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Vascular Endothelial Growth Factor (VEGF) and Its Role in Non-Endothelial Cells: Autocrine Signalling by VEGF

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Vascular endothelial growth factor (VEGF) is a potent angiogenic factor and was first described as an essential growth factor for vascular endothelial cells. VEGF is up-regulated in many tumors and its contribution to tumor angiogenesis is well defined. In addition to endothelial cells, VEGF and VEGF receptors are expressed on numerous non-endothelial cells including tumor cells. This review examines the relevance of VEGF signalling in non-endothelial cells and explores the probable mechanisms involved. The existence of autocrine VEGF signalling pathways in tumor cells is discussed in relation to anti-VEGF anti-tumor strategies now being developed.


Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), was originally described as an endothelial cell-specific mitogen.1 VEGF is produced by many cell types including tumor cells,2,3 macrophages,4 platelets,5 keratinocytes,6 and renal mesangial cells.7 The activities of VEGF are not limited to the vascular system; VEGF plays a role in normal physiological functions such as bone formation,8 hematopoiesis,9 wound healing,10 and development.11

Anti-VEGF strategies to treat cancers were designed to target the pro-angiogenic function of VEGF and thereby inhibit neovascularization. However, anti-VEGF therapies may have a dual effect since evidence is accumulating to support the existence of both paracrine and autocrine VEGF loops within tumors. It has been suggested that direct stimulation of tumor cells by VEGF may protect the cells from apoptosis and increase their resistance to conventional chemotherapy and radiotherapy.12 Chemotherapy and radiotherapy have been shown to increase VEGF within tumors,13 and this increased VEGF may in fact protect tumor cells from these interventions. Anti-VEGF therapies are therefore likely to target both the pro-angiogenic activity of VEGF and the anti-apoptotic/pro-survival functions of VEGF. Combination therapies using anti-VEGF therapies with chemotherapy and/or radiotherapy are effective against many types of tumor, possibly because in addition to angiogenesis inhibition, VEGF blockade renders tumor cells more susceptible to conventional treatment. This chapter reviews the evidence for VEGF autocrine signalling in non-endothelial cells, including tumor cells.

VEGF in the Cardiovascular System

VEGF plays an important role within the cardiovascular system. Recently VEGF expression has been demonstrated in cardiac myofibroblasts, non-endothelial cells with the morphological features of fibroblasts. Myofibroblasts play a major role in the growth, development and repair of normal tissue and are found at the site of infarction. RT-PCR, Northern blot and Western blot analysis confirmed the presence of mRNA and protein for VEGF, VEGFR-1 (VEGF receptor 1 also known as Flt-1, fms-like tyrosine kinase) and VEGFR-2 (KDR/Flk-1, Fetal liver kinase 1 is the murine homologue of human Kinase insert Domain-containing Receptor) in rat myofibroblasts isolated from heart infarcts.10 Coexpression of VEGF and its receptors on the myofibroblasts suggests that VEGF contributes to tissue remodelling at the site of infarction in an autocrine manner. VEGF may also play a role in atherosclerosis.14 Uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages initiates foam cell formation in atherosclerotic lesions.15 Oxidised LDL increased VEGF production by the U937 monocyte cell line14 and by macrophages.16 As VEGF also increases vascular permeability, VEGF production by foam cells and macrophages may aggravate atherosclerosis by enhancing vessel permeability to LDL.

VEGF and the Central Nervous System (CNS)

In the central nervous system (CNS) both positive (pro-migratory) and negative (anti-migratory) regulatory factors are essential for axonal guidance.17 Following prolonged exposure, Sema3A, a member of the semaphorin family, acts as an inhibitor of neuronal migration and induces neuronal cell death18 through the neuropilin-1 receptor (NP-1).19 However, in addition to Sema3A binding, NP-1 also acts as an additional receptor for VEGF165 isoform.20 The relationship between Sema3A and VEGF was explored in Dev cells,21 undifferentiated cells derived from a cerebellar medullablastoma that behave as pluripotential neural progenitor cells.22 NP-1 mRNA expression was detected in Dev cells by RT-PCR and in situ hybridization. Western blotting and immunohistochemical analysis confirmed that NP-1 was expressed on the cell surface. VEGF165 or anti-NP-1 antibody blocked the effect of Sema3A on these cells, suggesting that VEGF165 binds competitively to NP-1 to block Sema3A signalling. VEGF165 stimulated migration and promoted proliferation of the Dev cells whereas Sema3A binding inhibited cell migration and induced cell death. A recent paper has shown that the Sema3A/VEGF balance in breast carcinoma cells determines the chemotactic rate of the tumor cells towards conditioned NIH3T3 medium.23 Breast carcinoma cell lines with the lowest chemotatic rate have the highest ratio of Sema3A to VEGF. Overexpression of VEGF by tumor cells may enhance tumor cell migration via inhibition of the Sema3A/ NP-1 pathway.

