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Updated: Jul 4, 2026
Bioluminescent Orthotopic Model of Pancreatic Cancer Progression
Published on: June 28, 2013
Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in
Sean P Dineen1, Kristi D Lynn, Shane E Holloway
1Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
Abstract:
Macrophages are an abundant inflammatory cell type in the tumor microenvironment that can contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor (VEGF), which is thought to function primarily through VEGF receptor (VEGFR) 1 expressed on macrophages. Macrophage infiltration is affected by VEGF inhibition. We show that selective inhibition of VEGFR2 reduced macrophage infiltration into orthotopic pancreatic tumors. Our studies show that tumor-associated macrophages express VEGFR2. Furthermore, peritoneal macrophages from tumor-bearing animals express VEGFR2, whereas peritoneal macrophages from non-tumor-bearing animals do not. To our knowledge, this is the first time that tumor-associated macrophages have been shown to express VEGFR2. Additionally, we found that the cytokine pleiotrophin is sufficient to induce VEGFR2 expression on macrophages. Pleiotrophin has previously been shown to induce expression of endothelial cell markers on macrophages and was present in the microenvironment of orthotopic pancreatic tumors. Finally, we show that VEGFR2, when expressed by macrophages, is essential for VEGF-stimulated migration of tumor-associated macrophages. In summary, tumor-associated macrophages express VEGFR2, and selective inhibition of VEGFR2 reduces recruitment of macrophages into orthotopic pancreatic tumors. Our results show an underappreciated mechanism of action that may directly contribute to the antitumor activity of angiogenesis inhibitors that block the VEGFR2 pathway.
Insights
Tumor-associated macrophages express vascular endothelial growth factor receptor 2 (VEGFR2). Inhibiting VEGFR2 reduces macrophage infiltration into pancreatic tumors, suggesting a new target for cancer therapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Macrophages are key inflammatory cells in the tumor microenvironment, influencing tumor growth and metastasis.
- Vascular Endothelial Growth Factor (VEGF) signaling, primarily via VEGF Receptor 1 (VEGFR1), is implicated in macrophage recruitment.
- The role of other VEGF receptors, like VEGFR2, on tumor-associated macrophages (TAMs) is not well understood.
Purpose of the Study:
- To investigate the expression and function of VEGFR2 on TAMs.
- To determine if VEGFR2 inhibition affects macrophage infiltration into tumors.
- To explore the role of pleiotrophin in regulating VEGFR2 expression on macrophages.
Main Methods:
- Selective inhibition of VEGFR2 in orthotopic pancreatic tumor models.
- Analysis of VEGFR2 expression on TAMs and peritoneal macrophages from tumor-bearing and non-tumor-bearing animals.
- Assessment of pleiotrophin's effect on VEGFR2 expression in macrophages.
- Evaluation of VEGF-stimulated macrophage migration in the presence of VEGFR2 inhibition.
Main Results:
- Selective VEGFR2 inhibition reduced macrophage infiltration into orthotopic pancreatic tumors.
- Tumor-associated macrophages (TAMs) were found to express VEGFR2, a novel finding.
- Peritoneal macrophages from tumor-bearing animals expressed VEGFR2, unlike those from non-tumor-bearing animals.
- Pleiotrophin induced VEGFR2 expression on macrophages.
- VEGFR2 on macrophages was essential for VEGF-driven TAM migration.
Conclusions:
- TAMs express functional VEGFR2, which is crucial for their migration.
- Selective inhibition of VEGFR2 effectively reduces TAM infiltration into pancreatic tumors.
- Targeting VEGFR2 on TAMs represents a potential therapeutic strategy for enhancing the efficacy of anti-angiogenic therapies.
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