Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective

Abstract

Th e establishment of a vascular supply is one of the earliest and most important events occurring during embryonic development. Growth and maturation of a functional vascular network are complex and still incompletely understood processes involving orchestrated activation of vascular progenitors in the early stages of embryonic development followed by vasculogenesis and angiogenesis. Th ese processes require a tightly regulated activation of several growth factors and their receptors. Th e role of vascular endothelial growth factors (VEGF) and their receptors has been studied extensively due to their prominent role during blood vessel formation. Mice defi cient in various VEGF ligands or receptors show serious defects in vascular formation and maturation. Moreover, members of the VEGF family are involved in other signifi cant biological processes, including lymphangiogenesis, vascular permeability, and hematopoiesis. Importantly, VEGF is released by tumor cells and induces tumor neovascularization. It is now well established that the VEGF axis represents an important target for antitumor therapy. Aberrant VEGF signaling is also a feature of several other pathologic conditions, such as age-related macular degeneration and rheumatoid arthritis.

Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy

“…In 1971, Folkman (1971 hypothesised that blocking angiogenesis in tumours could be used a method of treatment for patients with cancer. Pharmacological agents designed to block VEGF or VEGF receptor signalling are currently in various phases of clinical trials and have demonstrating promising results (Kowanetz and Ferrara, 2006;Roskoski, 2007;Willett et al, 2007). The VEGF blockade results in A B Figure 1 Representative immunostains of VEGF (A) and EGFR (B) from pretreatment rectal tumour biopsies.…”

MKK signaling and vascularization

“…During angiogenesis endothelial cells proliferate, produce proteolytic enzymes that degrade the extracellular matrix, change their adhesive properties, migrate and differentiate into new blood vessels. This process of tumor vascularization is directed mainly by paracrine angioproliferative tumor factors and extracellular matrix components that bind to specialized receptors such as G-protein-coupled receptors or receptor tyrosine kinases and integrins on endothelial cells (Eliceiri et al, 1998;Ruegg and Mariotti, 2003;Kowanetz and Ferrara, 2006). Ligand activation of these receptors triggers signaling pathways leading to altered protein activity and gene transcription that modulate the cellular behavior.…”

New Model of In-situ Xenograft Lymphangiogenesis by a Human Colonic Adenocarcinoma Cell Line in Nude Mice

“…markers have been successively found and the molecular mechanism of lymphangiogenesis have been revealed step by step, thus the role of lymphangiogenesis in tumor metastasis, recurrence, treatment is gradually being recognized, the related research is also increasingly in-depth (Kowanetz and Ferrara, 2006;Mylona et al, 2007;Zwaans and Bielenberg, 2007;Liersch et al, 2010). Because the tumor metastasis animal models is important in cancer metastasis research, as well as lymphatic (node) metastasis as the main path of the cancer spreading take more and more attach of colorectal cancer metastasis, it is inevitably put forward higher requirements of animal models in the related mechanisms research of colorectal cancer metastasis, especially lymphatic metastasis (Tsutsumi et al, 2001;Flatmark et al, 2004;Sasaki et al, 2008).…”

“…LYVE-1 (Jackson et al, 2001;Prevo et al, 2001;, D2-40 (Breiteneder et al, 1999;Renyi et al, 2000;Kowanetz and Ferrara, 2006;Wissmann and Detmar, 2006) are the most important lymphatic endothelial cell-specific markers. While LYVE-1, D2-40 and VEGFR-3 expression is positive lymphangiogenesis rather than angiogenesis.…”

“…While LYVE-1, D2-40 and VEGFR-3 expression is positive lymphangiogenesis rather than angiogenesis. VEGF-C and VEGF-D and VEGFR-3 are recognized as lymphatic endothelial growth factor and receptors in the lymphatic-VEGFR-3 signaling pathway (Kubo et al, 2000;Kowanetz and Ferrara, 2006;Wissmann and Detmar, 2006;Sundar and Ganesan, 2007;Nagahashi et al, 2010). Our results suggest that the models of orthotopic transplantation of colorectal cancer in nude mice showed LYVE-1, D2-40 immunohistochemical staining strongly positive, LYVE-1, D2-40, VEGF-C, VEGF-D and VEGFR-3 protein capillaries and the VEGF-C, -D/VEGFR-3 signaling axis control mechanism, which proved that the model of orthotopic transplantation of colorectal cancer in nude mice was a colorectal adenocarcinoma lymphangiogenesis animal model.…”