Dev cells also expressed VEGFR-1 and blockade of VEGFR-1 reduced the inhibition of neuronal cell migration by Sema3A.21 It appears that both NP-1 and VEGFR-1 are required for Sema3A activity in these neuronal cells. NP-1 binds with high affinity to VEGFR-1.24 NP-1 has a very short intracellular domain and appears to require a coreceptor to transduce a signal20 thus, VEGFR-1 may serve as a coreceptor for NP-1 in the modulation of Sema3A signalling. Both VEGF121 and VEGF165 inhibited Sema3A-induced apoptosis, and at higher concentrations reduced apoptosis below basal levels indicating an additional neuroprotective effect.

VEGF is induced in many CNS pathologies where it may have a neuroprotective role. VEGF has a neurotrophic effect and enhances survival of Schwann cells,25 and protects hippocampal neurons from ischemic injury.26 Impaired VEGF induction in the spinal cord results in motor neuron degeneration.27 In addition, when cerebellar granule neurons (CGNs) were exposed to 5% hypoxia for 9 hours VEGF, VEGFR-1 and VEGFR-2 expression increased, and a neutralizing antibody to VEGF, DC 101, inhibited hypoxic preconditioning.28 Thus, VEGF autocrine or paracrine mechanisms appear to play a role in CGN cell survival following hypoxic preconditioning. In CGNs Akt (also known as Protein Kinase B/ PKB) was phosphorylated in response to VEGF and other studies have shown that VEGF stimulation in neurons is linked to PI3-K (Phosphatidylinositol 3'-kinase) and Akt activation and neuronal protection.29

VEGF and Its Role in Bone

Although cartilage is essentially an avascular tissue, neovascularization does occur in the growth plate of developing bone.30 VEGF is produced by hypertrophic chondrocytes in the growth plate where it co-ordinates extracellular matrix (ECM) remodelling, angiogenesis, and bone formation.8 VEGF is expressed in the synovial fluid of patients with rheumatoid arthritis. 31 and the cartilage of patients with osteoarthritis (OA).32 VEGF is found in normal cartilage but only osteoarthritic cartilage expresses the VEGF receptors, VEGFR-1, VEGFR-2, and NP-1. The level of VEGF in the culture media from OA chondrocytes was 3.3-fold greater than in media from normal chondrocytes. These results suggest that autocrine and/or paracrine signalling by VEGF may play a role in the pathology of osteoarthritis.

VEGF in Hematopoietic Cells and Hematological Malignancies

VEGF plays a central role in hematopoiesis.9 VEGF is expressed in the bone marrow and cytokine stimulation of hematopoietic stem cells (HSCs) greatly increases VEGF levels within these cells.33 Both VEGFR-1 and VEGFR-2 are expressed on HSCs,34,35 and VEGFR-2 has been identified as a positive functional marker for pluripotent HSCs.36 Elevated levels of VEGF and VEGFR-2 in young mice resulted in mobilization and recruitment of HSCs to the spleen during vascular remodelling.37 VEGF and VEGFR-2 gene knockout resulted in embryonic lethality due to impaired hematopoiesis and angiogenesis.38 VEGF inhibited maturation of antigen-presenting cells, dendritic cells and many other hematopoietic cells in vivo.39

HSC survival is controlled by an internal autocrine VEGF loop.40 VEGF is coexpressed with its receptors on hematopoietic cells, suggesting that autocrine mechanisms are involved in the regulation of hematopoiesis. The ability of VEGF-deficient HSCs to form colonies in vitro was dramatically reduced, with most cells developing characteristics associated with apoptosis.40

