Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF).

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

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia.

Vascular endothelial growth factor (VEGF) is produced by most tumour types and stimulates the growth of new blood vessels in the tumour. The expansion of a solid tumour ultimately leads to the development of hypoxic regions, which increases VEGF production and further angiogenesis. In this study, we examined the role of VEGF in the survival of breast tumour cells under hypoxia. Murine 4T1 and human MDA-MB-231 tumour cells were cultured under normoxic and hypoxic growth conditions in the presence or absence of VEGF neutralising antibodies. Apoptosis was assessed in addition to changes in expression of the anti- and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The effect of hypoxia on the novel VEGF receptor, NP1 (neuropilin-1) and the role of the PI3K (phosphatidylinositol-3-kinase) signalling pathway in response to VEGF were examined. VEGF blockade resulted in direct tumour cell apoptosis of both tumour cell lines under normoxia and hypoxia. While blocking VEGF resulted in a downregulation of hypoxia-induced Bcl-2 expression, there was a significant increase in the pro-apoptotic protein Bad relative to cells cultured under hypoxia alone. Both hypoxia and VEGF phosphorylated Akt. Neutralising antibodies to VEGF abrogated this effect, implicating the PI3K pathway in VEGF-mediated cell survival of mammary adenocarcinoma cells. This study demonstrates that VEGF acts as a survival factor not only for endothelial cells as previously thought, but also for some breast tumour cells, protecting them from apoptosis, particularly under hypoxic stress. The data presented provide an additional rationale for combining anti-VEGF strategies with conventional anti-cancer therapies such as chemotherapy and radiotherapy

In vitro selectivity, in vivo biodistribution and tumour uptake of annexin V radiolabelled with a positron emitting radioisotope

The availability of a noninvasive method to detect and quantify apoptosis in tumours will enable tumour response to several cancer therapies to be assessed. We have synthesised two radiotracers, annexin V and the N-succinimidyl-3-iodobenzoic acid (SIB) derivative of annexin V, labelled with radio-iodine (124I and 125I) and provided proof of the concept by assessing specific binding and biodistribution of these probes to apoptotic cells and tumours. We have also assessed the tumour uptake of [124I]annexin V in a mouse model of apoptosis. RIF-1 cells induced to undergo apoptosis in vitro showed a drug concentration-dependent increased binding of [125I]annexin V and [125I]SIB–annexin V. In the same model system, there was an increase in terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL)-positive cells and a decrease in clonogenic survival. Radiotracer binding was completely inhibited by preincubation with unlabelled annexin V. In RIF-1 tumour-bearing mice, rapid distribution of [125I]SIB–annexin V-derived radioactivity to kidneys was observed and the radiotracer accumulated in urine. The binding of [125I]SIB–annexin V to RIF-1 tumours increased by 2.3-fold at 48 h after a single intraperitoneal injection of 5-fluorouracil (165 mg kg−1 body weight), compared to a 4.4-fold increase in TUNEL-positive cells measured by immunostaining. Positron emission tomography images with both radiotracers demonstrated intense localisation in the kidneys and bladder. Unlike [124I]SIB–annexin V, [124I]annexin V also showed localisation in the thyroid region presumably due to deiodination of the radiolabel. [124I]SIB–annexin V is an attractive candidate for in vivo imaging of apoptosis by PET

A randomized trial of photoselective vaporization of the prostate using the 80-w potassium-titanyl-phosphate laser vs transurethral prostatectomy, with a 1-year follow-up

OBJECTIVE To compare the potassium-titanyl-phosphate GreenlightTM 80-W laser ablation system for photovaporization of the prostate (PVP; Laserscope, San Jose, CA, USA) with transurethral resection of the prostate (TURP), as many technologies have been proposed as equivalent or superior to TURP without gaining widespread acceptance, due to lack of data from randomized trials. PATIENTS AND METHODS In all, 120 patients were randomized to undergo either TURP or PVP after a full urological evaluation, which was repeated at 1, 3, 6 and 12 months after surgery. Irrigation use, duration of catheterization (DOC), length of hospital stay (LOS), blood loss, cost and operative time were also assessed. RESULTS Both groups showed a significant increase in mean (sd) maximum urinary flow rate from baseline (P < 0.05); in the TURP group from 8.9 (3.0) to 19.4 (8.7) mL/s (154%), and in the PVP group from 8.8 (2.5) to 18.6 (8.2) mL/s (136%). The International Prostate Symptom Score (IPSS) decreased from 25.4 (5.7) to 10.9 (9.4) in the TURP group (53%), and from 25.3 (5.9) to 8.9 (7.6) in the PVP group (61%). The trends were similar for the bother and Quality of Life scores. There was no difference in sexual function as measured by Baseline Sexual Function Questionnaires. The DOC was significantly less in the PVP than the TURP group (P < 0.001), with a mean (range) of 13 (0-24) h vs 44.7 (6-192) h. The situation was similar for LOS (P < 0.001), with a mean (range) of 1.09 (1-2) and 3.6 (3-9) days in the PVP and TURP groups, respectively. Adverse events and complications were less frequent in the PVP group. Costs were also 22% less in the PVP group. CONCLUSIONS This trial shows that PVP is an effective technique when compared to TURP, producing equivalent improvements in flow rates and IPSS with the advantages of markedly reduced LOS, DOC and adverse events. A long-term follow-up is being undertaken to ensure durability of these results