Abstract
BackgroundMost 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.ResultsThe 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.ConclusionVEGF-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.
Highlights
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
We found that orthotopic urinary bladder cancer (OUBC) induces profound lymphangiogenesis in the tumor and sentinel lymph node (SLN) and substantial lymphatic metastasis to SLN through vascular endothelial growth factor (VEGF)-C/D-VEGF receptor-3 (VEGFR-3) signaling pathway
CD11b+/CD68+ tumor-associated macrophages (TAM) was largely infiltrated around the tumor lymphatic vessels, and they were closely involved in the OUBC-induced lymphangiogenesis and lymphatic metastasis, possibly through secretary lymphangiogenic factors such as VEGF-C/D
Summary
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. Blocking the VEGF-C/D-VEGFR-3 signaling pathway suppresses tumor lymphangiogenesis and lymph node metastasis in several tumor models [12,13,14,15]. These reports indicate that VEGF-C/D-mediated VEGFR-3 activation contributes to lymphatic vessel growth and tumor cell dissemination via lymphatic vessels. In this study, we investigated roles of VEGF-C/D and involvement of TAM in tumor lymphangiogenesis and lymphatic metastasis in the murine orthotopic urinary bladder cancer (OUBC) model. CD11b+/CD68+ TAM was largely infiltrated around the tumor lymphatic vessels, and they were closely involved in the OUBC-induced lymphangiogenesis and lymphatic metastasis, possibly through secretary lymphangiogenic factors such as VEGF-C/D. Our findings provide a novel insight and useful treatment strategy how to control lymphatic metastasis in the patients with bladder cancer through suppression of VEGFR-3 signaling pathway
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