The survival of leukemic cells in serum-free conditions is also dependent on an autocrine VEGF/VEGFR-2 loop.41 In vivo studies using mice inoculated with human HL-60 leukemic cells revealed that both paracrine and autocrine VEGF signalling pathways were necessary for tumor cell survival.42 Neutralizing antibodies to murine VEGFR-2, which targeted only the paracrine VEGF signalling in the host endothelial cells, prolonged mouse survival but did not eradicate the disease. However, coadministration of the murine antibodies with antibodies that neutralized human VEGFR-2 and inhibited autocrine VEGF signalling in the human leukemic cells of the tumor had a synergistic effect on the survival of the inoculated mice. Blocking both the paracrine and autocrine VEGF loops within the tumor decreased leukemia invasiveness and resulted in prolonged remission in 40% of the animals. Neutralizing antibodies to human and murine VEGFR-1 had no notable effect in this model, demonstrating that autocrine and paracrine VEGF/VEGFR-2 signalling pathways play an important role in leukemia proliferation and engraftment in vivo.

VEGF and its receptors, VEGFR-1 and VEGFR-2, are overexpressed in many human hematopoietic tumor cell lines,43 and in bone marrow failure states such as chronic myleomonocytic leukemia and acute myelogenous leukemia.44,45 In a study of patients with multiple myeloma, VEGF, VEGFR-1 and VEGFR-2 were detected in 78% of the bone marrow samples examined. 46 VEGF production has been correlated with disease progression in patients with a variety of hematological malignancies.47

In addition to expressing VEGF receptors on the cell surface, some leukemic cells also produce a VEGF antagonist. Soluble Flt-1/VEGFR-1 (sFlt-1) has been detected in NALM-16 and P30/OHKUBO hematopoietic cell lines,48 derived from patients with ALL.49,50 RT-PCR analysis identified sFlt-1 mRNA expression in an additional fifteen hematopoietic cell lines. sFlt-1 purified from NALM-16 cells bound to VEGF with high affinity, and cell supernatants from NALM-16 and P30/OHKUBO cell lines reduced VEGF production in KATO-III cell cultures and inhibited VEGF-dependent growth of human umbilical vein endothelial cells (HUVECs).48

VEGF Signalling in Hematopoietic Cells

VEGF has been shown to inhibit nuclear factor kappa B (NFκB) activation in hematopoietic progenitor cells (HPCs).51 Tumor Necrosis Factor alpha (TNFα)-mediated activation of IκB kinase (IKK) and NFκB was substantially reduced in the presence of VEGF. The inhibitory effect of VEGF on NFκB activation was shown to be independent of VEGFR-1 and VEGFR-2 since SU5416, a potent inhibitor of VEGFR-1 and VEGFR-2, did not prevent VEGF-induced inhibition of NFκB. NFκB plays an important role in B-cell, T-cell and dendritic cell development.52,53 The physiological consequences of VEGF-mediated NFκB inactivation in these cells has yet to be elucidated.

Studies have shown that VEGF acts as an anti-apoptotic factor, protecting hematopoietic cells from programmed cell death.54 Both VEGF and VEGFR-2 are expressed in normal hematopoietic cells and in leukemic cells, and VEGF suppresses apoptosis induced by ionizing irradiation in both cell types.55 In addition, survival of CMK86 leukemia cells is increased by VEGF treatment in the presence of both etoposide and doxorubicin,56 with MCL1, a member of the Bcl-2 family of anti-apoptotic proteins, up-regulated in response to VEGF. Transfection of U937 myeloid leukemia cells with MCL1 decreased caspase 3 activity and increased cell viability in the presence of etoposide. When CMK86 cells were treated with VEGF, northern blot analysis revealed amplification of ZK7 mRNA.57 Transcription factor ZK7 is a member of the Krüppel family of genes58 and is associated with the apoptotic-signalling pathway. ZK7 mRNA was increased in multiple leukemia cell lines and numerous normal tissues following VEGF treatment. U937 cells transfected with constitutively expressed ZK7 survived irradiation doses 3-4 times higher than nontransfected cells, and the number of apoptotic cells among ZK7-transfected U937 cells was reduced significantly. 57 It is clear from these findings that VEGF protects hematopoietic cells from apoptosis and may directly contribute to tumorigenesis by prolonging the survival of leukemic cells, as well as indirectly via angiogenesis.

