Activation of the ras/raf-1 signal transduction pathway in carcinoid tumor cells results in morphologic transdifferentiation

Academic Article


  • Background. Recent studies of neuroendocrine tumor cell lines suggest that ras/raf-1 activation could be detrimental to tumorigenesis. The mechanism by which it alters neuroendocrine tumor cells is unclear. We hypothesize that activation of the ras/raf signal transduction pathway may alter gastrointestinal carcinoid cells by inducing morphologic transdifferentiation. Methods. Pancreatic carcinoid (BON) cells were transduced in a stable manner with an estrogen inducible raf-1 fusion protein (creating "BON-raf cells"). BON and BON-raf cells were then treated with either control or 1 ╬╝mol/L estradiol (E2). Western blots were used to confirm the phosphorylation of extracellular signal-regulated kinase 1/2. Morphologic changes were evaluated using light and electron microscopy. Results. Western blots using antibodies against phosphorylated and unphosphorylated extracellular signal-regulated kinase 1/2. confirmed that phosphorylation was only present in the BON-raf E2 cells. BON cells treated with control and E2 and BON-raf cells treated with control all looked identical in culture. After treatment with E2 to induce raf-1, the BON-raf cells underwent dramatic morphologic changes. Under light and electron microscopy the cells became flatter and developed much sharper cellular borders mimicking cellular differentiation. Conclusions. Activation of the ras/raf-1 signal transduction pathway leads to prominent phenotypic changes that resemble differentiation of gastrointestinal carcinoid cells in vitro.
  • Published In

  • Surgery  Journal
  • Digital Object Identifier (doi)

    Author List

  • Sippel RS; Chen H; Zarnegar R
  • Start Page

  • 1035
  • End Page

  • 1039
  • Volume

  • 132
  • Issue

  • 6