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Molecular and clinical aspects of targeting the VEGF pathway in tumors.

Korpanty G, Sullivan LA, Smyth E, Carney DN, Brekken RA - J Oncol (2010)

Bottom Line: Tumor angiogenesis is a complex process resulting from many signals from the tumor microenvironment.Continued research into the complex signaling cascades that promote tumor angiogenesis may yield new targets or improve upon current therapies.In addition, the development of reliable tools to track tumor responses to antiangiogenic therapy will enable a better understanding of current therapeutic efficacy and may elucidate mechanisms to predict patient response to therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland.

ABSTRACT
Tumor angiogenesis is a complex process resulting from many signals from the tumor microenvironment. From preclinical animal models to clinical trials and practice, targeting tumors with antiangiogenic therapy remains an exciting area of study. Although many scientific advances have been achieved, leading to the development and clinical use of antiangiogenic drugs such as bevacizumab, sorafenib, and sunitinib, these therapies fall short of their anticipated benefits and leave many questions unanswered. Continued research into the complex signaling cascades that promote tumor angiogenesis may yield new targets or improve upon current therapies. In addition, the development of reliable tools to track tumor responses to antiangiogenic therapy will enable a better understanding of current therapeutic efficacy and may elucidate mechanisms to predict patient response to therapy.

No MeSH data available.


Related in: MedlinePlus

VEGF signaling interactions. The VEGF family can bind to VEGFR1, VEGFR2, and VEGFR3 inducing signaling cascades to promote vasculogenesis, angiogenesis, and lymphangiogenesis, respectively.
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fig1: VEGF signaling interactions. The VEGF family can bind to VEGFR1, VEGFR2, and VEGFR3 inducing signaling cascades to promote vasculogenesis, angiogenesis, and lymphangiogenesis, respectively.

Mentions: VEGFR2 is the key mediator of VEGF-driven angiogenesis. VEGFR2 is crucial during embryonic vascular development. Heterozygous and homozygous VEGFR-2 knockout mice die in utero due to disrupted vasculogenesis and hematopoiesis [24]. Upon VEGF binding, VEGFR2 undergoes auto-transphosphorylation and downstream effectors including phospholipase C gamma, protein kinase C, Raf, the MAP kinase signaling cascades, and the PI3K and FAK pathways are activated, leading to endothelial cell proliferation, migration, and survival (Figure 1) [25, 26]. VEGFR3 binds VEGF-C and -D and is directly involved in formation of the lymphatic vasculature physiologic and tumor development [27, 28]. There is also experimental evidence that VEGFR3 mediated activation of lymphatic endothelial cells is crucial for metastasis [29]. Neuropilin-1 (Nrp-1) and Neuropilin-2 (Nrp-2) are coreceptors originally identified for their involvement in neuronal guidance, and that bind members of collapsin/semaphorin protein family [30]. The Nrps can also bind to certain heparin binding isofoms of VEGF (e.g., VEGF165) to enhance the binding of VEGF to VEGFR1, and VEGFR2 (Figure 1) [31, 32]. Nrps lack tyrosine kinase domains but do contain an intracellular PDZ domain, which has been suggested to facilitate VEGF specific signaling.


Molecular and clinical aspects of targeting the VEGF pathway in tumors.

Korpanty G, Sullivan LA, Smyth E, Carney DN, Brekken RA - J Oncol (2010)

VEGF signaling interactions. The VEGF family can bind to VEGFR1, VEGFR2, and VEGFR3 inducing signaling cascades to promote vasculogenesis, angiogenesis, and lymphangiogenesis, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2902148&req=5

fig1: VEGF signaling interactions. The VEGF family can bind to VEGFR1, VEGFR2, and VEGFR3 inducing signaling cascades to promote vasculogenesis, angiogenesis, and lymphangiogenesis, respectively.
Mentions: VEGFR2 is the key mediator of VEGF-driven angiogenesis. VEGFR2 is crucial during embryonic vascular development. Heterozygous and homozygous VEGFR-2 knockout mice die in utero due to disrupted vasculogenesis and hematopoiesis [24]. Upon VEGF binding, VEGFR2 undergoes auto-transphosphorylation and downstream effectors including phospholipase C gamma, protein kinase C, Raf, the MAP kinase signaling cascades, and the PI3K and FAK pathways are activated, leading to endothelial cell proliferation, migration, and survival (Figure 1) [25, 26]. VEGFR3 binds VEGF-C and -D and is directly involved in formation of the lymphatic vasculature physiologic and tumor development [27, 28]. There is also experimental evidence that VEGFR3 mediated activation of lymphatic endothelial cells is crucial for metastasis [29]. Neuropilin-1 (Nrp-1) and Neuropilin-2 (Nrp-2) are coreceptors originally identified for their involvement in neuronal guidance, and that bind members of collapsin/semaphorin protein family [30]. The Nrps can also bind to certain heparin binding isofoms of VEGF (e.g., VEGF165) to enhance the binding of VEGF to VEGFR1, and VEGFR2 (Figure 1) [31, 32]. Nrps lack tyrosine kinase domains but do contain an intracellular PDZ domain, which has been suggested to facilitate VEGF specific signaling.

Bottom Line: Tumor angiogenesis is a complex process resulting from many signals from the tumor microenvironment.Continued research into the complex signaling cascades that promote tumor angiogenesis may yield new targets or improve upon current therapies.In addition, the development of reliable tools to track tumor responses to antiangiogenic therapy will enable a better understanding of current therapeutic efficacy and may elucidate mechanisms to predict patient response to therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland.

ABSTRACT
Tumor angiogenesis is a complex process resulting from many signals from the tumor microenvironment. From preclinical animal models to clinical trials and practice, targeting tumors with antiangiogenic therapy remains an exciting area of study. Although many scientific advances have been achieved, leading to the development and clinical use of antiangiogenic drugs such as bevacizumab, sorafenib, and sunitinib, these therapies fall short of their anticipated benefits and leave many questions unanswered. Continued research into the complex signaling cascades that promote tumor angiogenesis may yield new targets or improve upon current therapies. In addition, the development of reliable tools to track tumor responses to antiangiogenic therapy will enable a better understanding of current therapeutic efficacy and may elucidate mechanisms to predict patient response to therapy.

No MeSH data available.


Related in: MedlinePlus