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Leptin’s Pro-Angiogenic Signature in Breast Cancer  [PDF]
Ruben Rene Gonzalez-Perez,Viola Lanier,Gale Newman
Cancers , 2013, DOI: 10.3390/cancers5031140
Abstract: 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.
Notch regulates the angiogenic response via induction of VEGFR-1
Yasuhiro Funahashi, Carrie J Shawber, Marina Vorontchikhina, Anshula Sharma, Hasina H Outtz, Jan Kitajewski
Vascular Cell , 2010, DOI: 10.1186/2040-2384-2-3
Abstract: Vascular endothelial growth factor-A (VEGF-A) is essential to the multistep process of vascular development, and proper vessel formation in a variety of settings is exquisitely sensitive to levels of VEGF-A [1-4]. VEGF-A signals through two receptor tyrosine kinases: VEGFR-1 (flt1) and VEGFR-2 (flk1), while placenta growth factor (PlGF) signals exclusively through VEGFR-1. Both VEGF-A and PlGF induce endothelial cell proliferation, survival, and migration [3,5,6]. The role of VEGFR-1 in angiogenesis has largely been defined in terms of its opposition to VEGFR-2. VEGFR-2 is considered the primary VEGF-A receptor that drives angiogenesis, while VEGFR-1 has high binding affinity for VEGF-A but weak kinase activity. Thus, VEGFR-1 is thought to function mainly as a decoy receptor that sequesters VEGF-A [7-11]. This concept is supported by analysis of mouse models where deletion of flt1 led to vessel overgrowth and disruption of vascular patterning [12]. In addition, mice expressing a mutant allele of flt1 that lacks the tyrosine kinase domain (flt1TK-/-) did not exhibit the vascular patterning defects seen in flt1-/-mice, suggesting that in embryonic development, the kinase activity of VEGFR-1 was dispensable and that its predominant function is via its high affinity binding to VEGF-A [9]. Despite this, a positive function for VEGFR-1 in angiogenesis has been demonstrated in a variety of settings. flt1TK-/- mice displayed defects in tumor vessel formation and metastasis [13,14], and inhibition of VEGFR-1 led to defects in neovascularization of the eye [15]. The signaling pathways that regulate VEGFR-1 expression in endothelial cells remain unclear.Notch, a receptor that functions in cell fate decisions, has been shown to be downstream of VEGF-A in endothelial sprouting [16,17] and arterial specification [18,19]. The Notch proteins are highly conserved trans-membrane receptors that are required for normal embryonic development. In mammals, there are four Notch proteins (N
Notch-EGFR/HER2 Bidirectional Crosstalk in Breast Cancer  [PDF]
Andrew T. Baker,Andrei Zlobin
Frontiers in Oncology , 2014, DOI: 10.3389/fonc.2014.00360
Abstract: The Notch pathway is a well-established mediator of cell-cell communication that plays a critical role in stem cell survival, self-renewal, cell fate decisions, tumorigenesis, invasion, metastasis, and drug resistance in a variety of cancers. An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family which consists of HER-1, -2, -3, and -4. Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease. Continued assessment of interplay between these two critical signaling networks uncovers new insight into mechanisms used by HER-driven cancer cells to exploit Notch as a compensatory pathway. The compensatory Notch pathway maintains HER-induced downstream signals transmitted to pathways such as Mitogen Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3K), thereby allowing cancer cells to survive molecular targeted therapies, undergo EMT, and increase cellular invasion. Uncovering the critical crosstalk between the HER and Notch pathways can lead to improved screening for the expression of these oncogenes enabling patients to optimize their personal treatment options and predict potential treatment resistance. This review will focus on the current state of crosstalk between the HER and Notch receptors and the effectiveness of current therapies targeting HER-driven cancers.
