Details

Autor(en) / Beteiligte

• Erkan, Mert
• Kleeff, Jörg
• Gorbachevski, Andre
• Reiser, Carolin
• Mitkus, Tomas
• Esposito, Irene
• Giese, Thomas
• Büchler, Markus W
• Giese, Nathalia A
• Friess, Helmut

Titel

Periostin Creates a Tumor-Supportive Microenvironment in the Pancreas by Sustaining Fibrogenic Stellate Cell Activity

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2007-04, Vol.132 (4), p.1447-1464

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2007

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Background & Aims : Pancreatic cancer creates desmoplasia by stimulating stellate cells (PSCs), thereby influencing tumor aggressiveness. The aim of this study was to analyze the impact of the PSC-specific matrix protein periostin on tumor responses to radiochemotherapy. Methods : PSCs and cancer cells in primary and metastatic lesions of patients treated with or without neoadjuvant radiochemotherapy were evaluated by immunohistochemistry. Periostin messenger-RNA levels determined by quantitative reverse-transcription polymerase chain reaction were correlated to patient survival. Interactions between PSCs and cancer cells and the effects of periostin in modulating cellular responses under conditions of hypoxia, starvation, and radiochemotherapy were assessed by immunoblotting and by growth, clonogenicity, and invasion assays. Results : Periostin messenger-RNA levels were elevated 42-fold in cancer, and patients with increased expression had a tendency toward shorter survival (19 vs 12 months; P = .14). Stromal cells were the only source of periostin in the pancreas and in metastatic sites. Cancer cell supernatants stimulated periostin secretion from PSCs. Recombinant periostin increased α–smooth muscle actin, periostin, collagen-1, fibronectin, and transforming growth factor-β1 expression while decreasing PSC invasiveness. These effects were reversed by silencing periostin expression and secretion by small interfering RNA transfection. In cancer cells, periostin stimulated growth and conferred resistance to starvation and hypoxia. In addition, the periostin downstream target collagen-1 significantly increased chemoresistance. Conclusions : Once stimulated by cancer cells, PSCs remain active via an autocrine periostin loop even under radiotherapy and produce excessive extracellular matrix proteins, creating a tumor-supportive microenvironment. Increased periostin expression may therefore reflect a more aggressive tumor phenotype.