Evidence for VEGF Autocrine Signalling in Solid Tumors

Not only is VEGF a major player in leukemias and lymphomas, it is also highly expressed in a variety of solid malignant tumors,5961 and correlates with malignant disease progression.62,63 VEGF overexpression in tumors is associated with increased angiogenesis, proliferation and metastasis.64,65 A recently published study showed phosphorylated VEGFR-2 (KDR) expression in numerous solid tumors including three lung carcinomas, three breast carcinomas, three Non Hodgkin's lymphomas, and one melanoma.66 Not only did endothelial cells stain positive for phosphorylated VEGFR-2 but many other cell types including macrophages, fibroblasts, and myofibrils. In all cases both neoplastic cells and surrounding stromal cells stained positive for phosphorylated VEGFR-2. The patterns of staining varied within and between sections with some cells displaying strong cytoplasmic staining and others having stronger nuclear staining. This may be explained by the internalization and redistribution of KDR once it is phosphorylated. 67 Although similar patterns were observed in normal tissues staining was noticeably weaker than in tumors. Many other studies show that VEGFR-2 is expressed in a variety of nonmalignant tissues31,68,69 and tumors.7072

Ovarian carcinoma cells were the first non-endothelial tumor cells shown to express VEGFR-2.2 Primary tumors, metastases of ovarian tumors, and cell lines derived from ovarian carcinomas were examined for VEGF and VEGF receptor expression. Three of four ovarian carcinoma cell lines expressed VEGF, VEGFR-1 and VEGFR-2 mRNA. VEGF protein was detected in the culture media from these cell lines. VEGF mRNA was elevated in all primary tumors and metastases, with immunoreactivity for VEGF localized to clusters of tumor cells and patches of stromal matrix, demonstrating VEGF production in primary ovarian tumors and metastases. VEGF was also released into the surrounding stromal matrix, where it is likely to contribute to tumor growth and metastasis in a paracrine manner through angiogenesis and increased vascular permeability. VEGFR-1 and VEGFR-2 were expressed on some tumor cells, and VEGFR-2 was expressed in primary tumor sites raising the possibility of an autocrine VEGF loop in ovarian cancer regulation.

Pancreatic cancer is extremely aggressive with very poor prognosis.73 VEGF expression was demonstrated in pancreatic cancer,74,75 and both VEGF and VEGF receptor expression was elevated in pancreatic tumor cells in comparison to normal pancreatic tissue.3 VEGF colocalized with its receptors, VEGFR-1 and VEGFR-2, in many of the cancer cells. VEGF was detected in culture supernatants from all pancreatic cell lines tested.76 Coexpression of VEGF and its receptors in vivo and in vitro suggests a role for autocrine as well as paracrine stimulation of pancreatic tumor growth by VEGF. p44/42 MAPK was shown to mediate VEGF signalling via VEGFR-2, with c-fos transactivation as a possible downstream event.76

VEGF treatment increased DNA synthesis in Dan-G and AsPc-1 pancreatic cells. This effect was antagonized by an anti-VEGF neutralizing antibody and by soluble receptor fragments of VEGFR-1 and VEGFR-2. Transfection of truncated soluble forms of VEGFR-1 and VEGFR-2 disrupted the VEGF signalling pathway and significantly inhibited the growth of each cell type.76 VEGF did not stimulate VEGF-VEGFR signalling in normal pancreatic cells or in chronic pancreatitis, suggesting that this VEGF receptor system is a feature of transformed pancreatic cells and may contribute to the ‘angiogenic switch’ observed in the development of many tumors, promoting tumor progression.77 These observations provide evidence for the existence of a VEGF autocrine mitogenic loop in pancreatic cancer.

In another malignancy, mesothelioma, which responds poorly to treatment, a VEGF autocrine loop appears to directly stimulate tumor cell growth.78 As with ovarian cancer and pancreatic cancer, malignant pleural mesothelioma (MM) cells produce VEGF and express VEGFR-1 and VEGFR-2.79 In four MM cell lines treated with recombinant VEGF, VEGFR-1 and VEGFR-2 phosphorylation was observed and cell proliferation increased.78 VEGF, VEGFR-1 and VEGFR-2 expression was also observed in MM biopsies.78,80 No correlation was observed between serum VEGF levels and vascular density within tumors,78,79 suggesting that in addition to its angiogenic activity, VEGF may promote tumor growth by direct pro-survival effects in tumor cells.

