MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells.

MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells.

Cancer Res. 2012 Jul 25;

Authors: Plummer PN, Freeman R, Taft R, Vider J, Sax M, Umer BA, Gao D, Johns CA, Mattick JS, Wilton SD, Ferro V, McMillan NA, Swarbrick A, Mittal V, Mellick AS

Abstract
Bone marrow (BM)-derived endothelial progenitor cells (EPCs), contribute to the angiogenesis dependent growth of tumors in mice and humans. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors, and by direct luminal incorporation into sprouting nascent vessels. MicroRNAs (miRNAs) have emerged as key regulators of several cellular processes including angiogenesis; however, whether miRNAs contribute to BM-mediated angiogenesis has remained unknown. Here, we show that genetic ablation of microRNA processing enzyme Dicer, specifically in the BM, decreased the number of circulating EPCs, resulting in angiogenesis suppression and impaired tumor growth. Furthermore, genome-wide deep sequencing of small RNAs revealed tumor EPC-intrinsic miRNAs including miR-10b and miR-196b; which have been previously identified as key regulators of HOX signaling and adult stem cell differentiation. Notably, we found that both miR-10b and miR-196b, are responsive to vascular endothelial growth factor (VEGF) stimulation, and show elevated expression in human high-grade breast tumor vasculature. Strikingly, targeting miR-10b and miR-196b led to significant defects in angiogenesis-mediated tumor growth in mice. Targeting these miRNAs may constitute a novel strategy for inhibiting tumor angiogenesis.

PMID: 22836757 [PubMed - as supplied by publisher]

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Thyroid hormone is highly permissive in angioproliferative pulmonary hypertension in rats.

Thyroid hormone is highly permissive in angioproliferative pulmonary hypertension in rats.

Eur Respir J. 2012 Jul 26;

Authors: Al Husseini A, Bagnato G, Farkas L, Gomez-Arroyo J, Farkas D, Mizuno S, Kraskauskas D, Abbate A, Van Tassel Pharm D B, Voelkel NF, Bogaard HJ

Abstract
Epidemiological evidence links pulmonary arterial hypertension (PAH) with thyroid disease, but a mechanistic explanation for this association is lacking. Because a central hallmark of vascular remodelling in pulmonary hypertension is lumen obliteration by endothelial cell growth and because thyroid hormones are known to be angiogenic, we hypothesized that thyroid hormones play a role in the control of endothelial cell proliferation in experimental PAH in rats. Hypothyroidism was induced by subtotal thyroidectomy and treatment with propylthiouracil (PTU) in rats with experimental PAH after combined exposure to VEGF-R inhibition and hypoxia (the SuHx model). Subtotal thyroidectomy prevented and PTU treatment reversed the development of severe experimental PAH. T4 repletion restored the PAH phenotype in thyroidectomised SuHx rats. The prevention of PAH by thyroidectomy was associated with a reduced rate of cell turnover, reduced Erk1/2 phosphorylation, and reduced expression of ?v?3 integrin, fibroblast growth factor (FGF)2 and FGF receptor. Thyroidectomy mitigated hypoxia-induced pulmonary hypertension, but this effect was not associated with a decreased pulmonary vascular resistance. These data suggest that thyroid hormone permits endothelial cell proliferation in PAH. A causal link between thyroid diseases and the onset or progression of vascular remodeling in PAH patients remains to be determined.

PMID: 22835607 [PubMed - as supplied by publisher]

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Multi-scale modeling of tissues using CompuCell3D.

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Multi-scale modeling of tissues using CompuCell3D.

