Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer

Brown, Lawrence F.; Berse, Brygida; Jackman, Robert W.; Tognazzi, Kathi; Guidi, Anthony J.; Dvorak, Harold F.; Senger, Donald R.; Connolly, James L.; Schnitt, Stuart J.

doi:10.1016/0046-8177(95)90119-1

Cited by 817 publications

(674 citation statements)

References 27 publications

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“…It was found to be expressed in normal human tissues including liver, kidney, adrenal glands, lung and stomach (Ferrara and Davis-Smyth, 1997). In the study of Brown et al, (1993), VEGF-A mRNA was detected in the breast cancer cells whereas the corresponding proteins were found in both tumour cells and the ECs, indicating that VEGF-A is secreted by tumour cells then undergoes processing in the ECM to be entrapped by the receptors on the surface of the ECs. In the current report, and in agreement with such previous findings, positive staining for VEGF-A was detected in the ECs, in the normal epithelial mammary duct cells as well as in the tumour cells.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

et al. 2007

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Vascular endothelial cell growth factors (VEGF)-A, -C and -D have potent angio and lymphangiogenic functions in experimental models, although their role in the progression of human breast cancer is unclear. The aims of the current study were to examine the relationship between the expression of the aforementioned growth factors with the angio and lymphangiogenic characteristics of breast cancer, and to assess their suitability as potential prognostic factors. Paraffin-embedded sections of 177 primary invasive breast cancer, with complete clinical follow-up information for 10 years, were stained for VEGF-A, -C, -D, podoplanin and CD34 using standard immunohistochemical approaches. The expression of the growth factors was correlated with clinicopathological criteria and patients' survival. Lymph vessel density (LVD) and microvessel density (MVD) were assessed and correlated with expression of the growth factors. Vascular endothelial cell growth factor-A, -C and -D were highly expressed in 40, 37 and 42% of specimens, respectively. High expression of VEGF-A and -C, but not of -D, was associated with a higher LVD (P ¼ 0.013 and P ¼ 0.014, respectively), a higher MVD (Po0.001 and P ¼ 0.002, respectively), the presence of lymph node metastasis (Po0.001 and Po0.001, respectively), distant metastasis (P ¼ 0.010 and P ¼ 0.008, respectively) and a shorter Overall Survival (P ¼ 0.029 and 0.028, respectively). In conclusion, breast cancers that express high levels of VEGF-A and -C are characterised by a poor prognosis, likely through the induction of angio and lymphangiogenesis. Examination of expression of VEGF-A and -C in breast cancer may be beneficial in the identification of a subset of tumours that have a higher probability of recurrence and metastatic spread.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

et al. 2007

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“…Similar findings have been published for tumour blood vessels. These studies showed by immunohistochemistry that vascular endothelial cells stained strongly for VEGF but did not express detectable levels of VEGF mRNA by in situ hybridization, indicating that immunohistochemical staining of tumour vessels with antibodies to VEGF peptides reflects binding of VEGF secreted by adjacent cells (Duorak et al, 1991;Brown et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Enhanced expression of vascular endothelial growth factor in metastatic melanoma