Integrin β3 Crosstalk with VEGFR Accommodating Tyrosine Phosphorylation as a Regulatory Switch  [PDF]
Xiaoxia Z. West, Nahum Meller, Nikolay L. Malinin, Lalit Deshmukh, Julia Meller, Ganapati H. Mahabeleshwar, Malory E. Weber, Bethany A. Kerr, Olga Vinogradova, Tatiana V. Byzova
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031071
Abstract: Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between β3 integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of β3 and VEGFR2. Specifically, the membrane-proximal motif around 801YLSI in VEGFR2 mediates its binding to non-phosphorylated β3CT, accommodating an α-helical turn in integrin bound conformation. We also show that Y747 phosphorylation of β3 enhances the above interaction. To demonstrate the importance of β3 phosphorylation in endothelial cell functions, we synthesized β3CT-mimicking Y747 phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y747 but not F747 significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y747 peptide exhibits inhibitory effect only in WT but not in β3 integrin knock-out or β3 integrin knock-in cells expressing β3 with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2.
Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis
Elena Fiorio, Anna Mercanti, Marianna Terrasi, Rocco Micciolo, Andrea Remo, Alessandra Auriemma, Annamaria Molino, Veronica Parolin, Bruno Di Stefano, Franco Bonetti, Antonio Giordano, Gian Cetto, Eva Surmacz
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-305
Abstract: Expression of ObR, HER2, phospo-HER2 was assessed by immonoblotting. Physical interactions between ObR and HER2 were probed by immunoprecipitation and fluorescent immunostaining. Expression of leptin and ObR in breast cancer tissues was detected by immunohistochemistry (IHC). Associations among markers studied by IHC were evaluated using Fisher's exact test for count data.HER2 and ObR were coexpressed in all studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. In 59 breast cancers, the presence of leptin was correlated with ObR (the overall association was about 93%). This result was confirmed both in HER2-positive and in HER2-negative subgroups. The expression of leptin or ObR was numerically more frequent in larger (> 10 mm) tumors.Coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments.Recent epidemiological and clinical data confirmed that obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive breast tumors and resistance to certain anti-breast cancer treatments [1-4]. The molecular mechanisms of this link are not clear, but several studies in animal and cellular models suggested that excess body weight could promote breast cancer through increased production of an adipocyte-derived hormone leptin [5-7]. The primary function of leptin is to regulate energy balance and food intake by acting in the brain, but the hormone also plays an important role in peripheral organs, modulating fertility, lactation, and immune response [8,9]. Leptin levels in humans correlate with adiposity and are usually higher in females than in males [8].Leptin action is mediated through the transmembrane leptin receptor ObR [10]. The human ObR can be expressed as at least four isoforms with different COOH-terminal cytoplasmic domains [11]. The full (long)
Accelerated Coronary Angiogenesis by Vegfr1-Knockout Endocardial Cells  [PDF]
Zheng Zhang, Bin Zhou
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070570
Abstract: During mouse heart development, ventricular endocardial cells give rise to the coronary arteries by angiogenesis. Myocardially-derived vascular endothelial growth factor-a (Vegfa) regulates embryonic coronary angiogenesis through vascular endothelial growth factor-receptor 2 (Vegfr2) expressed in the endocardium. In this study, we investigated the role of endocardially-produced soluble Vegfr1 (sVegfr1) in the coronary angiogenesis. We deleted sVegfr1 in the endocardium of the developing mouse heart and found that this deletion resulted in a precocious formation of coronary plexuses. Using an ex vivo coronary angiogenesis assay, we showed that the Vegfr1-null ventricular endocardial cells underwent excessive angiogenesis and generated extensive endothelial tubular networks. We also revealed by qPCR analysis that expression of genes involved in the Vegf-Notch pathway was augmented in the Vegfr1-null hearts. We further showed that inhibition of Notch signaling blocked the formation of coronary plexuses by the ventricular endocardial cells. These results establish that Vegfr1 produced in the endocardium negatively regulates embryonic coronary angiogenesis, possibly by limiting the Vegf-Notch signaling.