Methods Cell Biol. 2012;110:325-66

Authors: Swat MH, Thomas GL, Belmonte JM, Shirinifard A, Hmeljak D, Glazier JA

Abstract
The study of how cells interact to produce tissue development, homeostasis, or diseases was, until recently, almost purely experimental. Now, multi-cell computer simulation methods, ranging from relatively simple cellular automata to complex immersed-boundary and finite-element mechanistic models, allow in silico study of multi-cell phenomena at the tissue scale based on biologically observed cell behaviors and interactions such as movement, adhesion, growth, death, mitosis, secretion of chemicals, chemotaxis, etc. This tutorial introduces the lattice-based Glazier-Graner-Hogeweg (GGH) Monte Carlo multi-cell modeling and the open-source GGH-based CompuCell3D simulation environment that allows rapid and intuitive modeling and simulation of cellular and multi-cellular behaviors in the context of tissue formation and subsequent dynamics. We also present a walkthrough of four biological models and their associated simulations that demonstrate the capabilities of the GGH and CompuCell3D.

PMID: 22482955 [PubMed - indexed for MEDLINE]

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Cediranib: a VEGF receptor tyrosine kinase inhibitor.

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Cediranib: a VEGF receptor tyrosine kinase inhibitor.

Future Oncol. 2012 Jul;8(7):775-81

Authors: Sahade M, Caparelli F, Hoff PM

Abstract
Cediranib is a potent inhibitor of the VEGF family receptor tyrosine kinases, and a new agent in cancer treatment. The drug has shown promising activity in a variety of solid malignancies, in preclinical models and in clinical trials. Its pharmacokinetics allow for a convenient once-daily administration, with a toxicity profile that is very similar to other VEGF inhibitors. Its main side effects include hypertension, nausea, dysphonia, fatigue and diarrhea. Adverse events seem to be manageable, especially when used in doses lower than 45 mg/day. Studies have shown some activity as a single agent or in combination in advanced tumors, but not enough to secure its approval for routine use up to now. Clinical trials are still evaluating the role of cediranib in combination chemotherapy with cytotoxic agents.

PMID: 22830398 [PubMed - in process]

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Imbalance of apoptosis and cell proliferation contributes to the development and persistence of emphysema.

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Imbalance of apoptosis and cell proliferation contributes to the development and persistence of emphysema.

Lung. 2012 Feb;190(1):69-82

Authors: Lee JH, Hanaoka M, Kitaguchi Y, Kraskauskas D, Shapiro L, Voelkel NF, Taraseviciene-Stewart L

Abstract
BACKGROUND: We postulate that in adults there is an established lung structure maintenance program and that lung alveolar septal cells are undergoing both continuous apoptosis and proliferation. Whereas lung cell apoptosis has been recognized in human emphysema, little is known about cell proliferation.
METHODS: Using a novel rat model of emphysema, induced by intratracheal instillation of cigarette smoke extract (CSE), we investigated the dynamics of emphysematous lung destruction. Emphysematous lung destruction was determined by measuring mean linear intercept and destructive index. Lung injury and repair were assessed by immunohistochemistry and Western blot analysis for active caspase-3 and proliferating cell nuclear antigen (PCNA) after 4, 8, and 12 weeks of CSE instillations.
RESULTS: The emphysematous lung tissue destruction was present at 4 weeks of CSE treatment and progressed to 8 weeks. Spontaneous repair began at 12 weeks. Treatment with a peroxisome proliferator activated receptor (PPAR)?+? agonist or granulocyte and macrophage-colony stimulating factor (GM-CSF) for 4 weeks prevented the progression of emphysematous lung destruction and decreased the number of caspase-3-positive cells.
CONCLUSION: Apoptosis and cell proliferation occur in this new model of emphysema. Treatment with a PPAR?+? agonist or GM-CSF can inhibit the progression of emphysematous alveolar septal destruction by decreasing alveolar cell apoptosis.

PMID: 22015802 [PubMed - indexed for MEDLINE]

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Altered angiogenesis in caveolin-1 gene-deficient mice is restored by ablation of endothelial nitric oxide synthase.

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Altered angiogenesis in caveolin-1 gene-deficient mice is restored by ablation of endothelial nitric oxide synthase.

