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  • 1.
    Dixelius, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Larsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Sasaki, Takako
    Holmqvist, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lu, Lingge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Timpl, Rupert
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis2000In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 95, no 11, p. 3403-3411Article in journal (Refereed)
    Abstract [en]

    Endostatin, which corresponds to the C-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis. Fibroblast growth factor-2 (FGF-2)-induced angiogenesis in the chicken chorioallantoic membrane was inhibited by endostatin, but not by an endostatin mutant R158/270A, lacking heparin-binding ability. Endostatin was internalized by endothelial cells, but not by mouse fibroblasts. Treatment of murine brain endothelial (IBE) cells with endostatin reduced the proportion of cells in S phase, whereas growth-arrested IBE cells in collagen gels treated with endostatin displayed enhanced tubular morphogenesis. IBE cells overexpressing Shb, an adaptor protein implicated in angiostatin-induced apoptosis, displayed elevated apoptosis and decreased tubular morphogenesis in collagen gels in response to endostatin when added together with FGF-2. Induction of apoptosis was dependent on the heparin-binding ability of endostatin and the expression of Shb with a functional Src homology 2 (SH2)-domain. Endostatin treatment for 10 minutes or 24 hours induced tyrosine phosphorylation of Shb and formation of multiprotein complexes. An Shb SH2 domain fusion protein precipitated a 125-kd phosphotyrosyl protein in endostatin-treated cells. The 125-kd component either contained intrinsic tyrosine kinase activity or occurred in complex with a tyrosine kinase. In conclusion, our data show that endostatin induces tyrosine kinase activity and enhanced apoptosis in FGF-treated endothelial cells.

  • 2.
    Gerwins, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Anti-Vascular endothelial growth factor-based angiostatics2002In: Encyclopedia of Cancer / [ed] Joseph R. Bertino, Amsterdam: Elsevier , 2002, 2 ed., Vol. 1, p. 135-Chapter in book (Other academic)
  • 3.
    Lindberg, Nanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Jiang, Yiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Differential roles of p16Ink4a and p19Arf in suppressing gliomagenesis from oligodendrocyte progenitor cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Version:1.0 StartHTML:0000000226 EndHTML:0000029504 StartFragment:0000002830 EndFragment:0000029468 SourceURL:file://localhost/Users/nannalindberg/Ctva%20tumor%20suppressors/Manuskript/MS%20Ctva%20knockar%20091013NL.doc

    CDKN2a encodes the tumor suppressor proteins p16INK4a and p14ARF (p19Arf in mouse) whose functions are frequently lost in human glioblastoma. From previous studies using the RCAS/TV-Atv-a mouse model we have shown that p16Ink4a and p19Arf individually and combined couldan suppress glioma development in Nestin expressing cells (in Ntv-a mice) and in Gfap expressing cells (in Gtv-a mice) (Uhrbom, Dai et al. 2002; Uhrbom, Kastemar et al. 2005; Tchougounova, Kastemar et al. 2007). Recently, we showed that oligodendrocyte progenitor cells (OPCs) could act as cell of origin for glioma by making a Ctv-a mouse in which CNPase expressing cells couldan be targeted by retroviral infection (Lindberg, Kastemar et al. 2009). Here In the current study we have investigated the roles of p16Ink4a and p19Arf in tumor development from OPCs.

    Unexpectedly, we found that p19Arf only only could suppress oncogene induced gliomagenesis. Loss of Arf caused significantly increased incidence and malignancy of PDGF-B induced tumors and decreased survival compared to Ctv-a wt mice. In addition, Arf deficiency facilitated K-RAS+AKT induced glioma development. Loss of Ink4a, however, lead to nocould not enable tumor induction by (K-RAS++AKT and caused a slight decrease in (PDGF-B) induced tumor incidence. Similarly, wWhen inducing tumors in adult Ctv-a mice we found that Arf loss but not Ink4a loss  enabled tumor induction. Taken together, our data suggest that p19Arf but not p16Ink4a is a tumor suppressor in OPCs of both newborn and adult mice.

  • 4.
    Moore, Lynette M
    et al.
    MD Andersen Cancer Center.
    Holmes, Kristen M
    MD Andersen Cancer Center.
    Smith, Sarah M
    MD Andersen Cancer Center.
    Wu, Ying
    MD Andersen Cancer Center.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Sawaya, Raymond
    MD Andersen Cancer Center.
    Bruner, Janet M
    MD Andersen Cancer Center.
    Fuller, Gregory N
    MD Andersen Cancer Center.
    Zhang, Wei
    MD Andersen Cancer Center.
    IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 39, p. 16675-16679Article in journal (Refereed)
    Abstract [en]

    The levels of insulin-like growth factor-binding protein 2 (IGFBP2) are elevated during progression of many human cancers. By using a glial-specific transgenic mouse system (RCAS/Ntv-a), we reported previously that IGFBP2 is an oncogenic factor for glioma progression in combination with platelet-derived growth factor-beta (PDGFB). Because the INK4a-ARF locus is often deleted in high-grade gliomas (anaplastic oligodendroglioma and glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of PDGFB-initiated oligodendroglioma. We demonstrate here that homozygous deletion of Ink4a-Arf bypasses the requirement of exogenously introduced IGFBP2 for glioma progression. Instead, absence of Ink4a-Arf resulted in elevated endogenous tumor cell IGFBP2. An inverse relationship between p16(INK4a) and IGFBP2 expression was also observed in human glioma tissue samples and in 90 different cancer cell lines by using Western blotting and reverse-phase protein lysate arrays. When endogenous IGFBP2 expression was attenuated by an RCAS vector expressing antisense IGFBP2 in our mouse model, a decreased incidence of anaplastic oligodendroglioma as well as prolonged survival was observed. Thus, p16(INK4a) is a negative regulator of the IGFBP2 oncogene. Loss of Ink4a-Arf results in increased IGFBP2, which contributes to glioma progression, thereby implicating IGFBP2 as a marker and potential therapeutic target for Ink4a-Arf-deleted gliomas.

  • 5.
    Niklasson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Zhang, X-Q
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafsdottir, Sigrun M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjögren, Maria
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Vennström, Björn
    Forsberg, Maud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enlarged lateral ventricles and aberrant behavior in mice overexpressing PDGF-B in embryonic neural stem cells2010In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 316, no 17, p. 2779-2789Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) is important in central nervous system (CNS) development, and aberrant expression of PDGF and its receptors has been linked to developmental defects and brain tumorigenesis. We previously found that neural stem and progenitor cells in culture produce PDGF and respond to it by autocrine and/or paracrine signaling. We therefore aimed to examine CNS development after PDGF overexpression in neural stem cells in vivo. Transgenic mice were generated with PDGF-B under control of a minimal nestin enhancer element, which is specific for embryonic expression and will not drive adult expression in mice. The resulting mouse showed increased apoptosis in the developing striatum, which suggests a disturbed regulation of progenitor cells. Later in neurodevelopment, in early postnatal life, mice displayed enlarged lateral ventricles. This enlargement remained into adulthood and it was more pronounced in male mice than in transgenic female mice. Nevertheless, there was an overall normal composition of cell types and numbers in the brain and the transgenic mice were viable and fertile. Adult transgenic males, however, showed behavioral aberrations and locomotor dysfunction. Thus, a tightly regulated expression of PDGF during embryogenesis is required for normal brain development and function in mice.

  • 6. Pickering, Chris
    et al.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Rosendahl, Sofi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fex-Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    A low ethanol dose affects all types of cells in mixed long-term embryonic cultures of the cerebellum2010In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 106, no 6, p. 472-478Article in journal (Refereed)
    Abstract [en]

    The beneficial effect of the '1-drink-a-day' lifestyle is suggested by studies of cardiovascular health, and this recommendation is increasingly followed in many countries. The main objective of this study was to determine whether this pattern of ethanol use would be detrimental to a pregnant woman. We exposed a primary culture of rat cerebellum from embryonic day 17 (corresponding to second trimester in humans) to ethanol at a concentration of 17.6 mM which is roughly equivalent to one glass of wine. Acutely, there was no change in cell viability after 5 or 8 days of exposure relative to control. By 11 days, a reduction in the number of viable cells was observed without an accompanying change in caspase-3 activity (marker of apoptotic cell death), suggesting changes in cell proliferation. As the proportion of nestin-positive cells was higher in the ethanol-treated cultures after 5 days, we hypothesized that an increase in differentiation to neurons would compensate for the ongoing neuronal death. However, there were limits to this compensatory ability as the relative proportion of nestin-positive cells was decreased after 11 days. To further illustrate the negative long-term effects of this ethanol dose, cultures were exposed for 30 days. After this period, virtually no neurons or myelinating oligodendrocytes were present in the ethanol-treated cultures. In conclusion, chronic exposure to ethanol, even at small doses, dramatically and persistently affects normal development.

  • 7.
    Rolny, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Mazzone, Massimiliano
    Tugues, Sònia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Laoui, Damya
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Coulon, Cathy
    Squadrito, Mario Leonardo
    Segura, Inmaculada
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Knevels, Ellen
    Costa, Sandra
    Vinckier, Stefan
    Dresselaer, Tom
    Åkerud, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    De Mol, Maria
    Salomäki, Henriikka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wyns, Sabine
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Buysschaert, Ian
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Himmelreich, Uwe
    Van Ginderachter, Jo A.
    De Palma, Michele
    Dewerchin, Mieke
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Carmeliet, Peter
    HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PIGF2011In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 19, no 1, p. 31-44Article in journal (Refereed)
    Abstract [en]

    Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HAG relies substantially on downregulation of placental growth factor (PIGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PIGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment.

  • 8.
    Tchougounova, Elena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Jiang, Yiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Bråsäter, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Lindberg, Nanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence2009In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 12, p. 1537-1548Article in journal (Refereed)
    Abstract [en]

    SOX5 is a member of the high-mobility group superfamily of architectural non-histone proteins involved in gene regulation and maintenance of chromatin structure in a wide variety of developmental processes. Sox5 was identified as a brain tumor locus in a retroviral insertional mutagenesis screen of platelet-derived growth factor B (PDGFB)-induced mouse gliomas. Here we have investigated the role of Sox5 in PDGFB-induced gliomagenesis in mice. We show that Sox5 can suppress PDGFB-induced glioma development predominantly upon Ink4a-loss. In human glioma cell lines and tissues, we found very low levels of SOX5 compared with normal brain. Overexpression of Sox5 in human glioma cells led to a reduction in clone formation and inhibition of proliferation. Combined expression of Sox5 and PDGFB in primary brain cell cultures caused decreased proliferation and an increased number of senescent cells in the Ink4a-/- cells only. Protein analyses showed a reduction in the amount and activation of Akt and increased levels of p27(Kip1) upon Sox5 expression that was dominant to PDGFB signaling and specific to Ink4a-/- cells. Upon inhibition of p27(Kip1), the effects of Sox5 on proliferation and senescence could be reversed. Our data suggest a novel pathway, where Sox5 may suppress the oncogenic effects of PDGFB signaling during glioma development by regulating p27(Kip1) in a p19(Arf)-dependent manner, leading to acute cellular senescence.

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