Leptin in Anorexia and Cachexia Syndrome  [PDF]
Diana R. Engineer,Jose M. Garcia
International Journal of Peptides , 2012, DOI: 10.1155/2012/287457
Abstract: Leptin is a product of the obese (OB) gene secreted by adipocytes in proportion to fat mass. It decreases food intake and increases energy expenditure by affecting the balance between orexigenic and anorexigenic hypothalamic pathways. Low leptin levels are responsible for the compensatory increase in appetite and body weight and decreased energy expenditure (EE) following caloric deprivation. The anorexia-cachexia syndrome is a complication of many chronic conditions including cancer, chronic obstructive pulmonary disease, congestive heart failure, chronic kidney disease, and aging, where the decrease in body weight and food intake is not followed by a compensatory increase in appetite or decreased EE. Crosstalk between leptin and inflammatory signaling known to be activated in these conditions may be responsible for this paradox. This manuscript will review the evidence and potential mechanisms mediating changes in the leptin pathway in the setting of anorexia and cachexia associated with chronic diseases. 1. Introdiction Leptin was discovered in 1994 by Friedman and colleagues after cloning an obese (OB) gene responsible for obesity in ob/ob mice [1]. It is a 167 amino acid peptide produced by adipocytes and it is a member of the adipocytokine family. Leptin has been noted to play a major role in body mass regulation by acting in the central nervous system to both stimulate energy expenditure and decrease food intake [2–4]. Named after the Greek word leptos, meaning lean, leptin was the first adipocyte-secreted hormone discovered, proving the active role of adipocytes in metabolic signaling. Leptin crosses the blood-brain barrier in a process that is highly regulated [5–8] and its receptors are found both centrally, in the hypothalamus, and peripherally, in pancreatic islets, liver, kidney, lung, skeletal muscle, and bone marrow [9]. Besides its key role on body weight regulation, leptin affects various metabolic pathways, including growth hormone (GH) signaling [10], insulin sensitivity, and lipogenesis [11]. While leptin levels are directly related to adiposity, there are several other factors resulting in individual variability. Leptin secretion is regulated by insulin, glucocorticoids, and catecholamines [3, 12, 13]. Also, females have significantly higher levels of leptin than men, for any degree of fat mass [14]. Along with adiponectin, leptin assists in peripheral insulin sensitization independent of body weight [15–17]. In leptin-deficient (ob/ob) mice, leptin injections led to dose-dependent reductions in serum glucose levels compared to fed
Effects of varying Notch1 signal strength on embryogenesis and vasculogenesis in compound mutant heterozygotes
Changhui Ge, Pamela Stanley
BMC Developmental Biology , 2010, DOI: 10.1186/1471-213x-10-36
Abstract: Mouse embryos expressing the hypomorphic Notch112f allele, in combination with the inactive Notch1lbd allele which lacks the Notch1 ligand binding domain, died at ~E11.5-12.5. Notch112f/lbd ES cells signaled less well than Notch112f/12f ES cells but more strongly than Notch1lbd/lbd ES cells. However, vascular defects in Notch112f/lbd yolk sac were severe and similar to Notch1lbd/lbd yolk sac. By contrast, vascular disorganization was milder in Notch112f/lbd compared to Notch1lbd/lbd embryos. The expression of Notch1 target genes was low in Notch112f/lbd yolk sac and embryo head, whereas Vegf and Vegfr2 transcripts were increased. The severity of the compound heterozygous Notch112f/lbd yolk sac phenotype suggested that the allelic products may functionally interact. By contrast, compound heterozygotes with Notch112f in combination with a Notch1 null allele (Notch1tm1Con) were capable of surviving to birth.Notch1 signaling in Notch112f/lbd compound heterozygous embryos is more defective than in compound heterozygotes expressing a hypomorphic Notch112f allele and a Notch1 null allele. The data suggest that the gene products Notch1lbd and Notch112f interact to reduce the activity of Notch112f.Notch transmembrane receptors are important regulators of cell fate determination in numerous cell types [1-3]. Notch receptors in Drosophila and mammals are covalently modified with O-fucose on many epidermal growth factor-like (EGF) repeats of the extracellular domain [4]. An important O-fucose site resides in epidermal growth factor-like repeat 12 (EGF12) which, together with EGF11, is required for canonical Notch ligand binding to Drosophila Notch [5-7] and to mammalian Notch1 [8]. A point mutation that precludes the addition of fucose to EGF12 in Drosophila Notch results in enhanced binding of both Delta and Serrate Notch ligands, and a hyperactive Notch that is refractory to Fringe [9]. However, the same mutation (Notch112f) in cultured mammalian cells gives markedly reduced
Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer
Ruben Rene Gonzalez, Amber Watters, Yanbo Xu, Udai P Singh, David R Mann, Bo R Rueda, Manuel L Penichet
Breast Cancer Research , 2009, DOI: 10.1186/bcr2321
Abstract: To test the contribution of leptin signaling to BC growth and expression of leptin-targeted molecules, PEG-LPrA2 treatment was applied to severe immunodeficient mice hosting established ER+ (MCF-7 cells; ovariectomized/supplemented with estradiol) and ER- (MDA-MB231 cells) BC xenografts. To further assess leptin and PEG-LPrA2 effects on ER+ and ER- BC, the expression of VEGF and VEGFR2 (protein and mRNA) was investigated in cell cultures.PEG-LPrA2 more effectively reduced the growth of ER+ (>40-fold) than ER- BC (twofold) and expression of pro-angiogenic (VEGF/VEGFR2, leptin/leptin receptor OB-R, and IL-1 receptor type I) and pro-proliferative molecules (proliferating cell nuclear antigen and cyclin D1) in ER+ than in ER- BC. Mouse tumor stroma in ER+ BC expressed high levels of VEGF and leptin that was induced by leptin signaling. Leptin upregulated the transcriptional expression of VEGF/VEGFR2 in MCF-7 and MDA-MB231 cells.These results suggest that leptin signaling plays an important role in the growth of both ER+ and ER- BC that is associated with the leptin regulation of pro-angiogenic and pro-proliferative molecules. These data provide support for the potential use of leptin-signaling inhibition as a novel treatment for ER+ and ER- BC.Leptin is a small nonglycosylated protein (16 kDa) product of the ob gene. White adipose tissue is the primary source of leptin in benign tissue, but leptin is also expressed and secreted by cancer cells [1]. Leptin exclusively binds to its receptor, OB-R. Several isoforms of OB-R are found in diverse tissues and in cancer cells including the long isoform, OB-Rb [2,3]. Upon leptin activation, the OB-R isoforms can utilize a number of diverse signaling pathways relevant to cancer growth [4,5]. The well-documented biological actions of leptin at the hypothalamic level occur through OB-Rb signals that are linked to the control of appetite and energy balance [4].Evidence is mounting to support the idea that leptin is the link between
Glucose Enhances Leptin Signaling through Modulation of AMPK Activity  [PDF]
Haoran Su, Lin Jiang, Christin Carter-Su, Liangyou Rui
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031636
Abstract: Leptin exerts its action by binding to and activating the long form of leptin receptors (LEPRb). LEPRb activates JAK2 that subsequently phosphorylates and activates STAT3. The JAK2/STAT3 pathway is required for leptin control of energy balance and body weight. Defects in leptin signaling lead to leptin resistance, a primary risk factor for obesity. Body weight is also regulated by nutrients, including glucose. Defects in glucose sensing also contribute to obesity. Here we report crosstalk between leptin and glucose. Glucose starvation blocked the ability of leptin to stimulate tyrosyl phosphorylation and activation of JAK2 and STAT3 in a variety of cell types. Glucose dose-dependently enhanced leptin signaling. In contrast, glucose did not enhance growth hormone-stimulated phosphorylation of JAK2 and STAT5. Glucose starvation or 2-deoxyglucose-induced inhibition of glycolysis activated AMPK and inhibited leptin signaling; pharmacological inhibition of AMPK restored the ability of leptin to stimulate STAT3 phosphorylation. Conversely, pharmacological activation of AMPK was sufficient to inhibit leptin signaling and to block the ability of glucose to enhance leptin signaling. These results suggest that glucose and/or its metabolites play a permissive role in leptin signaling, and that glucose enhances leptin sensitivity at least in part by attenuating the ability of AMPK to inhibit leptin signaling.
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