Exploiting the tumor microenvironment in the development of targeted cancer gene therapy

Dougherty, Graeme J.; Dougherty, Shona T.

doi:10.1038/cgt.2008.72

Cited by 11 publications

(12 citation statements)

References 71 publications

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“…Hypoxia is a major characteristic of solid tumors and a condition that affects genome-wide changes in gene expression, which greatly impacts cellular and tumor tissue physiology particularly respiration and metabolism [23]–[29]. Expression of hypoxia-responsive genes is predominately regulated by hypoxia inducible factors (HIFs) [23], [25]–[34].…”

Section: Introductionmentioning

confidence: 99%

Expression of DDX3 Is Directly Modulated by Hypoxia Inducible Factor-1 Alpha in Breast Epithelial Cells

et al. 2011

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DEAD box protein, DDX3, is aberrantly expressed in breast cancer cells ranging from weakly invasive to aggressive phenotypes and functions as an important regulator of cancer cell growth and survival. Here, we demonstrate that hypoxia inducible factor-1α is a transcriptional activator of DDX3 in breast cancer cells. Within the promoter region of the human DDX3 gene, we identified three putative hypoxia inducible factor-1 responsive elements. By luciferase reporter assays in combination with mutated hypoxia inducible factor-1 responsive elements, we determined that the hypoxia inducible factor-1 responsive element at position -153 relative to the translation start site is essential for transcriptional activation of DDX3 under hypoxic conditions. We also demonstrated that hypoxia inducible factor-1 binds to the DDX3 promoter and that the binding is specific, as revealed by siRNA against hypoxia inducible factor-1 and chromatin immunoprecipitation assays. Thus, the activation of DDX3 expression during hypoxia is due to the direct binding of hypoxia inducible factor-1 to hypoxia responsive elements in the DDX3 promoter. In addition, we observed a significant overlap in the protein expression pattern of hypoxia inducible factor-1α and DDX3 in MDA-MB-231 xenograft tumors. Taken together, our results demonstrate, for the first time, the role of DDX3 as a hypoxia-inducible gene that exhibits enhanced expression through the interaction of hypoxia inducible factor-1 with hypoxia inducible factor-1 responsive elements in its promoter region.

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Section: Introductionmentioning

confidence: 99%

Expression of DDX3 Is Directly Modulated by Hypoxia Inducible Factor-1 Alpha in Breast Epithelial Cells

et al. 2011

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“…It is currently the fastest growing sector for target validation and therapeutic [14]. Further, considering cancer cells scape from immune system within the tumor microenvironment, immune targeted gene therapy appears to provide an effective tactic for activation of the immune systems in such intricate microenvironment, whereby targeted gene therapy of angiogenesis and lymphangiogenesis bestow robust treatment possibilities [15].…”

Section: Trajectory Of Gene Therapymentioning

confidence: 99%

Cancer Gene Therapy: Targeted Genomedicines

Omidi¹,

Barar²,

Coukos³

2013

Novel Gene Therapy Approaches

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“…Effective delivery of genes in vivo is a major obstacle to gene therapy. Nonspecific distribution, rapid clearance, and low transfection efficiency limit the clinical application of gene therapy 24 , 25 . Recently, nano-formulations such as micelles, liposomes, hybrid nanoparticles (NP), and exosomes have attracted increasing attention due to their biocompatibility, tumor specificity, and high transfection efficiency 26 , 27 , 28 .…”

Section: Introductionmentioning

confidence: 99%

A combination of LightOn gene expression system and tumor microenvironment-responsive nanoparticle delivery system for targeted breast cancer therapy

Hou

Shou

et al. 2020

Acta Pharmaceutica Sinica B

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A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light, and have great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system (NDDS) to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A (DTA) fragment-encoded plasmids to tumor sites. The expression of DTA was induced by exposure to blue light. Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond, and PEGylated hyaluronic acid modified with RGD peptide, accumulated in tumor tissues and were actively internalized into 4T1 cells via dual targeting to CD44 and α v β 3 receptors. The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure. In vitro studies showed that light-induced DTA expression reduced 4T1 cell viability and induced apoptosis. Furthermore, the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4T1 tumor xenograft model, which resulted in excellent antitumor effects, reduced tumor angiogenesis, and no systemic toxicity. The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.

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Exploiting the tumor microenvironment in the development of targeted cancer gene therapy

Cited by 11 publications

References 71 publications

Expression of DDX3 Is Directly Modulated by Hypoxia Inducible Factor-1 Alpha in Breast Epithelial Cells

Expression of DDX3 Is Directly Modulated by Hypoxia Inducible Factor-1 Alpha in Breast Epithelial Cells

Cancer Gene Therapy: Targeted Genomedicines

A combination of LightOn gene expression system and tumor microenvironment-responsive nanoparticle delivery system for targeted breast cancer therapy

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