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Trimming the Vascular Tree in Tumors: Metabolic and Immune Adaptations
Elizabeth Allen1, Rindert Missiaen1, Gabriele Bergers1
1KU-Leuven and VIB-Center for Cancer Biology, 3000 Leuven, Belgium.
Abstract:
Angiogenesis, the formation of new blood vessels, has become a well-established hallmark of cancer. Its functional importance for the manifestation and progression of tumors has been further validated by the beneficial therapeutic effects of angiogenesis inhibitors, most notably ones targeting the vascular endothelial growth factor (VEGF) signaling pathways. However, with the transient and short-lived nature of the patient response, it has become evident that tumors have the ability to adapt to the pressures of vascular growth restriction. Several escape mechanisms have been described that adapt tumors to therapy-induced low-oxygen tension by either reinstating tumor growth by vascular rebound or by altering tumor behavior without the necessity to reinitiate revascularization. We review here two bypass mechanisms that either instigate angiogenic and immune-suppressive polarization of intratumoral innate immune cells to facilitate VEGF-independent angiogenesis or enable metabolic adaptation and reprogramming of endothelial cells and tumor cells to adapt to low-oxygen tension.
Insights
Tumors adapt to anti-angiogenesis therapy by developing new blood vessels independently of VEGF or by altering cell metabolism to survive low oxygen. These mechanisms limit treatment effectiveness.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment
Background:
- Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and progression.
- Anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) show initial efficacy but often lead to transient responses.
- Tumors develop resistance through adaptive mechanisms to overcome therapy-induced low-oxygen conditions.
Purpose of the Study:
- To review tumor escape mechanisms from anti-angiogenesis therapy.
- To elucidate two key bypass pathways enabling tumor adaptation to vascular growth restriction.
- To highlight VEGF-independent angiogenesis and metabolic reprogramming as resistance strategies.
Main Methods:
- Literature review of established and emerging tumor adaptation mechanisms.
- Analysis of studies investigating immune cell polarization in the tumor microenvironment.
- Examination of research on endothelial and tumor cell metabolic reprogramming under hypoxia.
Main Results:
- Tumors employ immune-suppressive cell polarization to promote VEGF-independent angiogenesis.
- Tumor and endothelial cells undergo metabolic adaptation to survive and proliferate in low-oxygen environments.
- These bypass mechanisms allow tumors to circumvent anti-angiogenic therapies.
Conclusions:
- Tumor adaptation to anti-angiogenesis therapy involves both immune-mediated and metabolic reprogramming strategies.
- Understanding these VEGF-independent escape routes is critical for developing more effective cancer treatments.
- Targeting these adaptive mechanisms may overcome therapeutic resistance and improve patient outcomes.