The Role of Vascular Endothelial Growth Factor in Angiogenesis

Ferrara, Napoleone; Gerber, Hans‐Peter

doi:10.1159/000046610

Cited by 396 publications

(303 citation statements)

References 68 publications

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“…Now it is recognised as a key factor required for tumour neoangiogenesis (Ferrara and Gerber, 2001). Currently, several inhibitors of the VEGF-signaling pathway have entered clinical trials to test their efficacy as antiangiogenic drugs (reviewed in Verheul and Pinedo, 2003).…”

Section: Discussionmentioning

confidence: 99%

Real-time PCR of CD146 mRNA in peripheral blood enables the relative quantification of circulating endothelial cells and is an indicator of angiogenesis

et al. 2005

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Angiogenesis is a fundamental process in tumour growth and metastatic dissemination. Possible surrogate markers for tumour angiogenesis are the amounts of circulating endothelial cells (CEC) in peripheral blood and the plasma concentration of vascular endothelial growth factor (VEGF). We tested the suitability of real-time PCR for CD146, an endothelial cell-specific antigen, to quantify CEC numbers in comparison to a flow cytometry quantification. Real-time PCR of CD146 mRNA showed high sensitivity and linearity for the quantification of cultivated primary endothelial cells added in different amounts to blood samples. Circulating endothelial cell numbers were quantified in peripheral blood samples of breast cancer patients and healthy controls by four-colour flow cytometry analysis and CD146 real-time PCR, and VEGF plasma concentrations were measured by ELISA. The amounts of CEC detected with both methods correlated significantly and CEC numbers were significantly increased in newly diagnosed breast cancer patients compared to healthy controls. Vascular endothelial growth factor concentrations correlated significantly with CEC numbers, but there was no significant difference in VEGF levels between breast cancer patients and healthy controls indicating that VEGF plasma levels cannot be used as surrogate marker for tumour angiogenesis. Taken together, the quantification of CEC by CD146 realtime PCR showed equivalent results to the flow cytometry analysis. Thus, CD146 real-time PCR may be an easy and reliable approach to quantify CEC in peripheral blood samples and could facilitate the integration of CEC measurements in clinical studies exploring the efficacy of antiangiogenic therapies.

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Section: Discussionmentioning

confidence: 99%

Real-time PCR of CD146 mRNA in peripheral blood enables the relative quantification of circulating endothelial cells and is an indicator of angiogenesis

et al. 2005

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“…VEGF is a pro-angiogenic and vasculogenic growth factor involved in many physiological functions such as bone formation, hematopoiesis, and wound healing (177,178). Furthermore, its association with tumor growth and vascular disease is well documented (166,179,180).…”

Section: Vascular Endothelial Growth Factor (Vegf)mentioning

confidence: 99%

Hormonal regulation of immune modulators in human breast tissue

Morad¹

2015

Linköping University Medical Dissertations

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Breast cancer is the most common form of cancer and the second leading cause of malignancy-associated death in women worldwide. Estrogens are the main sex hormones in women. They are essential for the development and function of normal breast mammary glands; however, prolonged exposure to estrogens increases the risk of breast cancer development and progression. Approximately two-thirds of all breast cancer patients are positive for estrogen receptor (ER), but only 50% of those cases can benefit from antiestrogen therapy. In this thesis we investigated the effects of estrogen, diet modification, and anti-estrogen drugs on several immune modulators in normal human breast tissue. We used the microdialysis technique to sample the immune modulators in situ in normal human breast tissue, in malignant breast tissue, and in tumor tissue from both the immune competent mice with murine breast cancer and immune deficient mice bearing human breast tumors. Furthermore, we also used ex vivo culture of normal breast tissue and in vitro cell culture of breast cancer cell lines. A combined cell culture (co-culture) of breast cancer cell lines, together with the primary mature adipocytes, was also used in this thesis. In Paper I and Paper II, our results suggested that estrogen exerted both proinflammatory and pro-tumorigenic effects in normal human breast tissue. Estradiol increased extracellular interleukin-1β (IL-1β) and leptin levels and decreased IL-1Ra and adiponectin levels in normal human breast tissue. In contrast, tamoxifen decreased IL-1β and leptin levels and increased IL-1Ra and adiponectin levels, shifting the environment towards an antiinflammatory and antitumorigenic state. Diet modification with flaxseed for 30 days also increased IL-1Ra levels, creating an anti-inflammatory environment in normal breast tissue. In the breast cancer tissue, we found that extracellular IL-1β levels and leptin levels were significantly higher, whereas adiponectin levels were significantly lower, compared with normal adjacent breast tissue, which suggested a more proinflammatory state. In the third paper, our in vivo investigation of normal breast tissue revealed significant correlations between vascular endothelial growth factor (VEGF) and leptin, IL-1β and leptin, and between VEGF and IL-1β. No correlations were found in the abdominal subcutaneous (s.c.) fat tissue. Our in vitro inhibition experiments suggested that VEGF was a potent regulator of leptin, but that leptin was not a potent regulator of VEGF. Co-culture per se altered the release of VEGF and leptin and enhanced the effects of estradiol, compared with monocultures of the included cell types. In conclusion, the results presented in this thesis will increase the overall understanding of the role of estrogens in breast cancer, which may be useful in future treatment studies

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“…Vascular Endothelial Growth Factor (VEGF) is a hypoxiainducible secreted homodimeric glycoprotein of 45,000 Da that plays a major role in developmental (Ferrara and Bunting, 1996;Ferrara and Davis-Smyth, 1997;Ferrara and Gerber, 2001;Ferrara et al, 2003) and pathological angiogenesis (Plate et al, 1992;Dvorak, 2000;Marti et al, 2000;Greenberg and Jin, 2005;Lafuente et al, 2006;Ruiz de Almodovar et al, 2009). In pathological conditions, VEGFR mediates an antiapoptotic effect through Phosphoinositide 3-kinase (PI3K)-dependent signaling pathways that promote the survival of endothelial cells induced by VEGF (Jin et al, 2000(Jin et al, , 2001Geretti et al, 2008) and is related to the blood-brain barrier (BBB) opening in brain injury Lafuente et al, 2006;Ortuzar et al, 2010).…”

Section: Introductionmentioning

confidence: 99%