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Vascular normalization by loss of Siah2 results in increased chemotherapeutic efficacy
Christina S F Wong1, Jaclyn Sceneay, Colin M House
1Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria, Australia.
Abstract:
Tumor hypoxia is associated with resistance to antiangiogenic therapy and poor prognosis. The Siah E3 ubiquitin ligases regulate the hypoxic response pathway by modulating the turnover of the master proangiogenic transcription factor hypoxia-inducible factor-1α (Hif-1α). In this study, we show that genetic deficiency in the Siah family member Siah2 results in vascular normalization and delayed tumor growth in an established transgenic model of aggressive breast cancer. Tumors arising in a Siah2(-/-) genetic background showed increased perfusion and pericyte-associated vasculature, similar to that occurring with antiangiogenic therapy. In support of the role of Siah2 in regulating levels of Hif-1α, expression of angiogenic factors was decreased in Siah2(-/-) tumors. Blood vessel normalization in Siah2(-/-) tumors resulted in an increased response to chemotherapy and prolonged survival. Together, our findings offer a preclinical proof of concept that targeting Siah2 is sufficient to attenuate Hif-1α-mediated angiogenesis and hypoxia signaling, thereby improving responses to chemotherapy.
Insights
Targeting Siah2 in breast cancer models normalized tumor blood vessels and delayed growth. This vascular normalization improved chemotherapy response and survival by reducing hypoxia-driven angiogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor hypoxia correlates with resistance to antiangiogenic therapy and poor prognosis.
- Siah E3 ubiquitin ligases control the hypoxic response pathway by regulating hypoxia-inducible factor-1α (Hif-1α) turnover.
- Hif-1α is a master transcription factor for proangiogenic factors.
Purpose of the Study:
- To investigate the role of Siah2 in regulating tumor hypoxia and angiogenesis.
- To determine if genetic deficiency in Siah2 impacts aggressive breast cancer progression.
- To evaluate the therapeutic potential of targeting Siah2 in preclinical models.
Main Methods:
- Utilized a transgenic aggressive breast cancer model with a Siah2(-/-) genetic background.
- Assessed tumor vascularization, perfusion, and expression of angiogenic factors.
- Evaluated tumor growth, response to chemotherapy, and overall survival.
Main Results:
- Siah2 deficiency led to vascular normalization and delayed tumor growth.
- Tumors in Siah2(-/-) mice exhibited increased perfusion and pericyte-associated vasculature.
- Reduced expression of angiogenic factors was observed in Siah2(-/-) tumors.
- Vascular normalization in Siah2(-/-) tumors enhanced chemotherapy response and prolonged survival.
Conclusions:
- Genetic deficiency of Siah2 attenuates Hif-1α-mediated angiogenesis and hypoxia signaling.
- Targeting Siah2 offers a preclinical strategy to improve chemotherapy efficacy in aggressive breast cancer.
- Siah2 plays a critical role in regulating tumor hypoxia and response to therapy.
