title: ADAM17 silencing in mouse colon carcinoma cells: the effect on tumoricidal cytokines and angiogenesis.
abstract: ADAM17 (a disintegrin and metalloprotease 17) is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.
authors.affiliation: Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Das
authors.forename: Maria
authors.initials: M
authors.lastname: Czarnek
authors.forename: Monika
authors.initials: M
authors.lastname: Bzowska
authors.forename: Renata
authors.initials: R
authors.lastname: Mężyk-Kopeć
authors.forename: Krystyna
authors.initials: K
authors.lastname: Stalińska
authors.forename: Barbara
authors.initials: B
authors.lastname: Wyroba
authors.forename: Jolanta
authors.initials: J
authors.lastname: Sroka
authors.forename: Jarosław
authors.initials: J
authors.lastname: Jucha
authors.forename: Dawid
authors.initials: D
authors.lastname: Deneka
authors.forename: Paulina
authors.initials: P
authors.lastname: Stokłosa
authors.forename: Justyna
authors.initials: J
authors.lastname: Ogonek
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Madeja
authors.forename: Joanna
authors.initials: J
authors.lastname: Bereta
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D020890:Neuregulin-1; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; D051722:ADAM Proteins; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse