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STAT3 oligonucleotide inhibits tumor angiogenesis in preclinical models of squamous cell carcinoma
Jonah D Klein1, Daisuke Sano2, Malabika Sen1
1Department of Otolaryngology, School of Medicine, University of Pittsburgh, Pennsylvania, United States of America.
Purpose:
Signal transducer and activator of transcription 3 (STAT3) has shown to play a critical role in head and neck squamous cell carcinoma (HNSCC) and we have recently completed clinical trials of STAT3 decoy oligonucleotide in patients with recurrent or metastatic HNSCC. However, there is limited understanding of the role of STAT3 in modulating other aspects of tumorigenesis such as angiogenesis. In this study, we aimed to examine the effects of STAT3 decoy oligonucleotide on tumor angiogenesis.
Experimental Design:
A STAT3 decoy oligonucleotide and small interfering RNA (siRNA) were used to inhibit STAT3 in endothelial cells in vitro and in vivo. The biochemical effects of STAT3 inhibition were examined in conjunction with the consequences on proliferation, migration, apoptotic staining, and tubule formation. Additionally, we assessed the effects of STAT3 inhibition on tumor angiogenesis using murine xenograft models.
Results:
STAT3 decoy oligonucleotide decreased proliferation, induces apoptosis, decreased migration, and decreased tubule formation of endothelial cells in vitro. The STAT3 decoy oligonucleotide also inhibited tumor angiogenesis in murine tumor xenografts. Lastly, our data suggest that the antiangiogenic effects of STAT3 decoy oligonucleotide were mediatedthrough the inhibition of both STAT3 and STAT1.
Conclusions:
The STAT3 decoy oligonucleotidewas found to be an effective antiangiogenic agent, which is likely to contribute to the overall antitumor effects of this agent in solid tumors.Taken together with the previously demonstrated antitumor activity of this agent, STAT3 decoy oligonucleotide represents a promising single agent approach to targeting both the tumor and vascular compartments in various malignancies.
Insights
STAT3 decoy oligonucleotide effectively inhibits tumor angiogenesis by targeting endothelial cell proliferation and migration. This agent shows promise as a single therapy for solid tumors, impacting both tumor and vascular components.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Signal transducer and activator of transcription 3 (STAT3) is crucial in head and neck squamous cell carcinoma (HNSCC).
- The role of STAT3 in tumorigenesis, particularly angiogenesis, requires further investigation.
- Clinical trials of STAT3 decoy oligonucleotide in HNSCC have been completed.
Purpose of the Study:
- To investigate the antiangiogenic effects of STAT3 decoy oligonucleotide.
- To determine the impact of STAT3 inhibition on endothelial cell functions.
- To assess the efficacy of STAT3 decoy oligonucleotide in preclinical tumor models.
Main Methods:
- Inhibition of STAT3 using decoy oligonucleotide and siRNA in endothelial cells (in vitro and in vivo).
- Assessment of endothelial cell proliferation, migration, apoptosis, and tubule formation.
- Evaluation of tumor angiogenesis in murine xenograft models.
Main Results:
- STAT3 decoy oligonucleotide reduced endothelial cell proliferation, migration, and tubule formation while inducing apoptosis.
- The agent demonstrated significant inhibition of tumor angiogenesis in vivo.
- Antiangiogenic effects were mediated by the inhibition of both STAT3 and STAT1 signaling pathways.
Conclusions:
- STAT3 decoy oligonucleotide is an effective antiangiogenic agent.
- This agent contributes to the overall antitumor effects in solid tumors.
- STAT3 decoy oligonucleotide presents a promising therapeutic strategy targeting both tumor and vascular compartments.
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