Glioblastoma-derived Leptin Induces Tube Formation and Growth of Endothelial Cells: Comparison with VEGF Effects

Ferla, Rita; Bonomi, Maria; Ötvös, László; Surmacz, Eva

doi:10.1186/1471-2407-11-303

Cited by 53 publications

(56 citation statements)

References 72 publications

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“…Using our in vitro co-culture cell model, it was found that leptin did not alter tubule formation when VEGF was lacking but, addition of complete EGM-2 medium supplemented with VEGF did further increase tubule formation. These results are in contrast with the pro-angiogenic effect of leptin (10, 100 and 1000 ng/ml) on endothelial tube formation previously described in single-cell conditions using HUVECs and a matrigel matrix (25)(26)(27) or, HUVECs and a collagen I matrix (28); suggesting that the system used for studying angiogenesis in vitro might be critical even if the use of in vitro co-culture systems are more closely related to in vivo conditions. This study is also the first to use an in vitro endothelial cell/fibroblast co-culture cell system to investigate the effect of combining exogenous cytokines/adipokines.…”

Section: Discussioncontrasting

confidence: 96%

Circulating levels of angiogenesis-related growth factors in breast cancer: A study to profile proteins responsible for tubule formation

et al. 2017

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Abstract. The present study exploited a versatile in vitro endothelial cell/fibroblast co-culture cell system to investigate the association between angiogenesis and breast cancer by comparing the capacity of plasma from women with breast cancer and age-matched controls, to influence tubule formation and modulate angiogenesis in vitro, and to identify plasma circulating factors which might be responsible. Plasma from women with breast cancer (n=8) (added on day 7 after co-culture establishment) significantly increased tubule formation by 57% (P<0.01) when compared to cultures grown in culture medium lacking in vascular endothelial growth factor (VEGF) and fetal bovine serum (FBS), whereas plasma from controls (n=8) did not. Higher levels of VEGF, tumour necrosis factor-α (TNFα) and interleukin (IL)-6, but not leptin, were observed in plasma samples of the breast cancer group compared to the control group (n=20 in each group). In independent experiments, the effects of VEGF, TNFα, IL-6 and leptin were assessed and it was found that tubule formation was differentially affected whether these inflammatory cytokines or adipokines were added individually or in combination to the co-culture system. Using Proteome Profiler human angiogenesis array kits, 12 out of 55 angiogenesis-related proteins were differentially expressed in plasma from the breast cancer group compared to the control group. Pro-angiogenic proteins included: amphiregulin, artemin, coagulation factor III, fibroblast growth factor (FGF) acidic, GDNF, IL-8, macrophage inflammatory protein (MIP)-1α, platelet derived growth factor-AB/platelet derived growth factor-BB (PDGF-AB/PDGF-BB) and VEGF, whereas anti-angiogenic proteins were: angiopoietin-2, serpin F1 and serpin B5. In addition, FGF acidic was further identified as differentially expressed, with increased expression, when plasma samples from the normal and cancer groups, which induced an increase in tubule formation, were compared to one another. In conclusion, the present study identified angiogenesis-related proteins circulating in the serum of women with breast cancer that are likely to facilitate the growth and metastasis of breast cancer, in part through their influence on tubule formation, and, therefore, may be potential targets for new cancer therapies.

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Section: Discussioncontrasting

confidence: 96%

Circulating levels of angiogenesis-related growth factors in breast cancer: A study to profile proteins responsible for tubule formation

et al. 2017

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“…In addition to increasing the proliferation of endothelial cells [27,28,45,85], leptin also caused the proliferation of fibroblasts [86] and diverse malignant cells. In these cells, leptin induced pro-angiogenic, inflammatory and mitogenic actions that were reinforced through crosstalk with several cytokines/growth factors [11,31,87].…”

Section: Leptin’s Impact On Tumor Angiogenesismentioning

confidence: 99%

Leptin’s Pro-Angiogenic Signature in Breast Cancer

Gonzalez-Perez

Lanier

Newman

2013

Cancers

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Obesity is linked to increased incidence of breast cancer. The precise causes and mechanisms of these morbid relationships are unknown. Contradictory data on leptin angiogenic actions have been published. However, accumulating evidence would suggest that leptin’s pro-angiogenic effects in cancer play an essential role in the disease. Leptin, the main adipokine secreted by adipose tissue, is also abnormally expressed together with its receptor (OB-R) by breast cancer cells. Leptin induces proliferation and angiogenic differentiation of endothelial cells upregulates VEGF/VEGFR2 and transactivates VEGFR2 independent of VEGF. Leptin induces two angiogenic factors: IL-1 and Notch that can increase VEGF expression. Additionally, leptin induces the secretion and synthesis of proteases and adhesion molecules needed for the development of angiogenesis. Leptin’s paracrine actions can further affect stromal cells and tumor associated macrophages, which express OB-R and secrete VEGF and IL-1, respectively. A complex crosstalk between leptin, Notch and IL-1 (NILCO) that induces VEGF/VEGFR2 is found in breast cancer. Leptin actions in tumor angiogenesis could amplify, be redundant and/or compensatory to VEGF signaling. Current failure of breast cancer anti-angiogenic therapies emphasizes the necessity of targeting the contribution of other pro-angiogenic factors in breast cancer. Leptin’s impact on tumor angiogenesis could be a novel target for breast cancer, especially in obese patients. However, more research is needed to establish the importance of leptin in tumor angiogenesis. This review is focused on updated information on how leptin could contribute to tumor angiogenesis.

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“…Leptin produced by adjacent adipose might provide a local increased level of stimulation to tumors 60–62 , suggesting the presence of tumor associated adipose represents an important microenvironmental influence. Although normally secreted from adipose, self-sufficiency for leptin has recently been shown to be secreted from glioblastoma and breast cancer cells 63, 64 . Further, intra-tumoral mRNA leptin levels in patients with high leptin receptor levels correlated with decreased relapse-free survival 55 .…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: Adiponectin and Leptin Signaling in Cancer

VanSaun

2013

Clinical Cancer Research

207

156

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The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiological studies have highlighted associations between increased serum leptin levels and increased tumor growth, while adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify areas of intervention and facilitate advancement in the field.

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Glioblastoma-derived Leptin Induces Tube Formation and Growth of Endothelial Cells: Comparison with VEGF Effects

Cited by 53 publications

References 72 publications

Circulating levels of angiogenesis-related growth factors in breast cancer: A study to profile proteins responsible for tubule formation

Circulating levels of angiogenesis-related growth factors in breast cancer: A study to profile proteins responsible for tubule formation

Leptin’s Pro-Angiogenic Signature in Breast Cancer

Molecular Pathways: Adiponectin and Leptin Signaling in Cancer

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