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Search Results: 1 - 10 of 940 matches for " Kari Alitalo "
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Embryonic vascular endothelial cells are malleable to reprogramming via Prox1 to a lymphatic gene signature
Harold Kim, Vicky PKH Nguyen, Tatiana V Petrova, Maribelle Cruz, Kari Alitalo, Daniel J Dumont
BMC Developmental Biology , 2010, DOI: 10.1186/1471-213x-10-72
Abstract: Overexpression of Prox1 in vascular endothelial cells during embryonic development results in the reprogramming of genes to that of a more lymphatic signature. Consequent to this overexpression, embryos suffer from gross edema that results in embryonic lethality at E13.5. Furthermore, hemorrhaging and anemia is apparent along with clear defects in lymph sac development. Alterations in junctional proteins resulting in an increase in vascular permeability upon Prox1 overexpression may contribute to the complications found during embryonic development.We present a novel mouse model that addresses the importance of Prox1 in early embryonic lymphangiogenesis. It is clear that there needs to be a measured pattern of expression of Prox1 during embryonic development. Furthermore, Prox1 reprograms vascular endothelial cells in vivo by creating a molecular signature to that of a lymphatic endothelial cell.The specialization of the vasculature is driven by a number of molecular pathways that dictate the fate of blood vessels to that of an artery or vein [1]. Following this initial programming, the development of the lymphatic system is dependent on the further differentiation of the venous endothelium. The newly differentiated lymphatic endothelial cells migrate in a polarized fashion to coalesce into an early lymph sac, which then progress to form the lymphatic vasculature proper [2,3].A number of genes have been found to be associated with the lymphatic endothelial cell profile, for example LYVE-1, Podoplanin and VEGFR-3 [4-6]. In addition to this profile, the transcription factor Prox1 has been found to act as an important regulatory switch, altering the molecular identity of venous endothelium and imparting them with attributes that augment lymphatic development. Indeed, genetic ablation of prox1 results in embryonic lethality; hemizygous null mice are found to die shortly after birth [3]. In both cases, a major developmental defect was found to involve the emerging lympha
Blocking Fibroblast Growth Factor Receptor Signaling Inhibits Tumor Growth, Lymphangiogenesis, and Metastasis
Frédéric Larrieu-Lahargue, Alana L. Welm, Marion Bouchecareilh, Kari Alitalo, Dean Y. Li, Andreas Bikfalvi, Patrick Auguste
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039540
Abstract: Fibroblast Growth Factor receptor (FGFR) activity plays crucial roles in tumor growth and patient survival. However, FGF (Fibroblast Growth Factor) signaling as a target for cancer therapy has been under-investigated compared to other receptor tyrosine kinases. Here, we studied the effect of FGFR signaling inhibition on tumor growth, metastasis and lymphangiogenesis by expressing a dominant negative FGFR (FGFR-2DN) in an orthotopic mouse mammary 66c14 carcinoma model. We show that FGFR-2DN-expressing 66c14 cells proliferate in vitro slower than controls. 66c14 tumor outgrowth and lung metastatic foci are reduced in mice implanted with FGFR-2DN-expressing cells, which also exhibited better overall survival. We found 66c14 cells in the lumen of tumor lymphatic vessels and in lymph nodes. FGFR-2DN-expressing tumors exhibited a decrease in VEGFR-3 (Vascular Endothelial Growth Factor Receptor-3) or podoplanin-positive lymphatic vessels, an increase in isolated intratumoral lymphatic endothelial cells and a reduction in VEGF-C (Vascular Endothelial Growth Factor-C) mRNA expression. FGFs may act in an autocrine manner as the inhibition of FGFR signaling in tumor cells suppresses VEGF-C expression in a COX-2 (cyclooxygenase-2) or HIF1-α (hypoxia-inducible factor-1 α) independent manner. FGFs may also act in a paracrine manner on tumor lymphatics by inducing expression of pro-lymphangiogenic molecules such as VEGFR-3, integrin α9, prox1 and netrin-1. Finally, in vitro lymphangiogenesis is impeded in the presence of FGFR-2DN 66c14 cells. These data confirm that both FGF and VEGF signaling are necessary for the maintenance of vascular morphogenesis and provide evidence that targeting FGFR signaling may be an interesting approach to inhibit tumor lymphangiogenesis and metastatic spread.
Viral Oncogene–Induced DNA Damage Response Is Activated in Kaposi Sarcoma Tumorigenesis
Sonja Koopal,Johanna H Furuhjelm,Annika J?rviluoma,Sari J??maa,Pawan Pyakurel,Christel Pussinen,Maria Wirzenius,Peter Biberfeld,Kari Alitalo,Marikki Laiho,P?ivi M Ojala
PLOS Pathogens , 2007, DOI: 10.1371/journal.ppat.0030140
Abstract: Kaposi sarcoma is a tumor consisting of Kaposi sarcoma herpesvirus (KSHV)–infected tumor cells that express endothelial cell (EC) markers and viral genes like v-cyclin, vFLIP, and LANA. Despite a strong link between KSHV infection and certain neoplasms, de novo virus infection of human primary cells does not readily lead to cellular transformation. We have studied the consequences of expression of v-cyclin in primary and immortalized human dermal microvascular ECs. We show that v-cyclin, which is a homolog of cellular D-type cyclins, induces replicative stress in ECs, which leads to senescence and activation of the DNA damage response. We find that antiproliferative checkpoints are activated upon KSHV infection of ECs, and in early-stage but not late-stage lesions of clinical Kaposi sarcoma specimens. These are some of the first results suggesting that DNA damage checkpoint response also functions as an anticancer barrier in virally induced cancers.
Angiopoietin-Like 4 Mediates PPAR Delta Effect on Lipoprotein Lipase-Dependent Fatty Acid Uptake but Not on Beta-Oxidation in Myotubes
Marius R. Robciuc, Paulina Skrobuk, Andrey Anisimov, Vesa M. Olkkonen, Kari Alitalo, Robert H. Eckel, Heikki A. Koistinen, Matti Jauhiainen, Christian Ehnholm
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046212
Abstract: Peroxisome proliferator-activated receptor (PPAR) delta is an important regulator of fatty acid (FA) metabolism. Angiopoietin-like 4 (Angptl4), a multifunctional protein, is one of the major targets of PPAR delta in skeletal muscle cells. Here we investigated the regulation of Angptl4 and its role in mediating PPAR delta functions using human, rat and mouse myotubes. Expression of Angptl4 was upregulated during myotubes differentiation and by oleic acid, insulin and PPAR delta agonist GW501516. Treatment with GW501516 or Angptl4 overexpression inhibited both lipoprotein lipase (LPL) activity and LPL-dependent uptake of FAs whereas uptake of BSA-bound FAs was not affected by either treatment. Activation of retinoic X receptor (RXR), PPAR delta functional partner, using bexarotene upregulated Angptl4 expression and inhibited LPL activity in a PPAR delta dependent fashion. Silencing of Angptl4 blocked the effect of GW501516 and bexarotene on LPL activity. Treatment with GW501516 but not Angptl4 overexpression significantly increased palmitate oxidation. Furthermore, Angptl4 overexpression did not affect the capacity of GW501516 to increase palmitate oxidation. Basal and insulin stimulated glucose uptake, glycogen synthesis and glucose oxidation were not significantly modulated by Angptl4 overexpression. Our findings suggest that FAs-PPARdelta/RXR-Angptl4 axis controls the LPL-dependent uptake of FAs in myotubes, whereas the effect of PPAR delta activation on beta-oxidation is independent of Angptl4.
Essential Role of the Coxsackie - and Adenovirus Receptor (CAR) in Development of the Lymphatic System in Mice
Momina Mirza, Mei-Fong Pang, Mohamad Amr Zaini, Paula Haiko, Tuomas Tammela, Kari Alitalo, Lennart Philipson, Jonas Fuxe, Kerstin Sollerbrant
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037523
Abstract: The coxsackie- and adenovirus receptor (CAR) is a cell adhesion molecule predominantly associated with epithelial tight junctions in adult tissues. CAR is also expressed in cardiomyocytes and essential for heart development up to embryonic day 11.5, but not thereafter. CAR is not expressed in vascular endothelial cells but was recently detected in neonatal lymphatic vessels, suggesting that CAR could play a role in the development of the lymphatic system. To address this, we generated mice carrying a conditional deletion of the CAR gene (Cxadr) and knocked out CAR in the mouse embryo at different time points during post-cardiac development. Deletion of Cxadr from E12.5, but not from E13.5, resulted in subcutaneous edema, hemorrhage and embryonic death. Subcutaneous lymphatic vessels were dilated and structurally abnormal with gaps and holes present at lymphatic endothelial cell-cell junctions. Furthermore, lymphatic vessels were filled with erythrocytes showing a defect in the separation between the blood and lymphatic systems. Regionally, erythrocytes leaked out into the interstitium from leaky lymphatic vessels explaining the hemorrhage detected in CAR-deficient mouse embryos. The results show that CAR plays an essential role in development of the lymphatic vasculature in the mouse embryo by promoting appropriate formation of lymphatic endothelial cell-cell junctions.
Suppressive Effects of Vascular Endothelial Growth Factor-B on Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Tumorigenesis
Imke Albrecht,Lucie Kopfstein,Karin Strittmatter,Tibor Schomber,Annelie Falkevall,Carolina E. Hagberg,Pascal Lorentz,Michael Jeltsch,Kari Alitalo,Ulf Eriksson,Gerhard Christofori,Kristian Pietras
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014109
Abstract: The family of vascular endothelial growth factors (VEGF) contains key regulators of blood and lymph vessel development, including VEGF-A, -B, -C, -D, and placental growth factor. The role of VEGF-B during physiological or pathological angiogenesis has not yet been conclusively delineated. Herein, we investigate the function of VEGF-B by the generation of mouse models of cancer with transgenic expression of VEGF-B or homozygous deletion of Vegfb.
Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer
Hanseul Yang, Chan Kim, Min-Ju Kim, Reto A Schwendener, Kari Alitalo, Warren Heston, Injune Kim, Wun-Jae Kim, Gou Koh
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-36
Abstract: The orthotopic urinary bladder cancer (OUBC) model was generated by intravesical injection of MBT-2 cell lines. We investigated the angiogenesis, lymphangiogenesis, and CD11b+/CD68+ tumor-associated macrophages (TAM) by using immunofluorescence staining. OUBC displayed a profound lymphangiogenesis and massive infiltration of TAM in primary tumor and lymphatic metastasis in lymph nodes. TAM flocked near lymphatic vessels and express higher levels of VEGF-C/D than CD11b- cells. Because VEGFR-3 was highly expressed in lymphatic vascular endothelial cells, TAM could assist lymphangiogenesis by paracrine manner in bladder tumor. VEGFR-3 expressing adenovirus was administered to block VEGF-C/D signaling pathway and clodronate liposome was used to deplete TAM. The blockade of VEGF-C/D with soluble VEGF receptor-3 markedly inhibited lymphangiogenesis and lymphatic metastasis in OUBC. In addition, the depletion of TAM with clodronate liposome exerted similar effects on OUBC.VEGF-C/D are the main factors of lymphangiogenesis and lymphatic metastasis in bladder cancer. Moreover, TAM plays an important role in these processes by producing VEGF-C/D. The inhibition of lymphangiogenesis could provide another therapeutic target to inhibit lymphatic metastasis and recurrence in patients with invasive bladder cancer.Bladder cancer ranks as the second most common genitourinary cancer and is associated with frequent distant metastasis at the time of both initial diagnosis and recurrence [1,2]. Even though radical cystectomy and lymph node dissection may be curative, about 50% of patients with muscle-invasive bladder cancer eventually experience recurrence and metastases within 2 years of surgery, and most of them die of the disease [1]. In patients with bladder cancer, the presence of metastasis in regional lymph node is a strong indicator of high recurrence (~55% at 5 years after cystectomy) and relatively poor survival rate (~45% at 5 years after cystectomy) [3,4]. Intriguingly, pati