Autocrine VEGF Signalling in Breast Cancer

VEGF expression in breast cancer is well documented and VEGF is produced by both macrophages and cancer cells in breast carcinoma.81,82 VEGF receptor expression has also been demonstrated on breast cancer cells.83,84 Dual staining for VEGF and its receptors on frozen sections from invasive breast carcinomas revealed their coexpression on breast cancer cells,84 suggesting that both paracrine and autocrine VEGF pathways play a role in breast cancer progression. VEGFR-1 and VEGFR-2 mRNA was identified in a number of breast cancer cell lines including T-47D, MCF7, MDA-MB-453, and MDA-MB-231, and these cancer cells were shown to respond to VEGF.85,86 VEGF stimulation increased the invasiveness of T-47D cells in the presence of fibronectin.85 ERK-1 and -2 were activated in response to VEGF in T-47D cells; PI3-K and its downstream target Akt were also activated. Since T-47D cells secrete VEGF87 it is likely that an autocrine VEGF loop exists within these cells. PI3-K activation has often been implicated in cellular invasion88 and may be the signalling mechanism in T-47D cells that mediates VEGF-induced cell invasion.

VEGF Stimulates Breast Cancer Invasion

Anti-sense oligonucleotide inhibition of VEGF resulted in a sixty-five percent decrease in Matrigel invasion by MDA-MB-231 cells.89 Inhibition of invasion was reversed by the addition of recombinant VEGF demonstrating that cell invasion is a specific response to VEGF. Matrigel invasion by the highly invasive MDA-MB-435 cells was also inhibited by the anti-sense oligonucleotides. There are conflicting reports on VEGF receptor expression on the MDA-MB-231 and MDA-MB-435 cells but both cell lines have been shown to express NP-1 and VEGFR-1. Different results from studies of VEGF receptor expression may be due to differences in antibodies and techniques employed.85,89 VEGF-mediated invasion of these breast carcinoma cell lines was shown to be NP-1-dependent.89 Further investigations revealed that VEGF-mediated invasion was completely blocked by pertussis toxin, indicating that G-protein, Gαi, is essential to this pathway. The Gαi-coupled chemokine receptor, CXCR4, was previously shown to be expressed on breast cancer cells and to promote metastasis.90 CXCR4 expression on MDA-MB-231 and MDA-MB-435 cells was increased by VEGF, and anti-sense oligonucleotides to VEGF prevented cancer cell migration towards the CXCR4 ligand, SDF-1 (Stromal cell derived factor-1).89 Together this implies that CXCR4-dependent migration and invasion of these breast cancer cells requires VEGF. This was confirmed when a CXCR4-neutralizing peptide was shown to inhibit Matrigel invasion of the cells by seventy-five percent. Since the CXCR4 ligand, SDF-1, is found in tumor stroma and in tissues such as lymph and lung,90 the primary targets for breast cancer metastasis, VEGF-mediated CXCR4 expression may be important in breast cancer invasion and migration. Blockade of this pathway using anti-VEGF strategies and/or CXCR4-neutralizing peptides may help prevent tumor spread and metastasis in breast cancer patients.

VEGF Signalling in Tumor Cells

Not only does VEGF have a direct influence on breast cancer invasion and migration, it has also been shown to act as a survival factor for metastatic breast carcinoma cells.86,91 Reduced VEGF expression induces apoptosis in these cells. Anti-sense VEGF oligonucleotides not only reduce VEGF expression by MDA-MB-231 and MDA-MB-435 cells but induce cell death, seen as a four-fold increase in annexin V staining (a marker for early apoptosis) and a three-fold increase in propidium iodide staining in transfected cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assays confirmed that this increased cell death was due to apoptosis.92 VEGF stimulation of NP-1 maintained elevated levels of PI3-K activity in MDA-MB-231 cells and inhibition of this PI3-K activity induced apoptosis.92

Studies in our own laboratory have shown that VEGF protects both human and murine breast carcinoma cells from apoptosis.86 Additional studies in our laboratory have identified NP-1 as the receptor involved in VEGF mediated protection of these breast cancer cells.93 Although VEGFR-2 mRNA was identified in 4T1 and MDA-MB-231 cells, the corresponding protein was not found. However, NP-1 receptor protein was expressed on both cancer cell lines. Both cell lines were treated with peptides which blocked NP-1 or VEGFR-2. Treatment of these cells with the anti-NP-1 peptide induced apoptosis but the anti-VEGFR-2 peptide had no effect. Confocal microscopy revealed that only the anti-NP-1 peptide bound to the cancer cells (Fig. 1). This evidence confirms a role for the NP-1 receptor in VEGF-mediated breast cancer cell protection from apoptosis.

