Vascular endothelial growth factor receptor-2 in breast cancer

Abstract

Investigations over the last decade have established the essential role of growth factors and their receptors during angiogenesis and carcinogenesis. The vascular endothelial growth factor receptor (VEGFR) family in mammals contains three members, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4), which are transmembrane tyrosine kinase receptors that regulate the formation of blood and lymphatic vessels. In the early 1990s, the above VEGFR were structurally characterized by cDNA cloning. Among these three receptors, VEGFR-2 is generally recognized to have a principal role in mediating VEGF-induced responses. VEGFR-2 is considered as the earliest marker for endothelial cell development. Importantly, VEGFR-2 directly regulates tumor angiogenesis. Therefore, several inhibitors of VEGFR-2 have been developed and many of them are now in clinical trials. In addition to targeting endothelial cells, the VEGF/VEGFR-2 system works as an essential autocrine/paracrine process for cancer cell proliferation and survival. Recent studies mark the continuous and increased interest in this related, but distinct, function of VEGF/VEGFR-2 in cancer cells: the autocrine/paracrine loop. Several mechanisms regulate VEGFR-2 levels and modulate its role in tumor angiogenesis and physiologic functions, i.e.: cellular localization/trafficking, regulation of cis-elements of promoter, epigenetic regulation and signaling from Notch, cytokines/growth factors and estrogen, etc. In this review, we will focus on updated information regarding VEGFR-2 research with respect to the molecular mechanisms of VEGFR-2 regulation in human breast cancer. Investigations in the activation, function, and regulation of VEGFR-2 in breast cancer will allow the development of new pharmacological strategies aimed at directly targeting cancer cell proliferation and survival.

Downregulation of KDR expression induces apoptosis in breast cancer cells

“…VEGFR-2, also known as kinase insert domain receptor (KDR), is a key receptor involved in malignant angiogenesis. Its activation promotes a number of other cellular changes that lead to tumor development and metastases [8,9]. KDR is highly expressed in breast cancer [10], suggesting that breast cancer is potentially treatable by reducing KDR expression.…”

Inverse correlation of phospho-KDR/Flk-1 expression and stage of colorectal cancer: implication of the significance of neoangiogenesis in activated VEGFR-2 expressing early stage colorectal adenocarcinomas

“…The VEGF receptor family contains 3 members, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4), which are transmembrane tyrosine kinase receptors expressed on the surface of endothelial cells and are involved in the regulation and formation of blood and lymphatic vessels [2,3]. Among the VEGF receptors, VEGFR-2 is recognized to play a principal role in mediating VEGF-induced vessel formation [4]. Vascular endothelial growth factor receptor-2 is a marker for endothelial cell development and it directly regulates tumor angiogenesis, blocking VEGF and KDR/Flk-1 interaction by monoclonal neutralizing antibody targeting KDR/Flk-1 diminished tumor vascularity and inhibited tumor angiogenesis [5].…”

“…Vascular endothelial growth factors and their receptors were reported to be expressed in various tumor cells [9][10][11][12][13][14]. In addition to acting on endothelial cells to modulate angiogenesis and lymphangiogenesis, the VEGF signaling is also directly activated in tumor cells to regulate cancer progression [4]. In the study of VEGFR expression in ovarian cancer, Klasa-Mazurkiewicz et al reported that the highest relative level of VEGFR-2 was detected in the early stage cancer, indicating the significance of neoangiogenesis in high VEGFR-2 expressed early stage ovarian cancer [15].…”

A human IgG-like bispecific antibody co-targeting epidermal growth factor receptor and the vascular endothelial growth factor receptor 2 for enhanced antitumor activity

“…10 VEGFR2 is expressed by endothelial cells and various cancers including breast cancer and NSCLC. [11][12] As the principal receptor leading angiogenesis in tumoral tissue, VEGFR2 has potent tyrosine kinase activity and is primarily associated with the induction of angiogenesis mediated by VEGF. 13 VEGF-induced homodimerization of VEGFR2 leads to a strong autophosphorylation of VEGFR2 on tyrosine residues.…”