The mTOR pathway is frequently activated in pancreatic ductal adenocarcinoma and chronic pancreatitis

Appl Immunohistochem Mol Morphol. 2010 Oct;18(5):442-7. doi: 10.1097/PAI.0b013e3181de115b.

Abstract

Introduction: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase critical to cell growth and proliferation through its effects on protein translation. Activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway has been described in various tumor types. Earlier studies have demonstrated loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function in some pancreatic ductal adenocarcinomas (PDAs). We performed immunohistochemistry for PTEN and p-RPS6 (major downstream mTOR effector) in a group of PDAs. An assessment of chronic pancreatitis (CP) and normal pancreas (NL) was performed in parallel.

Materials and methods: Tissue microarrays were constructed from 49 PDA, 27 CP, and 12 NL. Cases were scored as follows: PTEN (intact: ≥ 5% staining and lost: < 5%) and p-RPS6 (0, 1+: modest intensity in ≥ 5% of cells and 2+: strong intensity ≥ 5% of cells).

Results: Forty-one percent of PDAs demonstrated loss of PTEN, and 75% demonstrated p-RPS6 immunoreactivity (1+ in 22 and 2+ in 3). PTEN was uniformly intact in NL and CP. Although p-RPS6 immunoreactivity was only noted in 1 NL control (8%), 1+ positivity was observed in 62% of CP.

Conclusions: mTOR pathway activation, as evidenced by p-RPS6 immunoreactivity, is frequent in PDA. p-RPS6 expression was also frequent in CP, highlighting the importance of this pathway in both neoplastic and inflammatory processes. Given evidence of pathway activation and the existence of specific anti-mTOR therapeutics, mTOR represents a logical target for directed biologic therapy.

MeSH terms

  • Carcinoma, Ductal / diagnosis*
  • Carcinoma, Ductal / metabolism
  • Carcinoma, Ductal / pathology
  • Humans
  • Immunohistochemistry
  • PTEN Phosphohydrolase / immunology
  • PTEN Phosphohydrolase / metabolism
  • Pancreas / metabolism
  • Pancreas / pathology
  • Pancreatic Neoplasms / diagnosis*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatitis, Chronic / diagnosis*
  • Pancreatitis, Chronic / metabolism
  • Pancreatitis, Chronic / pathology
  • Ribosomal Protein S6 Kinases, 90-kDa / immunology
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • PTEN Phosphohydrolase