title: Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells.
abstract: Tumor-associated angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate here that the critical step in establishing the angiogenic capability of human tumor cells is the repression of a key secreted anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. In transformed epithelial cells, a signaling pathway leading from Ras to Tsp-1 repression induces the sequential activation of PI3 kinase, Rho and ROCK, leading to activation of Myc through phosphorylation, thereby enabling Myc to repress Tsp-1 transcription. In transformed fibroblasts, however, the repression of Tsp-1 can be achieved by an alternative mechanism involving inactivation of both p53 and pRb. We thus describe novel mechanisms by which the activation of oncogenes in epithelial cells and the inactivation of tumor suppressors in fibroblasts permits angiogenesis and, in turn, tumor formation.
authors.affiliation: 1] Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA [2] Department of Surgery, Harvard Medical School, Boston, MA, USA [3] Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Watnick
authors.affiliation: 1] Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA [2] Department of Surgery, Harvard Medical School, Boston, MA, USA [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Rodriguez
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1] Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA [2] Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway.
authors.forename: A L
authors.initials: AL
authors.lastname: Blois
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rangarajan
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ince
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Cambridge, MA, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D018631:ras Proteins / Q000502:physiology
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins
references.citation: Nature. 1999 Jul 29;400(6743):468-72
references.pmid: 10440378
references.citation: J Cell Biol. 2005 Feb 14;168(4):643-53
references.pmid: 15716381
references.citation: EMBO J. 1996 May 1;15(9):2208-16
references.pmid: 8641286
references.citation: Oncogene. 1994 Jul;9(7):1925-9
references.pmid: 8208539
references.citation: Cell. 1997 Jan 24;88(2):277-85
references.pmid: 9008168
references.citation: Semin Cancer Biol. 2001 Feb;11(1):5-13
references.pmid: 11243894
references.citation: Genes Dev. 2001 Jan 1;15(1):50-65
references.pmid: 11156605
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9810-4
references.pmid: 7568223
references.citation: Int J Cancer. 1989 Feb 15;43(2):270-2
references.pmid: 2563720
references.citation: Int J Radiat Oncol Biol Phys. 1992;22(3):397-402
references.pmid: 1735668
references.citation: N Engl J Med. 1991 Jan 3;324(1):1-8
references.pmid: 1701519
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4622-7
references.pmid: 11274365
references.citation: Methods Enzymol. 2000;325:264-72
references.pmid: 11036609
references.citation: Lab Invest. 1999 Apr;79(4):427-38
references.pmid: 10211995
references.citation: Mol Cancer Res. 2006 Nov;4(11):821-9
references.pmid: 17114340
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Mol Cell Biol. 2000 Oct;20(20):7624-33
references.pmid: 11003658
references.citation: J Biol Chem. 1999 Nov 12;274(46):32580-7
references.pmid: 10551811
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12485-90
references.pmid: 11606713
references.citation: Proc Natl Acad Sci U S A. 1990 Apr;87(8):3092-6
references.pmid: 1691500
references.citation: Proc Natl Acad Sci U S A. 1986 Jan;83(2):470-3
references.pmid: 3001737
references.citation: Ann Surg Oncol. 1998 Oct-Nov;5(7):585-9
references.pmid: 9831105
references.citation: Semin Cancer Biol. 2001 Feb;11(1):23-30
references.pmid: 11243896
references.citation: Cell Growth Differ. 1994 Oct;5(10):1077-83
references.pmid: 7848909
references.citation: Cancer Genet Cytogenet. 2001 Apr 1;126(1):1-7
