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Updated: Jun 2, 2026
A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in
Hanseul Yang1, Chan Kim, Min-Ju Kim
1National Research Laboratory of Vascular Biology and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Republic of Korea.
Background:
Most bladder cancer patients experience lymphatic metastasis in the course of disease progression, yet the relationship between lymphangiogenesis and lymphatic metastasis is not well known. The aim of this study is to elucidate underlying mechanisms of how expanded lymphatic vessels and tumor microenvironment interacts each other and to find effective therapeutic options to inhibit lymphatic metastasis.
Results:
The orthotopic urinary bladder cancer (OUBC) model was generated by intravesical injection of MBT-2 cell lines. We investigated the angiogenesis, lymphangiogenesis, and CD11b+/CD68+ tumor-associated macrophages (TAM) by using immunofluorescence staining. OUBC displayed a profound lymphangiogenesis and massive infiltration of TAM in primary tumor and lymphatic metastasis in lymph nodes. TAM flocked near lymphatic vessels and express higher levels of VEGF-C/D than CD11b- cells. Because VEGFR-3 was highly expressed in lymphatic vascular endothelial cells, TAM could assist lymphangiogenesis by paracrine manner in bladder tumor. VEGFR-3 expressing adenovirus was administered to block VEGF-C/D signaling pathway and clodronate liposome was used to deplete TAM. The blockade of VEGF-C/D with soluble VEGF receptor-3 markedly inhibited lymphangiogenesis and lymphatic metastasis in OUBC. In addition, the depletion of TAM with clodronate liposome exerted similar effects on OUBC.
Conclusion:
VEGF-C/D are the main factors of lymphangiogenesis and lymphatic metastasis in bladder cancer. Moreover, TAM plays an important role in these processes by producing VEGF-C/D. The inhibition of lymphangiogenesis could provide another therapeutic target to inhibit lymphatic metastasis and recurrence in patients with invasive bladder cancer.
Insights
Vascular Endothelial Growth Factor (VEGF)-C/D drive lymphangiogenesis and lymphatic metastasis in bladder cancer. Tumor-associated macrophages (TAM) promote these processes, offering therapeutic targets to inhibit bladder cancer spread.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Lymphatic metastasis is common in bladder cancer, but its link to lymphangiogenesis remains unclear.
- Understanding the interaction between expanded lymphatic vessels and the tumor microenvironment is crucial for developing therapies.
- This study aims to elucidate mechanisms driving bladder cancer lymphatic metastasis and identify therapeutic strategies.
Purpose of the Study:
- To investigate the role of tumor-associated macrophages (TAM) and Vascular Endothelial Growth Factor (VEGF)-C/D in bladder cancer lymphangiogenesis and metastasis.
- To explore therapeutic strategies targeting these pathways to inhibit lymphatic spread.
Main Methods:
- An orthotopic urinary bladder cancer (OUBC) model using MBT-2 cell lines was established.
- Immunofluorescence staining was employed to assess angiogenesis, lymphangiogenesis, and TAM infiltration.
- VEGF-C/D signaling was blocked using VEGFR-3 expressing adenovirus, and TAM were depleted using clodronate liposome.
Main Results:
- OUBC models showed significant lymphangiogenesis and TAM infiltration in primary tumors and lymph nodes.
- TAM were found near lymphatic vessels and expressed high levels of VEGF-C/D, suggesting a role in promoting lymphangiogenesis.
- Blocking VEGF-C/D signaling or depleting TAM markedly reduced lymphangiogenesis and lymphatic metastasis in OUBC.
Conclusions:
- VEGF-C/D are key drivers of lymphangiogenesis and lymphatic metastasis in bladder cancer.
- TAM significantly contribute to these processes by producing VEGF-C/D.
- Inhibiting lymphangiogenesis presents a potential therapeutic strategy to combat bladder cancer metastasis and recurrence.
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