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Notch Pathway Modulation on Bone Marrow-Derived Vascular Precursor Cells Regulates Their Angiogenic and Wound Healing Potential  [PDF]
Francisco Caiado, Carla Real, Tania Carvalho, Sérgio Dias
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003752
Abstract: Bone marrow (BM) derived vascular precursor cells (BM-PC, endothelial progenitors) are involved in normal and malignant angiogenesis, in ischemia and in wound healing. However, the mechanisms by which BM-PC stimulate the pre-existing endothelial cells at sites of vascular remodelling/recovery, and their contribution towards the formation of new blood vessels are still undisclosed. In the present report, we exploited the possibility that members of the Notch signalling pathway, expressed by BM-PC during endothelial differentiation, might regulate their pro-angiogenic or pro-wound healing properties. We demonstrate that Notch pathway modulates the adhesion of BM-PC to extracellular matrix (ECM) in vitro via regulation of integrin alpha3beta1; and that Notch pathway inhibition on BM-PC impairs their capacity to stimulate endothelial cell tube formation on matrigel and to promote endothelial monolayer recovery following wounding in vitro. Moreover, we show that activation of Notch pathway on BM-PC improved wound healing in vivo through angiogenesis induction. Conversely, inoculation of BM-PC pre-treated with a gamma secretase inhibitor (GSI) into wounded mice failed to induce angiogenesis at the wound site and did not promote wound healing, presumably due to a lower frequency of BM-PC at the wound area. Our data suggests that Notch pathway regulates BM-PC adhesion to ECM at sites of vascular repair and that it also regulates the capacity of BM-PC to stimulate angiogenesis and to promote wound healing. Drug targeting of the Notch pathway on BM-PC may thus represent a novel strategy to modulate neo-angiogenesis and vessel repair.
Notch, IL-1 and Leptin Crosstalk Outcome (NILCO) Is Critical for Leptin-Induced Proliferation, Migration and VEGF/VEGFR-2 Expression in Breast Cancer  [PDF]
Shanchun Guo, Ruben R. Gonzalez-Perez
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021467
Abstract: High levels of pro-angiogenic factors, leptin, IL-1, Notch and VEGF (ligands and receptors), are found in breast cancer, which is commonly correlated with metastasis and lower survival of patients. We have previously reported that leptin induces the growth of breast cancer and the expression of VEGF/VEGFR-2 and IL-1 system. We hypothesized that Notch, IL-1 and leptin crosstalk outcome (NILCO) plays an essential role in the regulation of leptin-mediated induction of proliferation/migration and expression of pro-angiogenic molecules in breast cancer. To test this hypothesis, leptin's effects on the expression and activation of Notch signaling pathway and VEGF/VEGFR-2/IL-1 were determined in mouse (4T1, EMT6 and MMT) breast cancer cells. Remarkably, leptin up-regulated Notch1-4/JAG1/Dll-4, Notch target genes: Hey2 and survivin, together with IL-1 and VEGF/VEGFR-2. RNA knockdown and pharmacological inhibitors of leptin signaling significantly abrogated activity of reporter gene-luciferase CSL (RBP-Jk) promoter, showing that it was linked to leptin-activated JAK2/STAT3, MAPK, PI-3K/mTOR, p38 and JNK signaling pathways. Interestingly, leptin upregulatory effects on cell proliferation/migration and pro-angiogenic factors Notch, IL-1 and VEGF/VEGFR-2 were abrogated by a γ-secretase inhibitor, DAPT, as well as siRNA against CSL. In addition, blockade of IL-1R tI inhibited leptin-induced Notch, Hey2 and survivin as well as VEGF/VEGFR-2 expression. These data suggest leptin is an inducer of Notch (expression/activation) and IL-1 signaling modulates leptin effects on Notch and VEGF/VEGFR-2. We show for the first time that a novel unveiled crosstalk between Notch, IL-1 and leptin (NILCO) occurs in breast cancer. Leptin induction of proliferation/migration and upregulation of VEGF/VEGFR-2 in breast cancer cells were related to an intact Notch signaling axis. NILCO could represent the integration of developmental, pro-inflammatory and pro-angiogenic signals critical for leptin-induced cell proliferation/migration and regulation of VEGF/VEGFR-2 in breast cancer. Targeting NILCO might help to design new pharmacological strategies aimed at controlling breast cancer growth and angiogenesis.