references.pmid: 11343771
references.citation: Cell. 1991 Jun 14;65(6):1063-72
references.pmid: 1828393
references.citation: Clin Cancer Res. 1999 May;5(5):1041-56
references.pmid: 10353737
references.citation: J Clin Invest. 1991 Jun;87(6):1883-8
references.pmid: 2040684
references.citation: Mol Cell Biol. 2006 Jun;26(11):4240-56
references.pmid: 16705174
references.citation: Nature. 1998 Nov 5;396(6706):84-8
references.pmid: 9817205
references.citation: Princess Takamatsu Symp. 1991;22:339-47
references.pmid: 1726933
references.citation: Mol Cell Biol. 1996 Oct;16(10):5313-27
references.pmid: 8816443
references.citation: Genes Dev. 1999 Jun 1;13(11):1382-97
references.pmid: 10364156
references.citation: J Biol Chem. 1994 Feb 18;269(7):5241-8
references.pmid: 8106507
references.citation: Anticancer Res. 2001 Mar-Apr;21(2B):1321-5
references.pmid: 11396207
references.citation: J Biol Chem. 1998 Jul 17;273(29):18623-32
references.pmid: 9660836
references.citation: Cell. 1996 Aug 9;86(3):353-64
references.pmid: 8756718
references.citation: Cancer Res. 2008 Sep 1;68(17):7090-9
references.pmid: 18757424
references.citation: J Biol Chem. 1996 Nov 29;271(48):30741-7
references.pmid: 8940053
references.citation: Hum Mol Genet. 1999 Feb;8(2):185-93
references.pmid: 9931326
references.citation: Mol Biol Cell. 2005 Jul;16(7):3117-27
references.pmid: 15843433
references.citation: Eur J Cancer. 1996 Dec;32A(14):2386-93
references.pmid: 9059326
references.citation: Blood. 2012 Jun 7;119(23):5512-21
references.pmid: 22427202
references.citation: Zhonghua Yi Xue Za Zhi (Taipei). 1998 Aug;61(8):441-7
references.pmid: 9745159
references.citation: Nature. 1988 Jan 14;331(6152):173-5
references.pmid: 3340164
references.citation: J Biol Chem. 2006 May 19;281(20):13957-63
references.pmid: 16543245
references.citation: Nature. 1983 Aug 18-24;304(5927):596-602
references.pmid: 6308472
references.citation: Science. 1998 Jan 16;279(5349):349-52
references.pmid: 9454332
references.citation: Nature. 1999 Jul 29;400(6743):464-8
references.pmid: 10440377
references.citation: Cancer Metastasis Rev. 1995 Dec;14(4):351-62
references.pmid: 8821095
references.citation: Mol Cell Biol. 1994 Aug;14(8):5510-22
references.pmid: 8035827
references.citation: Nat Genet. 2006 Sep;38(9):1060-5
references.pmid: 16878133
references.citation: Nat Genet. 2003 Mar;33(3):401-6
references.pmid: 12590264
references.citation: Nature. 2000 Aug 3;406(6795):532-5
references.pmid: 10952316
references.citation: Biochem J. 1995 Nov 1;311 ( Pt 3):735-8
references.pmid: 7487926
references.citation: Cell. 1991 Jun 14;65(6):1053-61
references.pmid: 1828392
references.citation: Curr Biol. 1999 Feb 11;9(3):136-45
references.pmid: 10021386
references.citation: Cell Growth Differ. 2000 Apr;11(4):201-10
references.pmid: 10775037
references.citation: J Biol Chem. 2003 Jul 18;278(29):26435-42
references.pmid: 12748197
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12718-23
references.pmid: 14555767
references.citation: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4834-8
references.pmid: 3014513
references.citation: Am J Pathol. 1999 Oct;155(4):1253-60
references.pmid: 10514407
references.citation: Cancer Res. 2009 Nov 15;69(22):8742-51
references.pmid: 19887617
references.citation: Mol Cell Biol. 1991 Feb;11(2):1107-13
references.pmid: 1846663
references.citation: Cell. 1992 Aug 7;70(3):401-10
references.pmid: 1643658
references.citation: Nature. 1997 Oct 30;389(6654):990-4
references.pmid: 9353125
references.citation: Cancer Res. 1999 Nov 15;59(22):5808-14
references.pmid: 10582703
references.citation: Curr Top Microbiol Immunol. 1984;113:172-7
references.pmid: 6090062
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2110-5
references.pmid: 10051603
references.citation: EMBO J. 1994 Sep 1;13(17):4070-9
references.pmid: 8076602
references.citation: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6624-8
references.pmid: 1697685
references.citation: Proc Natl Acad Sci U S A. 1976 May;73(5):1513-7
references.pmid: 179089
references.citation: Genomics. 1996 Jul 1;35(1):207-14
references.pmid: 8661122
references.citation: Cell. 1995 Feb 24;80(4):533-41
references.pmid: 7867061
references.citation: Nat Med. 1995 Feb;1(2):149-53
references.pmid: 7585012
references.citation: Genes Dev. 2003 Aug 1;17(15):1813-6
references.pmid: 12897050
references.citation: Life Sci. 1994;55(19):1487-92
references.pmid: 7968216
references.citation: Mol Cell Biol. 2003 Nov;23(21):7648-57
references.pmid: 14560010
references.citation: Science. 1989 Dec 8;246(4935):1306-9
references.pmid: 2479986
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3216-20
references.pmid: 8386367
references.citation: Am J Physiol Renal Physiol. 2004 Feb;286(2):F278-87
references.pmid: 14583433
references.citation: Cell Mol Immunol. 2013 Nov;10(6):506-12
references.pmid: 23954950
references.citation: J Biol Chem. 1992 Mar 5;267(7):4357-63
references.pmid: 1347042
references.citation: Cancer Res. 1997 May 1;57(9):1735-42
references.pmid: 9135017
references.citation: Genes Dev. 1993 Oct;7(10):1850-61
references.pmid: 8405995
references.citation: Cancer Res. 1995 Oct 15;55(20):4575-80
references.pmid: 7553632
references.citation: Cell. 1995 Jun 2;81(5):727-36
references.pmid: 7774014
references.citation: Nucleic Acids Res. 1987 Aug 11;15(15):5963-71
references.pmid: 3627975
references.citation: Cytometry. 1995 Sep 1;21(1):18-22
references.pmid: 8529465
references.citation: J Virol. 1979 Jun;30(3):674-82
references.pmid: 225536
references.citation: J Cell Biol. 1997 Aug 11;138(3):707-17
references.pmid: 9245797
references.citation: Nucleic Acids Res. 1995 May 25;23(10):1686-90
references.pmid: 7784172
references.citation: Int J Cancer. 1998 Jul 29;77(3):449-54
references.pmid: 9663609
references.citation: Nat Med. 1996 Jun;2(6):689-92
references.pmid: 8640562
references.citation: Cancer Res. 1987 Dec 15;47(24 Pt 1):6517-21
references.pmid: 3677090
references.citation: J Biol Chem. 1991 Dec 15;266(35):23521-4
references.pmid: 1748630
references.citation: Cell. 1991 Jun 14;65(6):1073-82
references.pmid: 1828394
references.citation: Oncogene. 2001 Sep 13;20(41):5826-35
references.pmid: 11593388
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Science. 1995 Sep 1;269(5228):1270-2
references.pmid: 7652575
references.citation: Cancer Cell. 2002 Feb;1(1):99-108
references.pmid: 12086892
references.citation: Science. 2002 Jan 4;295(5552):140-3
references.pmid: 11778052
references.citation: Oncogene. 2010 Jul 1;29(26):3781-92
references.pmid: 20453885
references.citation: Science. 1992 Dec 11;258(5089):1798-801
references.pmid: 1281554
references.citation: Nature. 1983 Nov 10-16;306(5939):194-6
references.pmid: 6646201
references.citation: FASEB J. 2002 Sep;16(11):1361-70
references.pmid: 12205027
references.citation: Mol Carcinog. 1995 Dec;14(4):286-93
references.pmid: 8519418
references.citation: Science. 2002 Apr 19;296(5567):550-3
references.pmid: 11910072
references.citation: Cold Spring Harb Symp Quant Biol. 1980;44 Pt 1,:123-30
references.pmid: 6253125
references.citation: J Virol. 1976 May;18(2):664-71
references.pmid: 178902
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15587-91
references.pmid: 9861013
references.citation: EMBO J. 1993 Dec;12(12):4739-46
references.pmid: 8223482
references.citation: Mol Cancer Res. 2005 Jul;3(7):413-23
references.pmid: 16046552
references.citation: Cancer Res. 2000 Jan 15;60(2):490-8
references.pmid: 10667605
references.citation: J Cell Physiol. 1996 Apr;167(1):95-105
references.pmid: 8698846
references.citation: Genes Dev. 2000 Oct 1;14(19):2501-14
references.pmid: 11018017
references.citation: J Virol. 2002 Apr;76(7):3145-57
references.pmid: 11884539
references.citation: Mol Biol Cell. 1992 Feb;3(2):211-20
references.pmid: 1550962
references.citation: Science. 1994 Sep 9;265(5178):1582-4
references.pmid: 7521539