Am J Pathol. 2012 Apr;180(4):1702-14

Authors: Morais C, Ebrahem Q, Anand-Apte B, Parat MO

Abstract
Caveolin-1 is an essential structural protein of caveolae, specialized plasma membrane organelles highly abundant in endothelial cells, where they regulate multiple functions including angiogenesis. Caveolin-1 exerts a tonic inhibition of endothelial nitric oxide synthase (eNOS) activity. Accordingly, caveolin-1 gene-disrupted mice have enhanced eNOS activity as well as increased systemic nitric oxide (NO) levels. We hypothesized that excess eNOS activity, secondary to caveolin deficiency, would mediate the decreased angiogenesis observed in caveolin-1 gene-disrupted mice. We tested tumor angiogenesis in mice lacking either one or both proteins, using in vitro, ex vivo, and in vivo assays. We show that endothelial cell migration, tube formation, cell sprouting from aortic rings, tumor growth, and angiogenesis are all significantly impaired in both caveolin-1-null and eNOS-null mice. We further show that these parameters were either partially or fully restored in double knockout mice that lack both caveolin-1 and eNOS. Furthermore, the effects of genetic ablation of eNOS are mimicked by the administration of the NOS inhibitor N-nitro-L-arginine methyl ester hydrochloride (L-NAME), including the reversal of the caveolin-1-null mouse angiogenic phenotype. This study is the first to demonstrate the detrimental effects of unregulated eNOS activity on angiogenesis, and shows that impaired tumor angiogenesis in caveolin-1-null mice is, at least in part, the result of enhanced eNOS activity.

PMID: 22322296 [PubMed - indexed for MEDLINE]

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Control of microenvironmental cues with a smart biomaterial composite promotes endothelial progenitor cell angiogenesis.

Control of microenvironmental cues with a smart biomaterial composite promotes endothelial progenitor cell angiogenesis.

Eur Cell Mater. 2012;24:90-106

Authors: Aguirre A, Gonz�lez A, Navarro M, Casta�o O, Planell JA, Engel E

Abstract
Smart biomaterials play a key role when aiming at successful tissue repair by means of regenerative medicine approaches, and are expected to contain chemical as well as mechanical cues that will guide the regenerative process. Recent advances in the understanding of stem cell biology and mechanosensing have shed new light onto the importance of the local microenvironment in determining cell fate. Herein we report the biological properties of a bioactive, biodegradable calcium phosphate glass/polylactic acid composite biomaterial that promotes bone marrow-derived endothelial progenitor cell (EPC) mobilisation, differentiation and angiogenesis through the creation of a controlled bone healing-like microenvironment. The angiogenic response is triggered by biochemical and mechanical cues provided by the composite, which activate two synergistic cell signalling pathways: a biochemical one mediated by the calcium-sensing receptor and a mechanosensitive one regulated by non-muscle myosin II contraction. Together, these signals promote a synergistic response by activating EPCs-mediated VEGF and VEGFR-2 synthesis, which in turn promote progenitor cell homing, differentiation and tubulogenesis. These findings highlight the importance of controlling microenvironmental cues for stem/progenitor cell tissue engineering and offer exciting new therapeutical opportunities for biomaterial-based vascularisation approaches and clinical applications.

PMID: 22828988 [PubMed - in process]

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The impact of tumor microenvironment on cancer treatment and its modulation by direct and indirect antivascular strategies.

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The impact of tumor microenvironment on cancer treatment and its modulation by direct and indirect antivascular strategies.

Cancer Metastasis Rev. 2012 Jul 24;

