Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia

Cancer Cell. 2012 Jun 12;21(6):836-47. doi: 10.1016/j.ccr.2012.04.024.

Abstract

Stromal responses elicited by early stage neoplastic lesions can promote tumor growth. However, the molecular mechanisms that underlie the early recruitment of stromal cells to sites of neoplasia remain poorly understood. Here, we demonstrate an oncogenic Kras(G12D)-dependent upregulation of GM-CSF in mouse pancreatic ductal epithelial cells (PDECs). An enhanced GM-CSF production is also observed in human PanIN lesions. Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells. The suppression of GM-CSF production inhibits the in vivo growth of Kras(G12D)-PDECs, and, consistent with the role of GM-CSF in Gr1(+)CD11b(+) mobilization, this effect is mediated by CD8(+) T cells. These results identify a pathway that links oncogenic activation to the evasion of antitumor immunity.

Publication types

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

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • CD11b Antigen / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Transformation, Neoplastic*
  • Cells, Cultured
  • Epithelial Cells / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Myeloid Cells / metabolism
  • Pancreatic Ducts / cytology
  • Pancreatic Ducts / metabolism*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • RNA Interference
  • Receptors, Chemokine / metabolism

Substances

  • CD11b Antigen
  • Gr-1 protein, mouse
  • Receptors, Chemokine
  • Green Fluorescent Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)