Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo
Dana M Brantley1, Nikki Cheng, Erin J Thompson
1Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, TN 37232, USA.
Abstract:
The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression.
Insights
Blocking Eph A class receptors inhibits tumor angiogenesis and growth. This study demonstrates their role in regulating blood vessel recruitment by tumors, impacting tumor progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Developmental Biology
Background:
- Eph receptor tyrosine kinases and ephrin ligands are vital for embryonic vascular development.
- Their role in adult angiogenesis, particularly in cancer, remains largely uncharacterized.
Purpose of the Study:
- To investigate the role of Eph A class receptors in tumor angiogenesis and progression.
- To determine if blocking Eph A class receptor activation can inhibit tumor growth.
Main Methods:
- Utilized RIP-Tag and 4T1 tumor models in mice.
- Administered soluble EphA2-Fc or EphA3-Fc receptors to block Eph A class receptor activity.
- Assessed tumor angiogenesis, vascular density, tumor volume, cell proliferation, and apoptosis.
- Evaluated endothelial cell migration in response to tumor cells in vitro.
Main Results:
- Blocking Eph A class receptor activation significantly inhibited angiogenesis in both tumor models.
- Treatment with EphA2-Fc or EphA3-Fc reduced tumor vascular density, volume, proliferation, and increased apoptosis.
- Soluble EphA2-Fc inhibited endothelial cell migration towards tumor cells, suggesting impaired blood vessel recruitment.
Conclusions:
- Eph A class receptors critically regulate pathogenic angiogenesis induced by tumors.
- Targeting Eph A class receptors offers a potential strategy to inhibit tumor progression by disrupting tumor vascularization.
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