title: Overexpression of membrane metalloendopeptidase inhibits substance P stimulation of cholangiocarcinoma growth.
abstract: Substance P (SP) promotes cholangiocyte growth during cholestasis by activating its receptor, NK1R. SP is a proteolytic product of tachykinin (Tac1) and is deactivated by membrane metalloendopeptidase (MME). This study aimed to evaluate the functional role of SP in the regulation of cholangiocarcinoma (CCA) growth. NK1R, Tac1, and MME expression and SP secretion were assessed in human CCA cells and nonmalignant cholangiocytes. The proliferative effects of SP (in the absence/presence of the NK1R inhibitor, L-733,060) and of L-733,060 were evaluated. In vivo, the effect of L-733,060 treatment or MME overexpression on tumor growth was evaluated by using a xenograft model of CCA in nu/nu nude mice. The expression of Tac1, MME, NK1R, PCNA, CK-19, and VEGF-A was analyzed in the resulting tumors. Human CCA cell lines had increased expression of Tac1 and NK1R, along with reduced levels of MME compared with nonmalignant cholangiocytes, resulting in a subsequent increase in SP secretion. SP treatment increased CCA cell proliferation in vitro, which was blocked by L-733,060. Treatment with L-733,060 alone inhibited CCA proliferation in vitro and in vivo. Xenograft tumors derived from MME-overexpressed human Mz-ChA-1 CCA cells had a slower growth rate than those derived from control cells. Expression of PCNA, CK-19, and VEGF-A decreased, whereas MME expression increased in the xenograft tumors treated with L-733,060 or MME-overexpressed xenograft tumors compared with controls. The study suggests that SP secreted by CCA promotes CCA growth via autocrine pathway. Blockade of SP secretion and NK1R signaling may be important for the management of CCA.
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas;
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Han
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Holly
authors.initials: H
authors.lastname: Standeford
authors.forename: Shanika
authors.initials: S
authors.lastname: Avila
authors.forename: Kelly
authors.initials: K
authors.lastname: McDaniel
authors.forename: Matthew
authors.initials: M
authors.lastname: McMillin
authors.forename: Syeda
authors.initials: S
authors.lastname: Afroze
authors.forename: Micheleine
authors.initials: M
authors.lastname: Guerrier
authors.forename: Morgan
authors.initials: M
authors.lastname: Quezada
authors.forename: Debolina
authors.initials: D
authors.lastname: Ray
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kennedy
authors.forename: Laura
authors.initials: L
authors.lastname: Hargrove
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D053539:Keratin-19; D064729:Neurokinin-1 Receptor Antagonists; D018809:Proliferating Cell Nuclear Antigen; D018040:Receptors, Neurokinin-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013373:Substance P; D015260:Neprilysin
keywords: VEGF; autocrine; biliary cancer; neuroendocrine; sensory innervation