Authors: Fokas E, McKenna WG, Muschel RJ

Abstract
Tumor cells exploit their microenvironment by growth factors and cytokines such as vascular endothelial growth factor (VEGF) to stimulate abnormal vessel formation that is leaky and tortuous, causing irregular blood flow. The combination of poor perfusion, raised interstitial fluid pressure and areas of vascular collapse leads to hypoxia within tumor. The latter activates factors such as hypoxia inducible factor 1 (HIF-1) that serve to make cancer cells more aggressive and also markedly influences the response of malignant tumors to conventional irradiation and chemotherapy. Accumulating data now suggest that blockade of oncogenic signaling, for example by PI3K/Akt/mTOR inhibitors, might consist a promising strategy since these agents do not only possess antitumor effects but can also alter tumor vasculature and oxygenation to improve the response to radiation and chemotherapy. In many cases, these changes are related to downregulation of HIF-1? and VEGF. Here, we review the pathophysiology of tumor microenvironment (TME) and how it adversely affects cancer treatment. The complex interaction of tumor vasculature and radiotherapy is examined together the preclinical evidence supporting a proinvasive/metastatic role for ionising radiation. We will discuss the expanding role of oncogenic signaling, especially PI3K/Akt/mTOR, on tumor angiogenesis. Special emphasis will be paid to the potential of different oncogenic pathways blockade and other indirect antivascular strategies to alter the TME for the benefit of cancer treatment, as an alternative to the classical angiogenetic treatment.

PMID: 22825313 [PubMed - as supplied by publisher]

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Intravitreal bevacizumab for choroidal neovascularization secondary to laser photocoagulation for central serous chorioretinopathy.

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Intravitreal bevacizumab for choroidal neovascularization secondary to laser photocoagulation for central serous chorioretinopathy.

Eur J Ophthalmol. 2012 May-Jun;22(3):488-91

Authors: Pikkel J, Rumelt S

Abstract
PURPOSE: Choroidal neovascularization (CNV) is a rare complication after laser photocoagulation for disorders such as central serous chorioretinopathy (CSC).
METHODS: We report 2 patients who developed CNV after laser treatment for persistent CSC and were treated by 3 1.25-mg intravitreal injections of bevacizumab in 1-month intervals.
RESULTS: In both patients, best-corrected visual acuity improved from 20/120 to 20/80 and from counting fingers at 3 feet to 20/100 over 12 months of follow-up.
CONCLUSIONS: The favorable outcome suggests that intravitreal injection of bevacizumab may be beneficial for patients who develop CNV after laser photocoagulation. The favorable outcome may be related to the limited pathology.

PMID: 21928270 [PubMed - indexed for MEDLINE]

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The impact of tumor microenvironment on cancer treatment and its modulation by direct and indirect antivascular strategies.

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The impact of tumor microenvironment on cancer treatment and its modulation by direct and indirect antivascular strategies.

Cancer Metastasis Rev. 2012 Jul 24;

Authors: Fokas E, McKenna WG, Muschel RJ

Abstract
Tumor cells exploit their microenvironment by growth factors and cytokines such as vascular endothelial growth factor (VEGF) to stimulate abnormal vessel formation that is leaky and tortuous, causing irregular blood flow. The combination of poor perfusion, raised interstitial fluid pressure and areas of vascular collapse leads to hypoxia within tumor. The latter activates factors such as hypoxia inducible factor 1 (HIF-1) that serve to make cancer cells more aggressive and also markedly influences the response of malignant tumors to conventional irradiation and chemotherapy. Accumulating data now suggest that blockade of oncogenic signaling, for example by PI3K/Akt/mTOR inhibitors, might consist a promising strategy since these agents do not only possess antitumor effects but can also alter tumor vasculature and oxygenation to improve the response to radiation and chemotherapy. In many cases, these changes are related to downregulation of HIF-1? and VEGF. Here, we review the pathophysiology of tumor microenvironment (TME) and how it adversely affects cancer treatment. The complex interaction of tumor vasculature and radiotherapy is examined together the preclinical evidence supporting a proinvasive/metastatic role for ionising radiation. We will discuss the expanding role of oncogenic signaling, especially PI3K/Akt/mTOR, on tumor angiogenesis. Special emphasis will be paid to the potential of different oncogenic pathways blockade and other indirect antivascular strategies to alter the TME for the benefit of cancer treatment, as an alternative to the classical angiogenetic treatment.

PMID: 22825313 [PubMed - as supplied by publisher]

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SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases.

SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases.

