Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3
Dror Alishekevitz1, Svetlana Gingis-Velitski1, Orit Kaidar-Person2
1Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 3109601 Haifa, Israel.
Abstract:
While chemotherapy strongly restricts or reverses tumor growth, the response of host tissue to therapy can counteract its anti-tumor activity by promoting tumor re-growth and/or metastases, thus limiting therapeutic efficacy. Here, we show that vascular endothelial growth factor receptor 3 (VEGFR3)-expressing macrophages infiltrating chemotherapy-treated tumors play a significant role in metastasis. They do so in part by inducing lymphangiogenesis as a result of cathepsin release, leading to VEGF-C upregulation by heparanase. We found that macrophages from chemotherapy-treated mice are sufficient to trigger lymphatic vessel activity and structure in naive tumors in a VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 axis inhibits the activity of chemotherapy-educated macrophages, leading to reduced lymphangiogenesis in treated tumors. Overall, our results suggest that disrupting the VEGF-C/VEGFR3 axis not only directly inhibits lymphangiogenesis but also blocks the pro-metastatic activity of macrophages in chemotherapy-treated mice.
Insights
Chemotherapy can promote tumor spread. Macrophages in treated tumors drive metastasis by increasing lymphatic vessels. Blocking the VEGF-C/VEGFR3 pathway inhibits this pro-metastatic macrophage activity.
Area of Science:
- Oncology
- Immunology
- Cancer Metastasis
Background:
- Chemotherapy can paradoxically promote tumor regrowth and metastasis.
- Host tissue responses to therapy can limit anti-tumor efficacy.
- Macrophages infiltrating tumors play a complex role in cancer progression.
Purpose of the Study:
- To investigate the role of VEGFR3-expressing macrophages in chemotherapy-induced metastasis.
- To elucidate the mechanisms by which these macrophages promote lymphangiogenesis.
- To evaluate the therapeutic potential of targeting the VEGF-C/VEGFR3 axis.
Main Methods:
- Analysis of macrophages infiltrating chemotherapy-treated tumors.
- Assessment of lymphangiogenesis and lymphatic vessel activity.
- In vivo experiments involving blocking the VEGF-C/VEGFR3 axis.
- Investigating the role of cathepsin and heparanase in macrophage-mediated effects.
Main Results:
- VEGFR3-expressing macrophages in chemotherapy-treated tumors significantly contribute to metastasis.
- These macrophages induce lymphangiogenesis via cathepsin release and heparanase-mediated VEGF-C upregulation.
- Macrophages from treated mice can trigger lymphatic vessel activity in naive tumors in a VEGFR3-dependent manner.
- Blocking the VEGF-C/VEGFR3 axis reduced lymphangiogenesis and inhibited pro-metastatic macrophage activity.
Conclusions:
- Disrupting the VEGF-C/VEGFR3 axis is a promising strategy to inhibit chemotherapy-induced lymphangiogenesis.
- Targeting this axis can block the pro-metastatic activity of macrophages in treated tumors.
- This approach offers a potential method to improve therapeutic efficacy by preventing metastasis.
