title: Thyroid Transcription Factor 1 Reprograms Angiogenic Activities of Secretome.
abstract: Through both gain- and loss-of-TTF-1 expression strategies, we show that TTF-1 positively regulates vascular endothelial growth factor (VEGF) and that the VEGF promoter element contains multiple TTF-1-responsive sequences. The major signaling receptor for VEGF, i.e VEGFR2, also appears to be under a direct and positive regulation of TTF-1. The TTF-1-dependent upregulation of VEGF was moderately sensitive to rapamycin, implicating a partial involvement of mammalian target of rapamycin (mTOR). However, hypoxia did not further increase the secreted VEGF level of the TTF-1(+) lung cancer cells. The TTF-1-induced VEGF upregulation occurs in both compartments (exosomes and exosome-depleted media (EDM)) of the conditioned media. Surprisingly, the EDM of TTF-1(+) lung cancer cells (designated EDM-TTF-1(+)) displayed an anti-angiogenic activity in the endothelial cell tube formation assay. Mechanistic studies suggest that the increased granulocyte-macrophage colony-stimulating factor (GM-CSF) level in the EDM-TTF-1(+) conferred the antiangiogenic activities. In human lung cancer, the expression of TTF-1 and GM-CSF exhibits a statistically significant and positive correlation. In summary, this study provides evidence that TTF-1 may reprogram lung cancer secreted proteome into an antiangiogenic state, offering a novel basis to account for the long-standing observation of favorable prognosis associated with TTF-1(+) lung adenocarcinomas.
authors.affiliation: Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA.|Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, USA.
authors.forename: Lauren W
authors.initials: LW
authors.lastname: Wood
authors.affiliation: Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA.|Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, USA.
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Cox
authors.affiliation: Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA.|Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, USA.
authors.forename: Cody A
authors.initials: CA
authors.lastname: Phelps
authors.affiliation: Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA.|Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, USA.
authors.forename: Shao-Chiang
authors.initials: SC
authors.lastname: Lai
authors.affiliation: Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Poddar
authors.affiliation: Institute for Basic Biomedical Sciences, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Conover
authors.initials: C
authors.lastname: Talbot
authors.affiliation: Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA.|Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mu
mesh_terms: D000072283:A549 Cells; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D055354:Exosomes / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007211:Indoles / Q000633:toxicity; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; D000906:Antibodies; D017077:Culture Media, Conditioned; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D011758:Pyrroles; D034741:RNA, Small Interfering; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases