Expression of Thrombospondin-1 in Human Pancreatic Adenocarcinomas: Role in Matrix Metalloproteinase-9 Production

Xiaohua QIAN2, Vicki L ROTHMAN1, Roberto F NICOSIA2, George P TUSZYNSKI1

1Department of Surgery, MCP Hahnemann University, Philadelphia, USA
2Department of Pathology, MCP Hahnemann University, Philadelphia, USA


Human pancreatic adenocarcinoma, an aggressive malignant disease, shows a strong desmoplastic reaction characterized by a remarkable proliferation of interstitial connective tissues. Thrombospondin-1 (TSP-1), a 450 kDa platelet and matrix glycoprotein, has been implicated in tumor invasion, angiogenesis and metastasis. TSP-1 and MMP-9 expression in pancreatic adenocarcinoma and control pancreas tissues was measured by immunohistochemistry. TSP-1 expression in pancreatic carcinoma cell lines, fibroblasts, and endothelial cells was measured by a competitive TSP-1 enzyme linked immunosorbent assay (ELISA). The effect of TSP-1 on MMP-9 production in pancreatic carcinoma cell lines was measured by zymography and Western blot analysis. Eighty five per cent (23/27) of cases of pancreatic adenocarcinoma showed increased TSP-1 staining in the desmoplastic stroma adjacent to tumor cells. No specific positive staining for TSP-1 was observed in the normal pancreatic tissues and the inflammatory areas. TSP-1 localized in tumor stroma surrounding the tumor cells expressing MMP-9. Using TSP-1 competitive ELISA, the secretion of TSP-1 by different pancreatic cancer cell lines into culture medium varied from 11.45 ± 14.08 to 275.82 ± 45.56 ng/10 6 cells/24 hours. The amounts of TSP-1 detected in both culture media and cell extracts from fibroblasts or endothelial cells were at least 2-3 fold higher than those from pancreatic cancer cells. TSP-1 augmented the production of matrix metalloproteinase-9, a matrix degrading enzyme, in pancreatic cancer cells in vitro. Stromally-derived TSP-1 up-regulates the production of MMP-9 by pancreatic adenocarcinoma. These data are consistent with the conclusion that TSP-1-rich stroma is involved in regulating matrix remodeling in tumor invasion. Pathology & Oncology Research, Vol 7, Nr 4, 251-259, 2001

Key words: extracellular matrix; thrombospondin-1; matrix metalloproteinase; pancreatic cancer; tumor invasion; tissue inhibitor of metalloproteinase

Received: Sep 10, 2001; accepted: Oct 8, 2001
Correspondence: George P TUSZYNSKI, Department of Surgery, MCP Hahnemann University, Broad and Vine Streets Philadelphia 19102-1192, USA; Tel: (215) 762-6299, Fax: (215) 762-8787; E-mail:

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