title: Expression of Ras GTPase isoforms in normal and diseased pancreas.
abstract: BACKGROUND
  Ki-Ras is well studied in its oncogenic form in relation to pancreatic pathologies. However, the individual contribution of each of the wild-type Ras isoforms (Ha-, Ki-, and N-) in pancreatic cells in health and disease is unknown.
  
  
  METHODS
  Archival formalin-fixed, paraffin-embedded specimens of normal (n = 6) and malignant pancreas (n = 35) were used for immuno-histochemical detection of Ras isoforms using a modified polymer system. In addition, immunogold labelling for Ras isoforms was done for subcellular localisation under electron microscopy.
  
  
  RESULTS
  Pancreatic ductal cells expressed Ha-Ras in the cytoplasm, with Ki-Ras in the apical region and N-Ras (50% of cases) in a supranuclear distribution. Pancreatic acinar cells express all three isoforms with some nuclear expression of Ki-Ras and supranuclear expression of N-Ras. Islets show Ki- and Ha-Ras mainly with differential expression of Ha-Ras (beta cells showing less Ha-Ras and more Ki-Ras than alpha cells). Electron microscopy shows that Ha-Ras is mainly localised in the endoplasmic reticulum and Golgi apparatus of the acinar cells with some plasma membrane localisation of Ki-Ras in the ductal cells. There was no change in any of the Ras isoform expression in the ductal or acinar cells in various malignancies studied (Mann-Whitney U test, p > 0.1).
  
  
  CONCLUSIONS
  Ras isoforms have distinct and separate cellular and subcellular distribution that may persist even in the malignantly transformed state. Understanding this distinct functional distribution patterns in detail is an essential step if mutant Ki-Ras is to be targeted in the pancreas by genetic or molecular therapeutic tools.
authors.affiliation: Department of Surgery, King's College Hospital, Guy's King's and St Thomas' School of Medicine, King's College London, London, UK.
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
authors.forename: Ron
authors.initials: R
authors.lastname: Senkus
authors.forename: Jane
authors.initials: J
authors.lastname: Moorhead
authors.forename: Mashal
authors.initials: M
authors.lastname: Al-Nawab
authors.forename: Ameet G
authors.initials: AG
authors.lastname: Patel
authors.forename: Irving S
authors.initials: IS
authors.lastname: Benjamin
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Hendry
mesh_terms: D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D015388:Organelles / Q000201:enzymology / Q000648:ultrastructure; D046790:Pancreas, Exocrine / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D010182:Pancreatic Diseases / Q000378:metabolism* / Q000473:pathology; D010183:Pancreatic Ducts / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D018631:ras Proteins