title: SPRR2A expression in cholangiocarcinoma increases local tumor invasiveness but prevents metastasis.
abstract: Cholangiocarcinoma morbidity and mortality is attributable to local invasiveness and regional lymph node and distant organ metastasis. Cholangiocarcinoma progression follows a series of sequential events that resemble wound healing reactions: local invasion resembles the epithelial migration phase involving epithelial-mesenchymal transition (EMT); colonization at distant sites resembles epithelial restitution seen during the reverse process, mesenchymal-epithelial transition (MET). In this study we compare the in vivo local and metastatic growth potential of cholangiocarcinoma cell lines with respect to expression of a novel pSTAT3-dependent, biliary epithelial cell wound healing protein, small proline-rich protein 2A (SPRR2A). SPRR2A has been associated with local aggressiveness, but decreased metastatic capabilities in other cancers. Stable SPRR2A transfection into two cholangiocarcinoma cell lines (SG231 and HuCCT-1), previously shown by us to induce permanent EMT, resulted in local aggressiveness but an inability to form metastases. In contrast, SPRR2A-negative epithelial control cells showed relatively poor local aggressiveness, but readily formed metastatic tumors. Post-intrasplenic injection cell tracking showed that: (a) mesenchymal (SPRR2A+) cells were not trapped in the liver, but were rapidly cleared through mesenteric lymph nodes and did not form metastases; whereas (b) epithelial (SPRR2A-) controls were primarily entrapped within MUC-1-associated liver "micro-infarcts" that later evolved into metastatic colonies. SPRR2A-associated tumor behavior was mimicked by MUC1 shRNA, which induced EMT and, like SPRR2A+ cells, showed reduced metastatic capabilities. Cholangiocarcinoma local invasion involves EMT processes, whereas MET and MUC1 expression promote metastasis. A better understanding of disease progression should help target treatment for this deadly neoplasm.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, 15260, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Specht
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.forename: Isao
authors.initials: I
authors.lastname: Nozaki
authors.forename: John G
authors.initials: JG
authors.lastname: Lunz
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D018396:Mucin-1 / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D016133:Polymerase Chain Reaction
chemical_list: D055233:Cornified Envelope Proline-Rich Proteins; D018396:Mucin-1; C101744:SPRR2A protein, human