DCLK1 Regulates Pluripotency and Angiogenic Factors via microRNA-Dependent Mechanisms in Pancreatic Cancer  [PDF]
Sripathi M. Sureban, Randal May, Dongfeng Qu, Nathaniel Weygant, Parthasarathy Chandrakesan, Naushad Ali, Stan A. Lightfoot, Panayotis Pantazis, Chinthalapally V. Rao, Russell G. Postier, Courtney W. Houchen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073940
Abstract: Stem cell pluripotency, angiogenesis and epithelial-mesenchymal transition (EMT) have been shown to be significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) and many other aggressive cancers. The dysregulation of these processes is believed to play key roles in tumor initiation, progression, and metastasis, and is contributory to PDAC being the fourth leading cause of cancer-related deaths in the US. The tumor suppressor miRNA miR-145 downregulates critical pluripotency factors and oncogenes and results in repressed metastatic potential in PDAC. Additionally, the miR-200 family regulates several angiogenic factors which have been linked to metastasis in many solid tumors. We have previously demonstrated that downregulation of DCLK1 can upregulate critical miRNAs in both in vitro and in vivo cancer models and results in downregulation of c-MYC, KRAS, NOTCH1 and EMT-related transcription factors. A recent report has also shown that Dclk1 can distinguish between normal and tumor stem cells in Apcmin/+ mice and that ablation of Dclk1+ cells resulted in regression of intestinal polyps without affecting homeostasis. Here we demonstrate that the knockdown of DCLK1 using poly(lactide-co-glycolide)-encapsulated-?DCLK1-siRNAresults in AsPC1 tumor growth arrest. Examination of xenograft tumors revealed, (a) increased miR-145 which results in decreased pluripotency maintenance factors OCT4, SOX2, NANOG, KLF4 as well as KRAS and RREB1; (b) increased let-7a which results in decreased pluripotency factor LIN28B; and (c) increased miR-200 which results in decreased VEGFR1, VEGFR2 and EMT-related transcription factors ZEB1, ZEB2, SNAIL and SLUG. Specificity of DCLK1 post-transcriptional regulation of the downstream targets of miR-145, miR-200 and let-7a was accomplished utilizing a luciferase-based reporter assay. We conclude that DCLK1 plays a significant master regulatory role in pancreatic tumorigenesis through the regulation of multiple tumor suppressor miRNAs and their downstream pro-tumorigenic pathways. This novel concept of targeting DCLK1 alone has several advantages over targeting single pathway or miRNA-based therapies for PDAC.