Salvén

Heikkilä²,

Joensuu³

1997

Br J Cancer

139

104

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Summary Tumour growth is dependent on angiogenesis. Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific cytokine. VEGF is angiogenic in vivo and it also acts as a vascular permeability factor. VEGF is overexpressed in many skin disorders characterized by angiogenesis and increased vascular permeability. We Folkman, 1996). One such stimulus is vascular endothelial growth factor (VEGF), which is a secreted, dimeric 46-kDa protein active as an endothelial cellspecific mitogen and as a vascular permeability factor. VEGF expression has been detected in a large variety of malignant human tumours, and it has been concluded that VEGF has an important role in tumour biology and in the process of tumour angiogenesis (reviewed in Dvorak et al, 1995;Ferrara, 1995). VEGF mRNA has also been detected in metastatic melanoma cells in cerebral melanoma metastases (Hatva et al, 1995).Progression of melanoma is supposed to be associated with an angiogenic response, and several histological studies have shown an increase in vascular structures in malignant melanoma, which is not the case in common naevocellular naevi (reviewed in Denijn and Ruiter, 1993). Expression of VEGF in mouse VEGF cDNAtransected melanoma cells is associated with increased tumour growth, angiogenesis and experimental metastasis in vivo in a nude mouse model (Claffey et al, 1996). This suggests a role for VEGF as a positive regulatory stimulus in angiogenesis, progression and dissemination of malignant melanoma. The aim of the Received 30 October 1996 Revised 13 March 1997 Accepted 20 March 1997 Correspondence to: P Salven present study was to investigate the expression of VEGF in normal dermis, naevocellular naevi and in primary and metastatic melanoma and to study the relationship between VEGF expression and tumour microvessel density, patient survival and other clinicopathological variables. MATERIALS AND METHODS Patients and tissue samplesThe study includes six patients with a common naevocellular naevus and 55 randomly selected patients with histologically diagnosed malignant melanoma treated with surgery and chemotherapy or chemoimmunotherapy in Helsinki University Central Hospital, during the time period from 1989 to 1995. The prognostic significance of VEGF expression was investigated in a series of 33 patients with a lymph node metastasis from malignant melanoma. Twenty of the patients with metastatic melanoma were male and 13 were female; age at the time of surgery ranged from 30 to 84 years (median 56 years). All patients with metastatic disease were followed up until death or for at least 4 years, as calculated from the surgical removal of the lymph node metastasis. The overall 2-year survival was 35% and 4-year survival 24%.Determination of VEGF expression VEGF expression was determined using a mouse monoclonal antihuman VEGF antibody (MAB293, IgG2b, R&D Research, MN, USA) raised against the 165 amino acid species of the polypeptide. The 5-,um frozen sections were rehydrated, incubated for 30 min in 0.3% hydrogen...

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“…The disruption of the vascular basement membrane may facilitate extravasation of endothelial cells, leading to the formation of neovascular sprouts, as well as intravasation of tumour cells into the vessels. The overexpression of the members of VEGF, FGF and IGF families, as well as their receptors, has been reported in a significant percentage of breast tumours (Peyrat et al, 1992;Brown et al, 1995;Yee, 1998). Moreover, the overexpression of human epidermal growth factor receptor-2 (ErbB-2/HER-2), which is associated with poor survival in several human malignancies including breast cancers, is closely correlated with increased angiogenesis and expression of VEGF (reviewed in Kumar and Yarmand-Bagheri, 2001).…”

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confidence: 99%

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

et al. 2004

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The overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and insulin-like growth factors (IGFs) plays a role in the migration and proliferation of endothelial cells in many cancers. Consequently, we investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonists on the expression of these angiogenic factors, the activities of matrix metalloproteinases (MMPs)-2 and -9, as well as the vascular density in MDA-MB-435 human oestrogenindependent breast cancers. Nude mice bearing orthotopic xenografts of MDA-MB-435 breast cancers were treated with bombesin/ GRP antagonists for 6 weeks. Daily administration of 20 mg of RC-3095 or 10 mg of RC-3940-II significantly decreased the weight of MDA-MB-435 cancers by 44 and 53%, respectively. The inhibition of tumour growth was associated with a substantial reduction in the expression of mRNA and protein levels of basic fibroblast growth factor (bFGF), IGF-II and VEGF-A in the tumours. Both bombesin/GRP antagonists significantly decreased the vessel density of the tumours by about 37%, as shown by immunohistochemical detection of vessels on tumour slides. Gelatinolytic activities, detected by zymography, revealed a 33 -46% reduction in MMP-9 activity after the treatment with either antagonist. In vitro studies revealed that MDA-MB-435 cells secrete bFGF, IGF-II and VEGF-A, and the secretion of these factors is inhibited by RC-3095 and RC-3940-II. This study demonstrates the antiangiogenic effect of bombesin/GRP antagonists RC-3095 and RC-3940-II, and underscores their possible therapeutic application for treatment of breast cancers.

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Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer

Cited by 817 publications

References 27 publications

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

Enhanced expression of vascular endothelial growth factor in metastatic melanoma

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

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