BMP9 signaling promotes the normalization of tumor blood vessels
Claire Viallard1,2, Cindy Audiger1,3, Natalija Popovic1,2
1Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.
Abstract:
The presence of an immature tumor vascular network contributes to cancer dissemination and the development of resistance to therapies. Strategies to normalize the tumor vasculature are therefore of significant therapeutic interest for cancer treatments. VEGF inhibitors are used clinically to normalize tumor blood vessels. However, the time frame and dosage of these inhibitors required to achieve normalization is rather narrow, and there is a need to identify additional signaling targets to attain vascular normalization. In addition to VEGF, the endothelial-specific receptor Alk1 plays a critical role in vascular development and promotes vascular remodeling and maturation. Therefore, we sought to evaluate the effects of the Alk1 ligand BMP9 on tumor vascular formation. BMP9 overexpression in Lewis Lung Carcinoma (LLC) tumors significantly delayed tumor growth. Blood vessels in BMP9-overexpressing LLC tumors displayed markers of vascular maturation and were characterized by increased perivascular cell coverage. Tumor vasculature normalization was associated with decreased permeability and increased perfusion. These changes in vascular function in BMP9-overexpressing LLC tumors resulted in significant alterations of the tumor microenvironment, characterized by a decrease in hypoxia and an increase in immune infiltration. In conclusion, we show that BMP9 promotes vascular normalization in LLC tumors that leads to changes in the microenvironment.
Insights
Bone morphogenetic protein 9 (BMP9) promotes tumor vascular normalization in Lewis Lung Carcinoma (LLC) models. This vascular normalization enhances anti-cancer effects by reducing hypoxia and increasing immune cell infiltration.
Area of Science:
- Oncology
- Vascular Biology
- Cancer Therapeutics
Background:
- Immature tumor vasculature promotes cancer spread and treatment resistance.
- Current vascular normalization strategies using VEGF inhibitors have limitations in timing and dosage.
- Identifying novel targets for vascular normalization is crucial for effective cancer therapy.
Purpose of the Study:
- To investigate the effects of the endothelial receptor Alk1 ligand, bone morphogenetic protein 9 (BMP9), on tumor vascular formation.
- To evaluate BMP9 as a potential therapeutic agent for normalizing tumor vasculature.
Main Methods:
- Overexpression of BMP9 in Lewis Lung Carcinoma (LLC) cells.
- Analysis of tumor growth, vascular maturation markers, and perivascular cell coverage.
- Assessment of tumor vascular permeability, perfusion, hypoxia, and immune cell infiltration.
Main Results:
- BMP9 overexpression significantly delayed LLC tumor growth.
- Tumor vessels exhibited enhanced maturation, increased perivascular cell coverage, reduced permeability, and improved perfusion.
- BMP9-induced vascular normalization led to decreased tumor hypoxia and increased immune cell infiltration.
Conclusions:
- BMP9 promotes vascular normalization in LLC tumors.
- BMP9-mediated vascular normalization alters the tumor microenvironment, reducing hypoxia and enhancing immune infiltration.
- BMP9 represents a promising target for improving cancer therapy through vascular normalization.
Related Concept Videos
Regulation of Angiogenesis and Blood Supply
The Tumor Microenvironment
Mechanism of Angiogenesis
Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
Abnormal Proliferation


