
Mice
Mice, Inbred C57BL
NIH 3T3 Cells
Osteonectin genetics
Serine Endopeptidases genetics
Snail Family Transcription Factors genetics
Transcriptional Activation
Cancer-Associated Fibroblasts metabolism
Promoter Regions, Genetic
Transgenes
Tumor Microenvironment genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33804861
- Full Text :
- https://doi.org/10.3390/ijms22073298