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Updated: Mar 1, 2026
Blocking Lymph Flow by Suturing Afferent Lymphatic Vessels in Mice
Published on: May 14, 2020
A heparin conjugate, LHbisD4, inhibits lymphangiogenesis and attenuates lymph node metastasis by blocking VEGF-C
Jeong Uk Choi1, Seung Woo Chung1, Taslim A Al-Hilal2
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
Abstract:
Clinical studies have found that the incidence of cancer metastasis through the lymphatic vessels are 3-5 times higher than that through the blood vessels. These findings suggest the potency of anti-lymphangiogenic therapy in reducing the incidence of cancer metastasis. Previously, we reported LHbisD4, which is the conjugate of low molecular weight heparin (LMWH) and four bis-deoxycholates as a potent anti-angiogenic drug with less toxicity and orally active property. Here, we show that LHbisD4 could also suppress the formation of new lymphatic vessels and attenuate the incidence of metastasis by blocking VEGF-C signaling pathway. LHbisD4 significantly enhanced binding affinity with VEGF-C when compared with LMWH, which enables LHbisD4 to suppress the proliferation, migration and formation of tubular structures of human dermal lymphatic endothelial cells(HDLECs) in in vitro condition even in the presence of excessive amounts of VEGF-C. Similarly, we found that the density of lymphatic vessels in the primary tumor tissue in breast cancer bearing mice was significantly diminished when LHbisD4 was administered compared with the control group. Also, the incidence of axillary lymph nodes and distant organ metastasis was significantly reduced in the LHbisD4 administered group, which demonstrates that LHbisD4 could successfully lower the incidence of metastasis through blocking VEGF-C induced lymphangiogenesis. Based on these results, we propose LHbisD4 as a potent anti-cancer drug that can reduce the incidence of metastasis by suppressing lymphangiogenesis through blocking VEGF-C signaling pathway.
Insights
LHbisD4, a novel drug, effectively inhibits cancer metastasis by blocking the VEGF-C pathway, reducing new lymphatic vessel formation and spread to lymph nodes and distant organs.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Cancer metastasis via lymphatic vessels is 3-5 times more common than via blood vessels.
- Anti-lymphangiogenic therapy offers a promising strategy to reduce cancer spread.
- LHbisD4, a low molecular weight heparin (LMWH) conjugate, demonstrated prior anti-angiogenic and low-toxicity properties.
Purpose of the Study:
- To investigate the anti-lymphangiogenic and anti-metastatic potential of LHbisD4.
- To determine if LHbisD4 inhibits cancer metastasis by blocking the VEGF-C signaling pathway.
- To evaluate LHbisD4's efficacy in preclinical models of breast cancer metastasis.
Main Methods:
- In vitro studies using human dermal lymphatic endothelial cells (HDLECs) to assess proliferation, migration, and tube formation.
- In vivo studies in breast cancer-bearing mice to evaluate lymphatic vessel density and metastasis incidence.
- Assessment of LHbisD4's binding affinity to VEGF-C compared to LMWH.
Main Results:
- LHbisD4 exhibited enhanced binding affinity to VEGF-C compared to LMWH.
- LHbisD4 significantly suppressed HDLEC proliferation, migration, and tube formation in vitro, even with excess VEGF-C.
- Administration of LHbisD4 markedly reduced lymphatic vessel density in primary tumors and decreased lymph node and distant organ metastasis in mice.
Conclusions:
- LHbisD4 is a potent inhibitor of lymphangiogenesis by blocking VEGF-C signaling.
- LHbisD4 effectively reduces cancer metastasis incidence in preclinical models.
- LHbisD4 represents a promising therapeutic agent for reducing cancer metastasis through anti-lymphangiogenic action.
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