title: TGF-Beta suppresses VEGFA-mediated angiogenesis in colon cancer metastasis.
abstract: The FET cell line, derived from an early stage colon carcinoma, is non-tumorigenic in athymic nude mice. Engineered FET cells that express TGF-α (FETα) display constitutively active EGFR/ErbB signaling. These cells readily formed xenograft tumors in athymic nude mice. Importantly, FETα cells retained their response to TGF-beta-mediated growth inhibition, and, like the parental FET cells, expression of a dominant negative TGF-beta type II receptor (DNRII) in FETα cells (FETα/DNRII) abrogated responsiveness to TGF-beta-induced growth inhibition and apoptosis under stress conditions in vitro and increased metastatic potential in an orthotopic model in vivo, which indicates metastasis suppressor activity of TGF-beta signaling in this model. Cancer angiogenesis is widely regarded as a key attribute for tumor formation and progression. Here we show that TGF-beta signaling inhibits expression of vascular endothelial growth factor A (VEGFA) and that loss of autocrine TGF-beta in FETα/DNRII cells resulted in increased expression of VEGFA. Regulation of VEGFA expression by TGF-beta is not at the transcriptional level but at the post-transcriptional level. Our results indicate that TGF-beta decreases VEGFA protein stability through ubiquitination and degradation in a PKA- and Smad3-dependent and Smad2-independent pathway. Immunohistochemical (IHC) analyses of orthotopic tumors showed significantly reduced TGF-beta signaling, increased CD31 and VEGFA staining in tumors of FETα/DNRII cells as compared to those of vector control cells. These results indicate that inhibition of TGF-beta signaling increases VEGFA expression and angiogenesis, which could potentially contribute to enhanced metastasis of those cells in vivo. IHC studies performed on human colon adenocarcinoma specimens showed that TGF-beta signaling is inversely correlated with VEGFA expression, indicating that TGF-beta-mediated suppression of VEGFA expression exists in colon cancer patients.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Liying
authors.initials: L
authors.lastname: Geng
authors.forename: Anathbandhu
authors.initials: A
authors.lastname: Chaudhuri
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Talmon
authors.forename: James L
authors.initials: JL
authors.lastname: Wisecarver
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A
references.citation: Science. 1995 Jun 2;268(5215):1336-8
references.pmid: 7761852
references.citation: Cancer Res. 2013 Jan 15;73(2):725-35
references.pmid: 23139211
references.citation: Oncologist. 2012;17(8):1039-50
references.pmid: 22773560
references.citation: Arch Med Res. 2007 Jan;38(1):45-51
references.pmid: 17174722
references.citation: Mol Cancer Res. 2002 Nov;1(1):68-78
references.pmid: 12496370
references.citation: J Cell Biol. 1992 Jan;116(1):187-96
references.pmid: 1730743
references.citation: J Biol Chem. 2004 Sep 17;279(38):40237-44
references.pmid: 15271980
references.citation: Curr Biol. 1998 Nov 19;8(23):1243-52
references.pmid: 9822576
references.citation: J Biol Chem. 1996 Jul 19;271(29):17366-71
references.pmid: 8663343
references.citation: Prostate. 2010 Jan 1;70(1):17-26
references.pmid: 19725029
references.citation: J Biol Chem. 1995 Sep 15;270(37):22044-9
references.pmid: 7665626
references.citation: Cancer Res. 2008 May 1;68(9):3152-60
references.pmid: 18451140
references.citation: Oncol Rep. 2007 May;17(5):1095-9
references.pmid: 17390050
references.citation: Mol Cell Biol. 1996 Sep;16(9):4604-13
references.pmid: 8756616
references.citation: Br J Cancer. 2011 Mar 29;104(7):1079-84
references.pmid: 21386839
references.citation: PLoS One. 2011 May 03;6(5):e19335
references.pmid: 21559296
references.citation: Anticancer Res. 2008 Nov-Dec;28(6B):3865-70
references.pmid: 19192642
references.citation: Apoptosis. 2004 Nov;9(6):691-704
references.pmid: 15505412
references.citation: J Biol Chem. 1994 Oct 21;269(42):26449-55
references.pmid: 7929366
references.citation: J Biol Chem. 2001 Jul 27;276(30):28421-9
references.pmid: 11382768
references.citation: Ann Surg Oncol. 2010 Aug;17(8):2059-65
references.pmid: 20177795
references.citation: Cell Growth Differ. 1993 Feb;4(2):115-23
references.pmid: 8494782
references.citation: Endocr Rev. 1997 Feb;18(1):4-25
references.pmid: 9034784
references.citation: Oncogene. 1999 May 20;18(20):3098-103
references.pmid: 10340381
references.citation: Mol Reprod Dev. 2004 Jun;68(2):198-204
references.pmid: 15095341
references.citation: Cancer Res. 1999 Sep 15;59(18):4725-31
references.pmid: 10493532
references.citation: Circ Res. 2007 Feb 16;100(3):305-8
references.pmid: 17255526
references.citation: Cancer Res. 2011 Feb 1;71(3):998-1008
references.pmid: 21245094
references.citation: BMC Cancer. 2012 Jun 06;12:221
references.pmid: 22672900
references.citation: Oncology. 2005;69 Suppl 3:4-10
references.pmid: 16301830
references.citation: Gastroenterology. 2010 Mar;138(3):969-80.e1-3
references.pmid: 19909744
references.citation: Oncogene. 1998 Jul 16;17(2):227-36
references.pmid: 9674707
references.citation: EMBO J. 2002 Jul 15;21(14):3749-59
references.pmid: 12110587
references.citation: Nat Rev Cancer. 2003 Jun;3(6):401-10
references.pmid: 12778130
references.citation: Cancer Res. 2007 Jan 15;67(2):665-73
references.pmid: 17234777
references.citation: J Cell Biol. 2002 Jan 21;156(2):299-313
references.pmid: 11790801