Vascular endothelial growth factor (VEGF) was originally identified as an endothelial cell specific growth factor stimulating angiogenesis and vascular permeability. Some family members, VEGF C and D, are specifically involved in lymphangiogenesis. It now appears that VEGF also has autocrine functions acting as a survival factor for tumour cells protecting them from stresses such as hypoxia, chemotherapy and radiotherapy. The mechanisms of action of VEGF are still being investigated with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins which were not previously associated with angiogenesis. VEGF plays an important role in embryonic development and angiogenesis during wound healing and menstrual cycle in the healthy adult. VEGF is also important in a number of both malignant and non-malignant pathologies. As it plays a limited role in normal human physiology, VEGF is an attractive therapeutic target in diseases where VEGF plays a key role. It was originally thought that in pathological conditions such as cancer, VEGF functioned solely as an angiogenic factor, stimulating new vessel formation and increasing vascular permeability. It has since emerged it plays a multifunctional role where it can also have autocrine pro-survival effects and contribute to tumour cell chemoresistance. In this review we discuss the established role of VEGF in angiogenesis and the underlying mechanisms. We discuss its role as a survival factor and mechanisms whereby angiogenesis inhibition improves efficacy of chemotherapy regimes. Finally, we discuss the therapeutic implications of targeting angiogenesis and VEGF receptors, particularly in cancer therapy.

Endotoxin/lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, is a potent inflammatory stimulus. We previously reported that LPS increased the growth of experimental metastases in a murine tumor model. Here, we examined the effect of LPS exposure on key determinants of metastasis-angiogenesis, tumor cell invasion, vascular permeability, nitric oxide synthase (NOS) and matrix metalloproteinase 2 (MMP2) expression. BALB/c mice bearing 4T1 lung metastases were given an intraperitoneal (i.p.) injection of 10 g LPS or saline. LPS exposure resulted in increased lung weight and incidence of pleural lesions. LPS increased angiogenesis both in vivo and in vitro. Most cancer patients ultimately succumb to metastatic disease, and up to 50% of cancer patients already have metastatic deposits at the time of diagnosis. 1 In many cases, the primary tumor can be successfully treated by surgery, radiotherapy, chemotherapy or a combination but the subsequent growth of previously dormant or clinically undetectable metastatic deposits presents a serious obstacle to the complete eradication of the disease. Elucidating factors that influence the development and progression of metastatic disease is critical to the development of effective therapies for patients with metastatic deposits.Metastatic tumor growth involves a complex series of sequential events involving a number of cell types, cytokines and pathways. After the initial transformation event, growth of a primary tumor is accompanied by extensive angiogenesis. Cells with a metastatic phenotype invade the tissue stroma and penetrate the blood vessels to enter the circulation. The majority of tumor cells entering the circulation are rapidly destroyed but those that do survive can then become trapped in organ capillary beds and extravasate into the organ parenchyma. Cell proliferation and vascularization of the secondary deposit completes the metastatic process. 2 Endotoxin/lipopolysccharide (LPS), a cell wall constituent of Gram-negative bacteria, is released during growth or lysis of bacteria and acts as a potent inflammatory stimulus, eliciting a range of cytokines, growth factors and inflammatory mediators. LPS and some bacteria have been shown to have angiogenic activity. [3][4][5] Inflammation has been linked with angiogenesis, resulting in changes in permeability, activation of endothelium and vessel remodeling. 6 In support of a link between inflammation and tumor progression, there is a growing body of evidence that anti-inflammatory agents such as the nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclo-oxygenase activity, inhibit both tumorigenesis and growth of colon and mammary tumors. 7 Endotoxin is ubiquitously present in air, and we previously implicated endotoxin in surgically induced tumor growth. 8,9 Endogenous gut bacteria are a major source of endotoxin, which can translocate across the gut into the circulation following surgical trauma or thermal injury. 10 -12 Vascular endothelial growth factor (VEGF), also known as va...

There is increasing evidence that vascular endothelial growth factor (VEGF) has autocrine as well as paracrine functions in tumour biology. Vascular endothelial growth factor-mediated cell survival signalling occurs via the classical tyrosine kinase receptors Flt-1, KDR/Flk-1 and the more novel neuropilin (NP) receptors, NP-1 and NP-2. A 24-mer peptide, which binds to neuropilin-1, induced apoptosis of murine and human breast carcinoma cells, whereas a peptide directed against KDR had no effect. Both anti-NP1 and anti-KDR peptides induced endothelial cell apoptosis. Confocal microscopy using 5-(6)-carboxyfluorescein-labelled peptides showed that anti-NP1 bound to both tumour and endothelial cells, whereas anti-KDR bound endothelial cells only. This study demonstrates that NP-1 plays an essential role in autocrine antiapoptotic signalling by VEGF in tumour cells and that NP1-blockade induces tumour cell and endothelial cell apoptosis. Specific peptides can therefore be used to target both autocrine (tumour cells) and paracrine (endothelial cells) signalling by VEGF.