Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis

Kubo, Hajime; Fujiwara, Takashi; Jussila, Lotta; Hashi, Hiroyuki; Ogawa, Michio; Shimizu, Kenji; Awane, Masaaki; Sakai, Yoshiharu; Takabayashi, Arimichi; Alitalo, Kari; Yamaoka, Yoshio; Nishikawa, Shin Ichi

doi:10.1182/blood.v96.2.546

Cited by 189 publications

(45 citation statements)

References 32 publications

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“…Alitalo et al 40 showed that VEGFR-3 is involved in angiogenesis and growth of some tumors. Similarly, Kubo et al 41 have also reported that VEGFR-3 monoclonal antibody inhibits tumor xenograft growth in mice. Although it is not clear whether direct ligation and downstream signaling of VEGFR-3 can stimulate HA completely independent of VEGFR-2, it is clear through our studies that VEGFR-3 can directly functionally contribute to HA.…”

Section: Discussionmentioning

confidence: 82%

Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands

Chung

Chauhan

Jin

et al. 2009

The American Journal of Pathology

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Vascular endothelial growth factor receptor (VEGFR)-2 is a major stimulator of hemangiogenesis (HA), whereas VEGFR-3 stimulates lymphangiogenesis (LA). Contrary to this understanding, we demonstrate that implantation of pellets containing VEGFR-3-specific ligands (VEGF-C156S and recombinant murine VEGF-D) into the corneal stroma induce not only LA but also robust HA characterized by blood vessels that are positive for VEGFR-3 expression. The implantation of pellets containing VEGFR-3-specific ligands also leads to the recruitment of VEGF-A-secreting macrophages. Depletion of these infiltrating macrophages using clodronate-liposome administration shows a significant reduction in HA as well as LA. Blockade of either VEGFR-2 or VEGFR-3 signaling reduces both HA and LA; however, the percent reduction of HA is greater in the VEGFR-2 blockade group. In addition, in the VEGFR-3 blockade group, the percent reduction of HA is significantly greater with VEGFR-3-specific ligands than that by VEGF-A or VEGF-C. Collectively, our data suggest that VEGFR-3-specific signaling can induce new blood vessels, to which macrophages contribute a major role, and signify its potential as an additional therapeutic target to the existing VEGF-A/VEGFR-2 signaling-based antiangiogenesis strategies.

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Section: Discussionmentioning

confidence: 82%

Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands

Chung

Chauhan

Jin

et al. 2009

The American Journal of Pathology

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“…Immunohistochemistry to detect VEGFR‐3 expression was performed as described with minor modifications (Kubo et al, 2000). Briefly, histological slides, 4 µm in thickness, were deparaffinized in xylene and a graded ethanol series, and antigen retrieval was achieved by heating in Cytomation Target Retrieval solution (DAKO Cytomation, Glostrup, Denmark) for 10 min in a microwave oven.…”

Section: Methodsmentioning

confidence: 99%

Lack of lymphatic vessel phenotype in LYVE‐1/CD44 double knockout mice

Luong

Tam

Lin³

et al. 2009

Journal Cellular Physiology

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Lymphatic vessels play a key role in maintaining tissue-fluid homeostasis, immune surveillance and metastasis. The hyaluronan receptor, LYVE-1, is widely used as a molecular marker for adult and embryonic lymphatic endothelium, but its physiological functions have not yet been established in vivo. In agreement with a recent report, LYVE-1−/− mice, which are healthy and fertile, do not display any defects related to congenital abnormalities of the lymphatic system. One hypothesis for the absence of a phenotype in LYVE-1 null mice is that other hyaluronan receptors, such as CD44, may compensate for LYVE-1. To test this hypothesis, we created LYVE-1/CD44 double knockout mice with appropriate littermate controls. Lymphatic vessel structure and function, as determined by histological methods and intravital microscopy, show that LYVE-1−/−, CD44−/− and LYVE-1−/−/CD44−/− mice are indistinguishable from wild-type mice under normal conditions. Furthermore, resolution of carrageenan-induced paw edema is comparable in all genotypes. However, LYVE-1−/−/CD44−/− mice exhibit increased edema formation in a carrageenan-induced paw inflammation model compared to wild-type mice, but not to LYVE−/− or CD44−/− mice. These data suggest that LYVE-1 and CD44 are not required for the formation or function of lymphatics, but do not rule out a role for LYVE-1 in inflammation.

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“…VEGF‐R3, also known as Flt4, is specifically expressed by lymphatic, but not blood vascular endothelium in most normal tissues (Kaipainen et al, 1995; Partanen et al, 2000). However, there have been observations that VEGF‐R3 becomes re‐expressed by activated blood vascular endothelial cells associated with tumor growth and tissue repair (Partanen et al, 1999; Valtola et al, 1999; Kubo et al, 2000; Paavonen et al, 2000). Thus, VEGF‐R3 does not appear to represent a reliable marker for tumor‐associated lymphatics.…”

Section: New Growth Factors and Markers For Lymphatic Endotheliummentioning

confidence: 99%

Tumor lymphangiogenesis and melanoma metastasis

Rinderknecht

Detmar

2008

Journal Cellular Physiology

144

126

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Malignant melanomas of the skin primarily metastasize to lymph nodes, and the detection of sentinel lymph node metastases serves as an important prognostic parameter. There is now compelling evidence that melanomas can induce lymphangiogenesis (growth of lymphatic vessels), mainly at the tumor-stroma interface, and that the level of tumor lymphangiogenesis is correlated with the incidence of sentinel lymph node metastases and with disease-free survival. Thus, tumor lymphangiogenesis can serve as a novel prognostic predictor in melanoma. Vascular endothelial growth factor (VEGF)-C, released by melanoma cells and by tumor-associated macrophages, likely represents the major lymphangiogenic factor in melanoma, although other members of the VEGF family might also be involved. The recent discovery that tumors can induce a premetastatic niche, by inducing lymphatic vessel growth in sentinel lymph nodes even before metastasis, and that lymph node lymphangiogenesis enhances metastatic spread, indicates that activated lymphatic vessels represent novel targets for the detection and/or therapy of melanoma metastases.

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Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis

Cited by 189 publications

References 32 publications

Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands

Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands

Lack of lymphatic vessel phenotype in LYVE‐1/CD44 double knockout mice

Tumor lymphangiogenesis and melanoma metastasis

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