Biochem Soc Trans. 2012 Aug 1;40(4):831-5

Authors: Oltean S, Gammons M, Hulse R, Hamdollah-Zadeh M, Mavrou A, Donaldson L, Salmon AH, Harper SJ, Ladomery MR, Bates DO

Abstract
SRPK1 (serine-arginine protein kinase 1) is a protein kinase that specifically phosphorylates proteins containing serine-arginine-rich domains. Its substrates include a family of SR proteins that are key regulators of mRNA AS (alternative splicing). VEGF (vascular endothelial growth factor), a principal angiogenesis factor contains an alternative 3' splice site in the terminal exon that defines a family of isoforms with a different amino acid sequence at the C-terminal end, resulting in anti-angiogenic activity in the context of VEGF165-driven neovascularization. It has been shown recently in our laboratories that SRPK1 regulates the choice of this splice site through phosphorylation of the splicing factor SRSF1 (serine/arginine-rich splicing factor 1). The present review summarizes progress that has been made to understand how SRPK1 inhibition may be used to manipulate the balance of pro- and anti-angiogenic VEGF isoforms in animal models in vivo and therefore control abnormal angiogenesis and other pathophysiological processes in multiple disease states.

PMID: 22817743 [PubMed - in process]

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Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine.

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Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine.

BJU Int. 2012 Jun;109(12):1864-70

Authors: Audenet F, Yates DR, Cancel-Tassin G, Cussenot O, Roupr�t M

Abstract
What's known on the subject? and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by nutations of the VHL gene located on chromosome 3p in up to 90% of cases. This gene plays a critical role in hypoxia response, including stimulation of neoangiogenesis. Since 2006, anti-angiogenci therapies targeting this pathway are used in metastatic patients with objective response rate as high as 45%. However, these treatments don't target directly the tumour cell, allowing the potential for disease progession despite treatment. Large scale analysis recently showed that substantial genetic heterogeneity exists in ccRCC. Associated alterations include genes implicated in methylation regulation in 15% of cases, underlying the importance of epigenetic modifications, and truncating mutations in chromatin remodelling complex PRMB1 in 41% of cases. Systematic screening of these tumours is a way to fully determine the somatic genetic architecture of RCC in order to improve tumour classification, to develop prognostic and predictive markers and to target new molecular pathways involved in carcinogenesis. ? A critical review is provided of the recent progress in oncogenetics applied to renal cell carcinoma (RCC) by highlighting our current understanding of the genetic pathways involved in carcinogenesis and its current and future clinical application. ? RCC comprises a model of translational research because an improved understanding of molecular pathways has led to several targeted therapy options for patients with metastatic RCC. ? Alteration of the product of the Von Hippel-Lindau gene/hypoxia inductible factor/vascular endothelial growth factor pathway is well characterized in carcinogenesis and is the target of the current therapies for metastatic RCC. ? However, substantial genetic heterogeneity exists in this cancer and current treatments do not target directly the tumour cell. ? Improving overall survival still remains a challenging objective but, currently, there is a lack of prognostic and predictive biomarkers for response to treatment. ? Further information is awaited from the genomic approach to tumour classification, prognostic markers and predictive indicators of response to the treatment, as well as the personal susceptibility of developing RCC when exposed to risk factors. ? Recent technological developments, such as large-scale analysis and high-speed sequencing, will allow the systematic screening of tumours to fully determine the somatic genetic architecture of RCC.

PMID: 22035299 [PubMed - indexed for MEDLINE]

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Vascular Endothelial Growth Factor-Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts.

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Vascular Endothelial Growth Factor-Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts.

