PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential.

Wartenberg, Martin; Centeno, Irene; Haemmig, Stefan; Vassella, Erik; Zlobec, Inti; Galván, José A; Neuenschwander, Maja; Schlup, Cornelia; Gloor, Beat; Lugli, Alessandro; Perren, Aurel; Karamitopoulou, Evanthia (2016). PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential. European journal of cancer, 65, pp. 80-90. Elsevier 10.1016/j.ejca.2016.06.013

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BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology

UniBE Contributor:

Wartenberg, Martin; Vassella, Erik; Zlobec, Inti; Gloor, Beat; Lugli, Alessandro; Perren, Aurel and Karamitopoulou, Evanthia

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0959-8049

Publisher:

Elsevier

Language:

English

Submitter:

Aurel Perren

Date Deposited:

22 Dec 2016 08:49

Last Modified:

28 Apr 2017 10:23

Publisher DOI:

10.1016/j.ejca.2016.06.013

PubMed ID:

27475963

Uncontrolled Keywords:

MicroRNA-21; PTEN; Pancreatic cancer; Stromal cells; Tumour microenvironment

BORIS DOI:

10.7892/boris.91974

URI:

https://boris.unibe.ch/id/eprint/91974

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