title: PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential.
abstract: Neoplastic stroma is believed to influence tumour progression. Here, we examine phosphatase and tensin homolog deleted on chromosome ten (PTEN) status in the tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) focussing especially at the stromal cells.
  
  
  
  We asses PTEN at protein, messenger RNA and DNA level using a well-characterised PDAC cohort (n = 117). miR-21, known to target PTEN, is assessed after RNA extraction from different laser-capture-microdissected cell populations, including cancer cells and juxta-tumoural and tumour-remote stroma.
  
  
  
  PTEN deletion was the most frequent cause of PTEN protein loss in PDAC cells (71%) and correlated with vascular invasion (p = 0.0176) and decreased overall survival (p = 0.0127). Concomitant PTEN protein loss in tumour and juxta-tumoural stroma, found in 21.4% of PDACs, correlated with increased distant metastasis (p = 0.0045). Stromal cells with PTEN protein loss frequently showed PTEN genetic aberrations, including hemizygous PTEN deletion (46.6%) or chromosome 10 monosomy (40%). No alterations were found in the tumour-remote stroma. miR-21 was overexpressed by cancer- and juxta-tumoural stromal cells, in some cases without simultaneous PTEN gene alterations. No PTEN mutations or promoter methylation were detected.
  
  
  
  We find various mechanisms of PTEN protein loss in the different tumour cell populations, including allelic PTEN deletions, gross chromosomal 10 aberrations and altered miR-21 expression. PTEN deletion is a major cause of PTEN protein loss in PDAC and correlates with aggressive characteristics and worse outcome. PTEN protein loss in juxta-tumoural stromal cells is mostly due to PTEN haplo-insufficiency and characterises a subgroup of PDACs with enhanced metastatic potential. In the tumour microenvironment of the invasive front, PTEN silencing by miR-21 in cancer and surrounding stromal cells acts not only cooperatively but also independently of the genetic aberrations to precipitate PTEN protein loss and promote further tumour growth.
authors.affiliation: Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Wartenberg
authors.affiliation: Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Centeno
authors.affiliation: Molecular Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Haemmig
authors.affiliation: Molecular Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Erik
authors.initials: E
authors.lastname: Vassella
authors.affiliation: Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.affiliation: Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: José A
authors.initials: JA
authors.lastname: Galván
authors.affiliation: Molecular Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Neuenschwander
authors.affiliation: Molecular Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schlup
authors.affiliation: Department of Visceral Surgery, Insel University Hospital, Freiburgstrasse 4, CH-3010, Bern, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Gloor
authors.affiliation: Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
authors.affiliation: Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.affiliation: Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. Electronic address: eva.diamantis@pathology.unibe.ch.
authors.forename: Eva
authors.initials: E
authors.lastname: Karamitopoulou
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D017353:Gene Deletion; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000378:metabolism; D046228:Microarray Analysis; D015999:Multivariate Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D004273:DNA, Neoplasm; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D051059:PTEN Phosphohydrolase
keywords: MicroRNA-21; PTEN; Pancreatic cancer; Stromal cells; Tumour microenvironment