Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer

Cancer Lett. 2009 May 8;277(1):114-20. doi: 10.1016/j.canlet.2008.11.035. Epub 2009 Jan 14.

Abstract

Despite a primary tumor suppressor role, there is compelling evidence suggesting that TGF-beta can promote tumor growth, invasion and metastasis in advanced stages of colorectal cancer. Blocking these tumor-promoting effects of TGF-beta provides a potentially important therapeutic strategy for the treatment of colorectal cancer. However, little is known about how the inhibitors of TGF-beta receptor kinases affect colorectal carcinogenesis in vivo. Here, we have observed that a novel dual kinase inhibitor of TGF-beta type I and type II receptors, LY2109761, inhibits TGF-beta-mediated activation of Smad and non-Smad pathways in CT26 colon adenocarcinoma cells having K-Ras mutation. The inhibitor attenuates the oncogenic effects of TGF-beta on cell migration, invasion and tumorigenicity of CT26 cells. Furthermore, LY2109761 decreases liver metastases and prolongs survival in an experimental metastasis model. These findings suggest that the dual kinase inhibitor LY2109761 has potential therapeutic value for metastatic colorectal cancer.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Genes, ras
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / prevention & control*
  • Liver Neoplasms / secondary*
  • Mice
  • Mice, Inbred BALB C
  • Mutation
  • Neoplasm Invasiveness
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use*
  • Signal Transduction / drug effects
  • Smad Proteins / physiology
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / physiology

Substances

  • LY2109761
  • Pyrazoles
  • Pyrroles
  • Smad Proteins
  • Transforming Growth Factor beta