Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor

Terman, Bruce I.; Dougher-Vermazen, Maureen; Carrion, Miguel; Dimitrov, D; Armellino, Douglas; Gospodarowicz, Denis; Bőhlen, Peter

doi:10.1016/0006-291x(92)90483-2

Cited by 1,338 publications

(711 citation statements)

References 16 publications

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“…VEGF has been shown to be a specific endothelial cell mitogen in vitro (Gospodarowicz et al, 1989). Two high-affinity VEGF receptors (flt-I and KDR) have been recognized on human endothelial cells (de Vries et al, 1992;Terman et al, 1992). The expression of VEGF is correlated to vascular density in several histological types of human tumours (Guidi et al, 1995;Takahashi et al, 1995;Toi et al, 1995;Mattern et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma

Rofstad

Danielsen²

1998

Br J Cancer

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Summary Tumour cells exposed to hypoxia in vitro can show increased expression of several selected genes, including the gene encoding the vascular endothelial growth factor (VEGF), suggesting that hypoxia followed by reoxygenation might promote the malignant progression of tumours. An in vitro/in vivo study was conducted to investigate whether hypoxia can increase the angiogenic potential of tumour cells through increased VEGF secretion. Four human melanoma cell lines (A-07, D-12, R-18, U-25) were included in the study. Cell cultures were exposed to hypoxia (oxygen concentration <10 p.p.m.) in vitro using the steel chamber method. Rate of VEGF secretion was measured in vitro in aerobic and hypoxic cell cultures by ELISA. Angiogenesis was assessed in vivo using the intradermal angiogenesis assay. Aliquots of cells harvested from aerobic cultures or cultures exposed to hypoxia for 24 h were inoculated intradermally in the flanks of adult female BALB/cnu/nu mice. Tumours developed and angiogenesis was quantified by scoring the number of capillaries in the dermis oriented towards the tumours. The number of tumour-oriented capillaries did not differ significantly between tumours from hypoxic and aerobic cultures for A-07 and U-25, whereas tumours from hypoxic cultures showed a larger number of tumour-oriented capillaries than tumours from aerobic cultures for D-1 2 and R-1 8. The VEGF secretion under aerobic conditions and the absolute increase in VEGF secretion induced by hypoxia were lower for D-12 and R-18 than for A-07 and U-25, whereas the relative increase in VEGF secretion induced by hypoxia was higher for D-12 and R-18 than for A-07 and U-25. VEGF is not a limiting factor in the angiogenesis of some tumours under normoxic conditions. Hypoxia can increase the angiogenic potential of tumour cells by increasing the secretion of VEGF, but only of tumour cells showing low VEGF secretion under normoxia. Transient hypoxia might promote the malignant progression of tumours by temporarily increasing the angiogenic potential of tumour cells showing low VEGF expression under normoxic conditions. Keywords: angiogenesis; hypoxia; melanoma; vascularization; VEGF Many malignant tumours develop regions of hypoxic cells during growth (Coleman, 1988;Vaupel et al, 1989;Brown and Giaccia, 1994). Two types of hypoxia have been recognized: chronic hypoxia, arising from limitations in oxygen diffusion, and acute hypoxia, resulting from transient stoppages in microregional blood flow (Stone et al, 1993;Horsman, 1995). Reoxygenation of hypoxic cells occurs during unperturbed tumour growth as a result of reopening of temporarily closed vessels and during therapy as a result of therapy-induced tumour cell inactivation (Kallman, 1972;Brown, 1979;Chaplin et al, 1987). Hypoxia followed by reoxygenation might promote the malignant progression of tumours (Hill, 1990). Thus, tumour cells exposed to hypoxia in vitro can show increased expression of several selected genes, including genes encoding cell cycle-regulatory proteins, haematopoietic...

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Section: Discussionmentioning

confidence: 99%

Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma

Rofstad

Danielsen²

1998

Br J Cancer

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“…8 Another high-affinity VEGFR, Flt-1, binds VEGF about 10 times stronger than KDR, however Flt-1 activation does not significantly stimulate angiogenesis. 9,10 Both receptors, Flt-1 and KDR, have similar structure with extracellular regions consisting of seven domains, 1-7.…”

Section: Introductionmentioning

confidence: 99%

Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization

Pecháň¹,

Rubin²,

Lukason³

et al. 2008

Gene Ther

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“…32,33 VEGF binds to two highly specific tyrosine kinase receptors, Flt-1 and KDR/Flk-1, found almost exclusively on endothelial cells. [34][35][36] Following receptor binding, endothelial cells are stimulated to proliferate and form tube-like structures, the first steps in forming new blood vessels, a process known as angiogenesis. 37,38 Preclinical studies have demonstrated that delivery of the VEGF gene into ischemic tissue can stimulate the development of collateral arteries in animal models of peripheral and myocardial ischemia.…”

Section: Introductionmentioning

confidence: 99%

Increased revascularization efficacy after administration of an adenovirus encoding VEGF121

et al. 2004

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Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor

Cited by 1,338 publications

References 16 publications

Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma

Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma

Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization

Increased revascularization efficacy after administration of an adenovirus encoding VEGF121

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