SPRR2A expression in cholangiocarcinoma increases local tumor invasiveness but prevents metastasis

Clin Exp Metastasis. 2013 Oct;30(7):877-90. doi: 10.1007/s10585-013-9589-2. Epub 2013 Jun 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Duct Neoplasms / genetics*
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic / pathology*
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / pathology
  • Cornified Envelope Proline-Rich Proteins / genetics*
  • Down-Regulation
  • Epithelial-Mesenchymal Transition
  • Flow Cytometry
  • Humans
  • Mice
  • Mice, SCID
  • Mucin-1 / physiology
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Metastasis / genetics*
  • Polymerase Chain Reaction

Substances

  • Cornified Envelope Proline-Rich Proteins
  • Mucin-1
  • SPRR2A protein, human