Figure 1. Confocal Microscopy showing FITC-labelled anti-NP-1 peptide binding to MDA-MB-231 (A) and 4T1 (B) mammary adenocarcinoma cells, (original magnification x 400).

Figure 1

Confocal Microscopy showing FITC-labelled anti-NP-1 peptide binding to MDA-MB-231 (A) and 4T1 (B) mammary adenocarcinoma cells, (original magnification x 400). Images are representative of a scan zoom of between 1 to 4.2-fold.

The α6β4 integrin is associated with progression of many solid tumors and with poor prognosis. 94 Activation of α6β4 integrin promotes breast carcinoma cell survival.91,95 When MDA-MB-435 cells, which lack α6β4, were transfected with α6β4 their resistance to cell death increased. VEGF expression was also increased in these transfected cells, and their resistance to cell death was abrogated with the addition of VEGF anti-sense oligonucleotide. α6β4 was shown to increase VEGF translation through activation of the PI3-K/Akt pathway. Activation of this pathway induced phosphorylation of the transcriptional repressor, 4E-binding protein (4E-BP1), by mammalian target of rapamycin (mTOR), leaving it unable to associate with eukaryotic translation initiation factor 4E (eIF-4E). eIF-4E was then capable of initiating the translation of proteins such as VEGF. Transfection of the cells with eIF-4E anti-sense oligonucleotide significantly reduced the level of VEGF protein production in α6β4-transfected MDA-MB-435 cells. The PI3-K inhibitor, LY294002, and the mTOR inhibitor, rapamycin, had the same effect. Levels of apoptosis were greatly increased following these treatments, demonstrating the importance of the PI3K/mTOR pathway in regulating VEGF expression (Fig. 2). This study showed that the α6β4 integrin increased VEGF protein translation and thus protected breast carcinoma cells from apoptosis.

Figure 2. Diagram adapted from Bachelder RE, Ribick MJ, Marchetti A et al.

Figure 2

Diagram adapted from Bachelder RE, Ribick MJ, Marchetti A et al. p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB. J Cell Biol. 1999;147:1063-72.©Rockefeller University Press.

Anti-Angiogenic Therapy

With the confirmation that VEGF plays a major role in angiogenesis within tumors a variety of anti-VEGF strategies to inhibit tumor growth and angiogenesis have been designed. Monoclonal antibodies (mAb) directed against VEGF have been tested in phase I trials.96,97 In phase II trials humanized anti-VEGF mAb stabilized breast cancer and induced remission in patients with relapsed metastatic breast carcinoma.98 Tyrosine kinase inhibitors to target the VEGF receptors have shown promise, and phase I trials have been initiated.99,100 Studies using ribozymes targeting VEGF mRNA have also been conducted and have entered clinical trials.101,102

The success of these anti-VEGF methodologies may be due not only to the inhibition of angiogenesis, but also to the inhibition of paracrine/autocrine VEGF signalling in the tumor cells themselves.2,84 It is likely that VEGF produced by both tumor cells and stromal cells within tumors binds to VEGF receptors on both the endothelial and neoplastic cells. In addition, there is substantial data in support of the presence of autocrine VEGF loops on tumor cells themselves,42,70,76 thus tumor cells are likely to mediate their own survival, invasiveness and migration through VEGF pathways.

Development of anti-VEGF strategies to target angiogenesis and VEGF pathways in tumors should prove very effective in preventing the progression of many tumor types. However, with many other pro-angiogenic growth factors, such as basic fibroblast growth factor (bFGF) and transforming growth factor beta (TGFβ) also elevated within tumors, blockade of VEGF alone is unlikely to prove universally effective. Chemotherapy and radiotherapy both increase VEGF expression13 and may therefore increase tumor resistance. Anti-VEGF treatments should block this therapy-induced resistance and VEGF-induced tumor cell survival, as well as inhibiting angiogenesis. Anti-VEGF treatments used in combination with conventional chemotherapy and radiotherapy should dramatically improve treatment for cancer patients, with some initial studies already providing promising results.13,103,104 Studies in our own laboratory have shown that combining anti-NP-1 peptide with taxotere or cisplatin increases the anti-tumor effects of these chemotherapeutic agents (Byrne AM, Bouchier-Hayes DJ, Harmey JH et al unpublished data).


Funded under the Programme for Research in Third Level Institutions (PRTLI), administered by the HEA and Health Research Board Grant RP182/2000.


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