Arterioscler Thromb Vasc Biol. 2012 Jul 19;

Authors: Li XD, Chen J, Ruan CC, Zhu DL, Gao PJ

Abstract
OBJECTIVE: Adventitia acts as an active participant in vascular inflammation but the precise mechanism underlying adventitia-mediated vascular inflammation is not fully understood. In this study, we sought to determine whether vascular endothelial growth factor (VEGF) regulates osteopontin (OPN) expression through Flt-1 in adventitial fibroblasts (AFs) to mediate vascular inflammation and neointima formation. METHODS AND RESULTS: In primary cultured AFs, VEGF increased intracellular and secreted OPN expression in a time- and dose-dependent manner, which was effectively suppressed by a specific anti-Flt-1 hexapeptide. Interestingly, VEGF treatment of AFs enhanced the capability of AF-conditioned medium to stimulate macrophages chemotaxis, and this effect was attenuated after blockade of OPN from AF-conditioned medium. Furthermore, perivascular delivery of anti-Flt-1 peptide preferentially concentrated in the adventitia resulted in a decrease of neointima formation after balloon injury in carotid arteries. The inhibition of neointima formation was preceded by significant reduction of VEGF and OPN expression with concurrent macrophage infiltration into adventitia after injury. Activation of extracellular signal-regulated kinase 1/2 pathway was involved in OPN upregulation and macrophage chemotaxis. CONCLUSIONS: These results demonstrate that VEGF/Flt-1 signaling plays a significant role in vascular inflammation and neointima formation by regulating OPN expression in AFs and provide insight into Flt-1 as a potential therapeutic target for vascular diseases.

PMID: 22814749 [PubMed - as supplied by publisher]

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Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma.

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Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma.

Int J Cancer. 2012 Jul 19;

Authors: Szczyrba J, Nolte E, Hart M, D�ll C, Wach S, Taubert H, Keck B, Kremmer E, St�hr R, Hartmann A, Wieland W, Wullich B, Gr�sser FA

Abstract
In primary prostate cancer (PCa), a major cause of cancer-related death in men, the expression of various microRNAs (miRNAs) is deregulated. We previously detected several miRNAs, e.g., miR-24 and miR-22, as significantly down-regulated in PCa (1) . An in silico search predicted that zinc finger protein 217 (ZNF217) and importin 7 (IPO7) were potential target genes of these miRNAs. Additionally, for two genes that are deregulated in PCa (heterogeneous nuclear ribonucleoprotein K, hnRNP-K, and vascular endothelial growth factor A, VEGF-A), we identified two regulatory miRNAs, miR-205 and miR-29b. The regulation of the 3'-untranslated regions (3'UTRs) of the four genes by their respective miRNAs was confirmed by luciferase assays. As expected, the up-regulation of ZNF217, hnRNP-K, VEGF-A and IPO7 could be verified at the protein level in the PCa cell lines LNCaP and DU145. ZNF217 and IPO7, which had not yet been studied in PCa, were analyzed in more detail. ZNF217 mRNA is over-expressed in primary PCa samples, and this overexpression translates to an elevated protein level. However, IPO7 was upregulated at the protein level alone. The inhibition of ZNF217 and IPO7 by siRNA resulted in reduced proliferation of the PCa cell lines. ZNF217 could thus be identified as an oncogene that is overexpressed in PCa and affects the growth of PCa cell lines while the function of IPO7 remains to be elucidated in greater detail. � 2012 Wiley Periodicals, Inc.

PMID: 22815235 [PubMed - as supplied by publisher]

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Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways.

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Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways.

Cancer Chemother Pharmacol. 2012 Jul 20;

Authors: Li X, Wang X, Ye H, Peng A, Chen L

Abstract
PURPOSE: We previously reported that barbigerone (BA), an isoflavone isolated from Suberect Spatholobus, exhibited inhibitory effects on proliferation of many cancer cell lines in vitro. The objective of this study was to explore whether BA could effectively suppress tumor angiogenesis and tumor growth. METHODS: Zebrafish model and Matrigel assay were performed to access the anti-angiogenesis effects of BA. A549 and SPC-A1 tumor xenografts in mice models were used to examine the antitumor activity of BA. The anti-angiogenic effects and underlying mechanisms were also investigated using human umbilical vein endothelial cells (HUVECs) and A549 cells. RESULTS: In zebrafish model, 2.5�?mol/L of BA significantly inhibited angiogenesis. Intravenous administration of BA effectively inhibited the tumor growth of A549 and SPC-A1 xenograft models in mice. The anti-angiogenic effect was indicated by CD31 immunohistochemical staining, Matrigel plug assay, and mouse aortic ring assay. BA could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and capillary-like tuber formation of HUVECs in a dose-dependent manner, suggesting that BA inhibited tumorigenesis by targeting angiogenesis. Western blots revealed that BA directly inhibited the phosphorylation of VEGFR2, followed by inhibiting the activations of its downstream protein kinases, including ERK, p38, FAK, AKT, and expression of iNOS, but had no effect on COX2. Additionally, BA could also down-regulate VEGF secretion in A549 cancer cells, which may correlate with the suppression of ERK, AKT activation, indicating that BA inhibits tumor angiogenesis and tumor growth through VEGFR2 signaling pathways. CONCLUSIONS: These findings suggest that BA may be a novel candidate in inhibiting tumor angiogenesis and NSCLC tumor growth.

PMID: 22814678 [PubMed - as supplied by publisher]

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First-line chemotherapy in epithelial ovarian cancer.

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First-line chemotherapy in epithelial ovarian cancer.

Clin Obstet Gynecol. 2012 Mar;55(1):96-113

Authors: Bookman MA

Abstract
Advanced-stage epithelial ovarian cancer remains a highly lethal malignancy, despite effective cytoreductive surgery and primary chemotherapy. Phase III studies have evaluated multidrug combinations, dose-dense weekly scheduling, intraperitoneal delivery, neoadjuvant chemotherapy, maintenance therapy, and targeting of angiogenesis. Incremental gains in median progression-free or overall survival have been achieved, but without an impact on overall mortality. Data support intraperitoneal cisplatin, dose-dense weekly paclitaxel, or neoadjuvant chemotherapy with interval cytoreduction in appropriate patients. Encouraging data have emerged using antiangiogenic agents, but with questions regarding optimal timing and patient selection. The use of 3-drug combinations or maintenance chemotherapy is not supported.

PMID: 22343232 [PubMed - indexed for MEDLINE]

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Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease.

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Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease.

Clin Exp Nephrol. 2012 Jul 20;

Authors: Chen YT, Cheng BC, Ko SF, Chen CH, Tsai TH, Leu S, Chang HW, Chung SY, Chua S, Yeh KH, Chen YL, Yip HK

Abstract
BACKGROUND: Chronic renal failure on dialysis can reduce the number of circulating endothelial progenitor cells (EPCs), but this biomarker has not been fully investigated in patients with chronic kidney disease (CKD). A link between CKD and increased mononuclear cell apoptosis (MCA) in circulation has been reported but the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1?, two angiogenesis factors, on circulating EPC levels in CKD has not been clarified. This study examined the relationships between the numbers of circulating EPCs and the severity of CKD, degree of MCA and serum levels of VEGF and SDF-1? in CKD patients. METHODS: The numbers of circulating EPCs (CD31/CD34+, CD62E/CD34+, KDR/CD34+, CXCR4/CD34+) were measured in 166 patients with varying degrees of CKD under regular treatment at an outpatient department and in 30 volunteer control subjects. RESULTS: CKD patients had significantly lower numbers of EPCs (p�<�0.007), higher MCA in circulation and higher serum levels of VEGF and SDF-1 compared with the control subjects (all p�<�0.001). Compared with patients with early CKD (stages I-III), patients with late CKD [stage IV-V or end-stage renal disease (ESRD)] had significantly lower numbers of EPCs (CXCR4/CD34+), higher MCA, and elevated serum levels of VEGF and SDF-1? (all p�<�0.01). Serum VEGF level but not MCA or SDF-1? was strongly correlated with increased numbers of circulating EPCs. Multivariate analysis showed that ESRD along with lower serum albumin was independently predictive of lower numbers of circulating EPCs (p�<�0.04). CONCLUSION: Circulating EPCs were markedly reduced in CKD patients. ESRD was strongly and independently predictive of decreased numbers of circulating EPCs.

PMID: 22814956 [PubMed - as supplied by publisher]

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