Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)

Achen, Marc G.; Jeltsch, Michael; Kukk, Eola; Mäkinen, Taija; Vitali, Angela; Wilks, Andrew F.; Alitalo, Kari; Stacker, Steven A.

doi:10.1073/pnas.95.2.548

Cited by 1,077 publications

(830 citation statements)

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“…VEGF-D, a potent angiogenic factor in vivo, which stimulates endothelial cell proliferation and migration, 5 is involved in promoting tumor angiogenesis and lymphangiogenesis. 7 VEGF-D is also known to be required for the growth and establishment of lymphatic vessels within tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Vascular endothelial growth factor-D (VEGF-D, a novel VEGF member, has been found to induce not only angiogenesis but also lymphangiogenesis via VEGF receptor (VEGFR)-2 and VEGFR-3 (also known as Flt-4 5 ). Since VEGFR-3 has been demonstrated to be expressed almost exclusively in the lymphatic endothelium and thus considered to be a major regulator of lymphangiogenesis, 6 VEGF-D appears to be an important lymphangiogenic factor.…”

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confidence: 99%

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VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma

et al. 2005

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Papillary thyroid carcinoma frequently metastasizes to regional lymph nodes, and lymph node metastasis increases the risk of local regional relapse. Recent evidence suggests that vascular endothelial growth factor-D (VEGF-D) promotes lymphangiogenesis, which in turn promotes lymphatic metastasis. Therefore, the role of VEGF-D messenger RNA transcript levels and VEGF-D immunoreactivity in lymph node metastasis in papillary thyroid carcinoma was investigated. In addition, the role of blood vascular vessel, lymph vessel, and Flt-4-positive vessel densities were studied in relation to their suspected association with lymph node metastasis, and with VEGF-D expression. VEGF-D messenger RNA transcript levels by quantitative real-time reverse transcription-polymerase chain reaction and VEGF-D immunoreactivity by immunohistochemistry in 49 papillary thyroid carcinomas were also studied. This was followed by quantitative immunohistochemical staining for CD34, podoplanin, and Flt-4. Lymph node metastasis was significantly correlated with VEGF-D messenger RNA transcript levels (P ¼ 0.027) and VEGF-D immunoreactivity (P ¼ 0.019). Increased lymph vessel density was also correlated with VEGF-D expression and lymph node metastasis. In conclusion, our findings indicate that VEGF-D expression and increased lymph vessel density may have an important role for lymph node metastasis in papillary thyroid carcinoma.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma

et al. 2005

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“…The lymphangiogenic growth factors VEGF-C and VEGF-D are synthesised as proproteins consisting of a central VEGF homology domain (VHD), containing receptor-binding sites, flanked by Nand C-terminal propeptides (Joukov et al, 1996;Achen et al, 1998). Subsequently, the propeptides can be proteolytically removed to generate mature forms consisting of VHD dimers.…”

Section: Mechanisms Of Lymphangiogenic Signallingmentioning

confidence: 99%

“…The best validated signalling system for tumour lymphangiogenesis involves the secreted glycoproteins VEGF-C and VEGF-D that signal via VEGF receptor-3 (VEGFR-3; also known as Flt4), expressed on the surface of lymphatic endothelial cells (Joukov et al, 1996;Achen et al, 1998;Veikkola et al, 2001). Vascular endothelial growth factor-C and VEGF-D have been shown to promote tumour lymphangiogenesis, the metastatic spread of tumour cells to lymph nodes and, in some cases, distant organ metastasis in multiple animal models of cancer (for a review see Saharinen et al, 2004).…”

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confidence: 99%

Targeting lymphangiogenesis to prevent tumour metastasis

2006

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Recent studies involving animal models of cancer and clinicopathological analyses of human tumours suggest that the growth of lymphatic vessels (lymphangiogenesis) in or nearby tumours is associated with the metastatic spread of cancer. The best validated molecular signalling system for tumour lymphangiogenesis involves the secreted proteins vascular endothelial growth factor-C (VEGF-C) and VEGF-D that induce growth of lymphatic vessels via activation of VEGF receptor-3 (VEGFR-3) localised on the surface of lymphatic endothelial cells. In this review, we discuss the evidence supporting a role for this signalling system in the spread of cancer and potential approaches for blocking this system to prevent tumour metastasis.

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“…They also participate in immune defence and are important for metastatic tumor spread. 12 VEGF-C and-D stimulate lymphangiogenesis through VEGFR-3 which is predominantly expressed not only in lymphatic endothelium 13,14 but also in angiogenic sprouts. 15 Angiopoietins (Ang1-4) are ligands for the tyrosine kinase receptor Tie2.…”

Section: Introductionmentioning

confidence: 99%

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

et al. 2010

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Despite optimal surgery and chemotherapy, the prognosis of ovarian cancer patients remains poor and new treatments are urgently needed. Solid tumors require the formation of new vessels for growth and metastasis. In the present study, we have used soluble vascular endothelial growth factor (sVEGF) receptors sVEGFR-1 and -3, soluble receptors Tie1 and Tie2 and their combinations in an ovarian cancer xenograft model. Human ovarian cancer cells were injected intraperitoneally into nude mice (n ¼ 42) and magnetic resonance imaging (MRI) was used for confirming tumors before gene delivery. Treatment with combined AdsVEGFR-1, AdsVEGFR-3 and AdsTie2 significantly decreased the size of the intraperitoneal tumors compared with the controls (AdLacZ; P ¼ 0.038) with significantly less microvessels and vascular area. Unexpectedly, treatment with combined AdsTie1 and AdsTie2 led to a dramatic shortening of the survival which was not observed in the groups receiving either of the soluble receptors alone (P ¼ 0.031). The only difference to other treatments was liver toxicity observed after the combined Tie receptor treatment.In conclusion, combined inhibition of VEGFR-1, VEGFR-3 and Tie2 pathways was safe and provided efficient therapy for ovarian cancer in mice.

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Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)

Abstract: We have identified a member of the VEGF family by computer-based homology searching and have

Cited by 1,077 publications

References 37 publications

VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma

VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma

Targeting lymphangiogenesis to prevent tumour metastasis

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

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