Loss of Notch signalling induced by Dll4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli
Rui Benedito, Alexandre Trindade, Masanori Hirashima, Domingos Henrique, Luis da Costa, Janet Rossant, Parkash S Gill, António Duarte
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-117
Abstract: The current detailed analysis of these mutants shows that the arterial defect precedes the initiation of blood flow and that the arterial Dll4-/- endothelial cells proliferate and migrate more actively. Dll4-/- mutants reveal a defective basement membrane around the forming aorta and increased endothelial cell migration from the dorsal aorta to peripheral regions, which constitute the main causes of arterial lumen reduction in these embryos. The increased proliferation and migration of Dll4-/- endothelial cells was found to coincide with increased expression of the receptors VEGFR-2 and Robo4 and with downregulation of the TGF-β accessory receptor Endoglin.Together, these results strongly suggest that Notch signalling can increase arterial stability and calibre by decreasing the response of arterial endothelial cells to local gradients of pro-angiogenic factors like VEGF.The initial steps of embryonic blood vessel formation (vasculogenesis) involve differentiation and aggregation of mesodermal-derived endothelial precursors (angioblasts) to generate the primary vascular plexus. Blood vessels then grow and remodel into a mature network of hierarchically organized vessels, in a process designated as angiogenesis. During this remodelling, endothelial vessels differentiate into arteries and veins, grow, sprout, split and fuse according to a combination of autocrine signalling and cues provided by other tissues of the embryo [1].The formation of the initial vascular plexus is highly dependent on vascular endothelial growth factor (VEGF-A) and its receptors, VEGFR-1 and VEGFR-2, since mouse embryos lacking these genes display very early vascular defects and die between 8.5–9.5 dpc [2-4]. Notably, VEGF haploinsufficiency causes embryonic lethality. VEGFR-2 is thought to be the major mediator of the VEGF signalling since VEGFR-2-/- embryos fail to form blood islands or organized blood vessels [3], whereas VEGFR-1-/- embryos form blood vessels with an excess of endothelial a
Angiogenic factors in small vell lung cancer (VEGF, VEGFR-1, VEGFR-2)
Hilal O?UZ SOYD?N?,Derya DURANYILDIZ,Elif B?LG?N,Faruk TA?
Turkish Journal of Oncology , 2012,
Abstract: OBJECTIVES: Angiogenesis has an important role in metastasis. Vascular endothelial growth factor (VEGF) is one of the angiogenic factors that has the ability to increase the permeability of capillary blood vessels. Its mitogenic and angiogenic activities are specific for endothelial cells. VEGF was secreted both from normal and tumor cells. Small cell lung cancer (SCLC) is one of the main types of lung cancer that grows and spreads quickly. In this study, we investigated VEGF and its receptors VEGFR-1 (fms-related tyrosine kinase/FLT-1) and VEGFR-2 (kinase insert domain receptor/KDR) in SCLC.METHODS: Our study group consisted of 60 SCLC patients and 20 healthy subjects. The serum levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum levels of VEGF (p<0.001) and its receptors (p<0.001) were significantly higher in patients than controls before chemotherapy. CONCLUSION: Our data indicate that coexpression of serum levels of VEGF and its receptors can be used for deciding the antiangiogenic therapy.
KSHV Induction of Angiogenic and Lymphangiogenic Phenotypes  [PDF]
Terri A. DiMaio,Michael Lagunoff
Frontiers in Microbiology , 2012, DOI: 10.3389/fmicb.2012.00102
Abstract: Kaposi’s sarcoma (KS) is a highly vascularized tumor supporting large amounts of neo-angiogenesis. The major cell type in KS tumors is the spindle cell, a cell that expresses markers of lymphatic endothelium. KSHV, the etiologic agent of KS, is found in the spindle cells of all KS tumors. Considering the extreme extent of angiogenesis in KS tumors at all stages it has been proposed that KSHV directly induces angiogenesis in a paracrine fashion. In accordance with this theory, KSHV infection of endothelial cells in culture induces a number of host pathways involved in activation of angiogenesis and a number of KSHV genes themselves can induce pathways involved in angiogenesis. Spindle cells are phenotypically endothelial in nature, and therefore, activation through the induction of angiogenic and/or lymphangiogenic phenotypes by the virus may also be directly involved in spindle cell growth and tumor induction. Accordingly, KSHV infection of endothelial cells induces cell autonomous angiogenic phenotypes to activate host cells. KSHV infection can also reprogram blood endothelial cells to lymphatic endothelium. However, KSHV induces some blood endothelial specific genes upon infection of lymphatic endothelial cells creating a phenotypic intermediate between blood and lymphatic endothelium. Induction of pathways involved in angiogenesis and lymphangiogenesis are likely to be critical for tumor cell growth and spread. Thus, induction of both cell autonomous and non-autonomous changes in angiogenic and lymphangiogenic pathways by KSHV likely plays a key role in the formation of KS tumors.
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.
