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.
Highlights
Tumors represent the assembly of cancer and tumor microenvironment cells (TME).Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment and are critically involved in cancer progression
The human pancreatic cancer cell lines PANC-1 and MIA PaCa-2 were selected, which are characterized by high expression of mesenchymal markers and which are characterized as highly differentiated cancer cells [15], and AsPC-1 cell line representing low differentiated adenocarcinoma [16]
A primary cell culture obtained from the stroma of a patient with pancreatic cancer, IVP-9TS, was used as a model of cancer-associated fibroblasts [17]
Summary
Tumors represent the assembly of cancer and tumor microenvironment cells (TME).Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment and are critically involved in cancer progression. Great interest in the development of antitumor gene therapy is, where possible, the use of local (intratumoral) drug administration, which reduces the systemic toxicity of drugs [4,5]. By their nature, non-viral vectors are well suited for local administration [6,7]. Non-viral vectors are well suited for local administration [6,7] The production of such drugs in general is cheaper and easier than the production of viral vectors. Such vectors may be safer, they are inferior in transfection efficiency to viral vectors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
