Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer

Mol Cancer. 2011 Apr 11:10:36. doi: 10.1186/1476-4598-10-36.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / genetics
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • Cell Line, Tumor
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Immunohistochemistry
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphangiogenesis*
  • Lymphatic Metastasis
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C3H
  • Neovascularization, Pathologic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Solubility
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor D / genetics
  • Vascular Endothelial Growth Factor D / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD11b Antigen
  • CD68 antigen, human
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor D
  • Vascular Endothelial Growth Factor Receptor-3