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In Vivo Model for Testing Effect of Hypoxia on Tumor Metastasis
Published on: December 9, 2016
Systemic hypoxia suppresses solid tumor growth
Abstract:
Local hypoxia is a hallmark of solid tumors and a negative prognostic factor in the progression and treatment of cancer. Here, we showed that systemic hypoxia, in contrast to localized tumor hypoxia, decreases tumor growth in vivo across multiple cancer types and preclinical models. The reduced tumor growth in systemic hypoxia was not explained by hypoglycemia, hypoinsulinemia, or HIF activation. Instead, metabolite profiling in tumors and tumor interstitial fluid revealed extensive perturbations in purine-related metabolites. Stable isotope tracing demonstrated that systemic hypoxia caused tumors to suppress de novo purine synthesis. Furthermore, tumors did not develop resistance to systemic hypoxia therapy, and when used in combination with chemotherapy or immunotherapy, systemic hypoxia dramatically suppressed tumor growth. Finally, we showed that systemic hypoxia can be achieved pharmacologically with the small molecule HypoxyStat. These findings challenge the long-held paradigm of hypoxia as a negative prognostic factor in cancer progression, and they suggest a potential therapeutic role for systemic hypoxia in suppressing solid tumor growth.
Insights
Systemic hypoxia, unlike localized tumor hypoxia, inhibits cancer growth by suppressing purine synthesis. This novel approach, achievable with HypoxyStat, offers a potential therapeutic strategy against solid tumors.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer biology
Background:
- Local hypoxia is a known negative prognostic factor in cancer.
- The role of systemic hypoxia in tumor progression has been less understood.
Purpose of the Study:
- To investigate the effect of systemic hypoxia on tumor growth.
- To elucidate the underlying mechanisms of systemic hypoxia's impact on cancer.
- To explore the therapeutic potential of systemic hypoxia.
Main Methods:
- In vivo studies across multiple cancer types and preclinical models.
- Metabolite profiling of tumors and interstitial fluid.
- Stable isotope tracing to track metabolic pathways.
- Pharmacological induction of systemic hypoxia using HypoxyStat.
Main Results:
- Systemic hypoxia significantly decreased tumor growth across various cancer types.
- Reduced tumor growth was linked to suppressed de novo purine synthesis, not hypoglycemia or HIF activation.
- Tumors did not develop resistance to systemic hypoxia.
- Combination therapy with chemotherapy or immunotherapy enhanced tumor suppression.
Conclusions:
- Systemic hypoxia represents a novel therapeutic strategy for solid tumors, challenging the traditional view of hypoxia.
- Suppression of purine synthesis is a key mechanism by which systemic hypoxia inhibits cancer growth.
- Pharmacological induction of systemic hypoxia offers a promising avenue for cancer treatment.
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