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First published online 16 January 2007
doi: 10.1242/jcs.03347
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Research Article |
1 Department of Clinical Chemistry and Pathobiochemistry, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany
2 Department of Gastroenterology, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany
3 Department of Surgery, Hospital Aalen, Im Kälblesrain 1, 73430 Aalen, Germany
4 Department of Pathology, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany
5 Department of Urology, University of Ulm, Prittwitzstr. 43, 89075 Ulm, Germany
* Author for correspondence (e-mail: max.bachem{at}uniklinik-ulm.de)
Accepted 15 November 2006
The effect of the characteristic desmoplastic reaction of pancreatic cancer on tumor progression is largely unknown. We investigated whether pancreatic stellate cells, which are responsible for the desmoplastic reaction, support tumor progression. Immunohistology revealed that matrix metalloproteinase-2 (MMP-2), which is suggested to promote pancreatic cancer progression, is present in stellate cells adjacent to cancer cells. In vitro, stellate cells exhibited a much higher basal expression of MMP-2 compared with cancer cells. Panc1-, MiaPaCa2- and SW850-conditioned media stimulated MMP-2 release of stellate cells as detected by zymography. Cancer cells expressed and released basigin [BSG, extracellular matrix metalloproteinase inducer (EMMPRIN), CD147], a glycoprotein that is known to stimulate MMP-2 in mesenchymal cells, as detected by immunostaining, western blot and reverse transcription-polymerase chain reaction. Tumor cell-conditioned medium and BSG purified by affinity chromatography from supernatants of cancer cells, but not supernatants depleted from BSG, stimulated expression of MMP-1 and MMP-2 of stellate cells as demonstrated by western blot and zymography. Moreover, the interaction of stellate cells and cancer cells promoted the invasiveness of Panc-1 cells in the chorioallantoic membrane assay and increased the weight of tumors induced by all carcinoma cell lines in nude mice by 2.1-3.7-fold. Our findings support the assumption that the interaction of stellate cells and cancer cells promotes progression of pancreatic cancer.
Key words: Pancreatic adenocarcinoma, Tumor-host interaction, Matrix metalloproteinases, Pancreatic stellate cell, Mouse xenograft model
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