VEGFR2 heterogeneity and response to anti-angiogenic low dose metronomic cyclophosphamide treatment
Steven G Patten, Una Adamcic, Kristen Lacombe, Kanwal Minhas, Karolina Skowronski, Brenda L Coomber
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-683
Abstract: Double immunofluorescent staining was performed on formalin-fixed paraffin embedded sections of treated and control SW480 (colorectal) and WM239 (melanoma) xenografts, and tissue microarrays of human colorectal carcinoma and melanoma. Xenografts were developed using RAG1-/- mice by injection with WM239 or SW480 cells and mice were treated with 20 mg/kg/day of cyclophosphamide in their drinking water for up to 18 days. Treated and control tissues were characterized by double immunofluorescence using the mural cell marker α-SMA and CD31, while the ratio of desmin/CD31 was also determined by western blot. Hypoxia in treated and control tissues were quantified using both western blotting for HIF-1α and immunohistochemistry of CA-IX.VEGFR2 is heterogeneously expressed in tumor vasculature in both malignant melanoma and colorectal carcinoma. We observed a significant decrease in microvascular density (MVD) in response to low dose metronomic cyclophosphamide chemotherapy in both malignant melanoma (with higher proportion VEGFR2 positive blood vessels; 93%) and colorectal carcinoma (with lower proportion VEGFR2 positive blood vessels; 60%) xenografts. This reduction in MVD occurred in the absence of a significant anti-tumor effect. We also observed less hypoxia in treated melanoma xenografts, despite successful anti-angiogenic blockade, but no change in hypoxia of colorectal xenografts, suggesting that decreases in tumor hypoxia reflect a complex relationship with vascular density. Based on α-SMA staining and the ratio of desmin to CD31 expression as markers of tumor blood vessel functionality, we found evidence for increased stabilization of colorectal microvessels, but no such change in melanoma vessels.Overall, our study suggests that while heterogeneous expression of VEGFR2 is a feature of human tumors, it may not affect response to low dose metronomic cyclophosphamide treatment and possibly other anti-angiogenic approaches. It remains to be seen whether this heterogene
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.
Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip
Robert P Machold, Deborah Kittell, Gordon J Fishell
Neural Development , 2007, DOI: 10.1186/1749-8104-2-5
Abstract: Employing both gain- and loss-of-function methods, we find that Notch1 signaling in the cerebellar primordium regulates the responsiveness of progenitor cells to bone morphogenetic proteins (BMPs) secreted from the roof plate that stimulate the production of rhombic lip-derived neurons. In the absence of Notch1, cerebellar progenitors are depleted during the early production of hindbrain neurons, resulting in a severe decrease in the deep cerebellar nuclei that are normally born subsequently. Mechanistically, we demonstrate that Notch1 activity prevents the induction of Math1 by antagonizing the BMP receptor-signaling pathway at the level of Msx2 expression.Our results provide a mechanism by which a balance between neural induction and maintenance of neural progenitors is achieved in the rhombic lip throughout embryonic development.The mammalian cerebellum develops from neural progenitors within dorsal rhombomere 1 (r1) just caudal to the mid-hindbrain boundary and above the opening of the fourth ventricle. In the mouse embryonic brain, closure of the neural tube at around embryonic day 9.5 (E9.5) generally creates a ventricular zone of neural progenitors that give rise to successive waves of differentiating neurons; however, at the opening of the fourth ventricle the neuroepithelium extends directly to the roof plate, resulting in an edge along the cerebellar and hindbrain neural plate (r1–r8) termed the rhombic lip. Located at the caudal boundary of the cerebellar anlage in dorsal r1, the cerebellar rhombic lip is a unique germinal territory that gives rise to granule cells and other neurons of the cerebellum and hindbrain [1-4].Immediately following neural tube closure, the expression of the mouse Atonal homolog Math1 [5], a basic helix-loop-helix (bHLH) transcription factor that is required for the granule cell lineage and other rhombic lip derived neuronal populations [6-8], begins to be induced in rhombic lip cells that subsequently migrate away from the rhomb
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