Slit-Robo signaling mediates lymphangiogenesis and promotes tumor lymphatic metastasis

Biochem Biophys Res Commun. 2010 May 28;396(2):571-7. doi: 10.1016/j.bbrc.2010.04.152. Epub 2010 May 8.

Abstract

The Slit family of guidance cues binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit-Robo signaling had been reported to function as chemoattractive signal for vascular endothelial cells during angiogenesis. In this study, we found that Robo1 was expressed in lymphatic endothelial cells to mediate the migration and tube formation of these cells upon Slit2 stimulation, which were specifically inhibited by the function-blocking antibody R5 to Slit2/Robo1 interaction. To further explore the lymphangiogenic effect and significance mediated by Slit-Robo signaling, we intercrossed Slit2 transgenic mice with a non-metastatic RIP1-Tag2 mouse tumor model, and found that transgenic overexpression of Slit2 significantly enhanced tumor lymphangiogenesis and subsequently promoted mesenteric lymph node metastasis of pancreatic islet tumors. Taken together, our findings reveal that through interacting with Robo1, Slit2 is a novel and potent lymphangiogenic factor and contributes to tumor lymphatic metastasis.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma / metabolism
  • Carcinoma / pathology
  • Cell Line
  • Endothelial Cells / metabolism
  • Humans
  • Insulinoma / metabolism
  • Insulinoma / pathology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lymphangiogenesis / genetics*
  • Lymphatic Metastasis / genetics*
  • Lymphatic Metastasis / pathology
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction

Substances

  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • roundabout protein
  • Slit homolog 2 protein