Short and Long-Term Effects of hVEGF-A165 in Cre-Activated Transgenic Mice
Pia Lepp?nen, Ivana Kholová, Anssi J. M?h?nen, Kari Airenne, Suvi Koota, Hannu Mansukoski, Johanna N?rv?inen, Maria Wirzenius, Leena Alhonen, Juhani J?nne, Kari Alitalo, Seppo Yl?-Herttuala
PLOS ONE , 2006, DOI: 10.1371/journal.pone.0000013
Abstract: We have generated a transgenic mouse where hVEGF-A165 expression has been silenced with loxP-STOP fragment, and we used this model to study the effects of hVEGF-A165 over-expression in mice after systemic adenovirus mediated Cre-gene transfer. Unlike previous conventional transgenic models, this model leads to the expression of hVEGF-A165 in only a low number of cells in the target tissues in adult mice. Levels of hVEGF-A165 expression were moderate and morphological changes were found mainly in the liver, showing typical signs of active angiogenesis. Most mice were healthy without any major consequences up to 18 months after the activation of hVEGF-A165 expression. However, one mouse with a high plasma hVEGF-A165 level died spontaneously because of bleeding into abdominal cavity and having liver hemangioma, haemorrhagic paratubarian cystic lesions and spleen peliosis. Also, two mice developed malignant tumors (hepatocellular carcinoma and lung adenocarcinoma), which were not seen in control mice. We conclude that long-term uncontrolled hVEGF-A165 expression in only a limited number of target cells in adult mice can be associated with pathological changes, including possible formation of malignant tumors and uncontrolled bleeding in target tissues. These findings have implications for the design of long-term clinical trials using hVEGF-A165 gene and protein.
Subwavelength resolution with three-dimensional isotropic transmission-line lenses
Pekka Alitalo,Sergei Tretyakov
Physics , 2007, DOI: 10.1016/j.metmat.2007.09.001
Abstract: Dispersion, impedance matching and resolution characteristics of an isotropic three-dimensional flat lens ("superlens") are studied. The lens is based on cubic meshes of interconnected transmission lines and bulk loads. We study a practical realization of the lens, based on the microstrip technology. The dispersion equations that have been previously derived, are verified with full-wave simulations. The isotropy of the structure is verified with analytical as well as simulation results. The resolution characteristics of a practically realizable, lossy lens are studied analytically.
Electromagnetic cloaking of cylindrical objects by multilayer or uniform dielectric claddings
Constantinos A. Valagiannopoulos,Pekka Alitalo
Physics , 2012, DOI: 10.1103/PhysRevB.85.115402
Abstract: We show that dielectric or even perfectly conducting cylinders can be cloaked by a uniform or a layered dielectric cladding, without the need of any exotic or magnetic material parameters. In particular, we start by presenting a simple analytical concept that can accurately describe the cloaking effect obtained with conical silver plates in the visible spectrum. The modeled structure has been originally presented in [S. A. Tretyakov, P. Alitalo, O. Luukkonen, C. R. Simovski, Phys. Rev. Lett., vol. 103, p. 103905, 2009], where its operation as a cloak in the optical frequencies was studied only numerically. We model rigorously this configuration as a multi-layer dielectric cover surrounding the cloaked object, with excellent agreement to the simulation results of the actual device. The concept of using uniform or multilayer dielectric covers, with relative permittivities larger than unity, is then successfully extended to cloaking of impenetrable objects such as conducting cylinders.
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