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Published on: April 13, 2015
Inhibition of melanoma angiogenesis by telomere homolog oligonucleotides
Christina Coleman1, Danielle Levine, Raj Kishore
1Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA.
Abstract:
Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1alpha. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P < .004) total tumor microvascular density and the functional vessels density by 80% (P < .002). These findings suggest that restriction of tumor angiogenesis is among the host's innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment.
Insights
Telomere homolog oligonucleotides (T-oligos) demonstrate potent anticancer effects by inhibiting tumor angiogenesis. These T-oligos reduce key proteins involved in blood vessel formation, offering a promising new avenue for melanoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Angiogenesis Research
Background:
- Telomere homolog oligonucleotides (T-oligos) activate innate anticancer responses.
- T-oligos initiate signaling pathways involving Werner protein and ATM kinase.
- The antiangiogenic potential of T-oligos remains to be fully elucidated.
Purpose of the Study:
- To investigate the antiangiogenic effects of T-oligos in melanoma.
- To determine the molecular mechanisms underlying T-oligo-mediated antiangiogenesis.
Main Methods:
- Assessed expression of angiogenesis-related factors (VEGF, VEGFR2, angiopoietins) in T-oligo-treated melanoma cells.
- Evaluated the impact of T-oligos on transcription factors E2F1 and HIF-1alpha.
- Performed in vitro assays for endothelial cell (EC) tubulogenesis and invasion.
- Quantified tumor microvascular density in melanoma xenografts following T-oligo administration.
Main Results:
- T-oligos significantly decreased VEGF, VEGFR2, and angiopoietin expression and secretion.
- T-oligos activated E2F1 and inhibited HIF-1alpha activity.
- Inhibition of EC tubulogenesis and invasion was observed in vitro.
- Systemic T-oligo treatment reduced tumor microvascular density by 60% and functional vessels by 80% in vivo.
Conclusions:
- T-oligos exhibit significant antiangiogenic properties.
- The findings support the role of telomere-based responses in restricting tumor angiogenesis.
- T-oligos represent a potential therapeutic strategy for melanoma treatment by targeting tumor vascularization.
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