Pancreatic tumor cells influence the composition of the extracellular matrix q Jo ¨rg Ko ¨ ninger a , Thomas Giese b , Fabio F. di Mola a , Moritz N. Wente a , Irene Esposito c , Max G. Bachem d , Nathalia A. Giese a , Markus W. Bu ¨ chler a , Helmut Friess a, * a Department of General Surgery, University of Heidelberg, Germany b Department of Immunology, University of Heidelberg, Germany c Institute of Pathology, University of Heidelberg, Germany d Department of Clinical Chemistry, University of Ulm, Germany Received 22 June 2004 Abstract The malignant behavior of cancers depends on the microenvironmental context. We investigated compositional alterations of the extracellular matrix (ECM) in pancreatic cancer, with special emphasis on the proteoglycans decorin, lumican, and versican. Com- pared with normal controls (n = 18), marked overexpression of these proteoglycans was observed in pancreatic cancer tissues (n = 30) by quantitative RT-PCR (p < 0.0001). Immunohistochemistry revealed abundance of proteoglycans in the ECM of pancre- atic cancer specimens, whereas tumor cells themselves were devoid of either decorin, lumican or versican. RT-PCR confirmed pan- creatic stellate cells (PSCs) as the major source of these proteins. Interestingly, TGFb1 and conditioned medium derived from pancreatic cancer cell lines synergistically suppressed the expression of known anti-tumor factors decorin and lumican, but stimu- lated the expression of pro-metastatic factor versican in cultured PSCs. These findings indicate that malignant cells can actively influence the composition of the ECM through TGFb1 and other soluble factors, altering their microenvironment in a tumor-fa- vorable way. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Pancreatic cancer; Pancreatic stellate cells; Decorin; Lumican; Versican; Extracellular matrix Tumor environment emerges as one of the major fac- tors that determine the behavior of malignant cells. The interactions between cancer cells and their micro- and macroenvironment create a condition that promotes tumor growth and protects it from immune attack. The functional association of cancer cells with their sur- rounding tissues forms a new ÔorganÕ that changes as malignancy progresses [1,2]. Remodeling of the extracel- lular matrix (ECM) through altered expression of mole- cules integrated in the functional network of cell-to-cell and cell-to-matrix interactions is essential for local tumor cell invasion and the formation of metastases [3]. Investigation of this process might provide new insight into the mechanism of tumorigenesis and could also lead to new therapeutic targets. Extended desmoplastic reaction is a hallmark of pan- creatic cancer. The strong fibrotic reaction around can- cer tissue is supposed to be a host reaction to the growing tumor [4–6]. Myofibroblasts are the main source for excess production of this fibrotic tissue which consists mainly of collagen types I and IV. Beside colla- gens, a multiplicity of extracellular matrix proteins are 0006-291X/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2004.08.008 q Abbreviations: ECM, extracellular matrix; PSC, pancreatic stellate cell; SLRP, small leucine-rich proteoglycans; TGFb, tumor growth factor b. * Corresponding author. Fax: +49 6221 56 6903. E-mail address: Helmut_Friess@med.uni-heidelberg.de (H. Friess). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 322 (2004) 943–949 BBRC