Abstract
Background
Adenocarcinomas of the pancreas are characterized by a rapid progression, an early metastasis, a limited response to chemo- and radiotherapy, and an intense fibrotic reaction known as tumor desmoplasia. Carcinoma cells are surrounded by a dense stroma consisting of myofibroblast-like cells, collagens, and fibronectin.
Materials and methods
This review describes the interaction of activated pancreatic stellate cells (myofibroblast-like cells) with tumor cells in pancreas adenocarcinomas. Our data were obtained in cell culture experiments and in in vivo investigations.
Results
Carcinoma cells produce soluble mediators and stimulate motility, proliferation, matrix-, and MMP synthesis of stellate cells. Vice versa-activated stellate cells release mitogens, stimulating proliferation of cancer cells. Cancer cell proliferation and resistance to apoptosis might further be induced by the microenvironment (extracellular matrix), which is primarily provided by stellate cells. A very important aspect in the interaction of stellate cells with cancer cells is the expression of EMMPRIN (extracellular matrix metalloproteinase inducer) by cancer cells, the shedding of the extracellular part of EMMPRIN by matrix metalloproteinases (MMPs), and the induction of MMPs in stellate cells by soluble EMMPRIN. In particular, the stellate cells in close proximity to tumor cells therefore express MMPs and degrade connective tissue.
Conclusion
Through complex interactions between stellate cells and carcinoma cells, tumor progression and cancer cell invasion are accelerated. As we gain better understanding of these mechanisms, adequate therapies to reduce tumor cell invasion and cancer progression might be developed.
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Abbreviations
- DMEM:
-
Dulbecco’s modification of Eagle’s medium
- ECM:
-
extracellular matrix
- FAK:
-
focal adhesion kinase
- FCS:
-
fetal calf serum
- FN:
-
fibronectin
- PDAC:
-
pancreas ductal adenocarcinoma
- PDGF:
-
platelet-derived growth factor
- PSC:
-
pancreatic stellate cells
- SMA:
-
α-smooth muscle actin
- SN:
-
culture supernatant
References
Brand RE, Tempero MA (1998) Pancreatic cancer. Curr Opin Oncol 10:362–366 Review
Warshaw AL, Fernandez-del Castillo C (1992) Pancreatic carcinoma. N Engl J Med 326:455–465
Cruickshank AH (1986) Solid carcinomas of the exocrine pancreas. Pathology of the pancreas. Springer, London, UK, pp 155–177
Imamura T, Iguchi H, Manabe T, Ohshio G, Yoshimura T, Wang ZH, Suwa H, Ishigami S, Imamura M (1995) Quantitative analysis of collagen and collagen subtypes I, III, and V in human pancreatic cancer, tumor-associated chronic pancreatitis, and alcoholic chronic pancreatitis. Pancreas 11:357–364
Mollenhauer J, Roether I, Kern HF (1987) Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas 2:14–24
Löhr M, Trautmann B, Gottler M, Peters S, Zauner I, Maillet B, Klöppel G (1994) Human ductal adenocarcinomas of the pancreas express extracellular matrix proteins. Br J Cancer 69:144–151
Kuniyasu H, Abbruzzese JL, Cleary KR, Fidler IL (2001) Induction of ductal and stromal hyperplasia by basic fibroblast growth factor produced by human pancreatic carcinoma. Int J Oncol 19:681–685
Gress TM, Menke A, Bachem MG, Müller-Pillasch F, Ellenrieder V, Weidenbach H, Wagner M, Schmid RM, Adler G (1998) Extracellular matrix and pancreatic diseases. Digestion 59:625–637 (Review)
Gress TM, Müller-Pillasch F, Lerch MM, Friess H, Buchler M, Adler G (1995) Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int J Cancer 62:407–413
Yen TW, Aardal NP, Bronner MP, Thorning DR, Savard CE, Lee SP, Bell RH (2002) Myofibroblasts are responsible for the desmoplastic reaction surrounding human pancreatic carcinomas. Surgery 131:129–134
Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, Ramm GA, Buchler M, Friess H, McCarroll JA, Keogh G, Merrett N, Pirola R, Pirola R, Wilson JS (2004) Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29:179–187
Yoshida S, Yokota T, Ujiki M, Ding XZ, Pelham C, Adrian TE, Talamonti MS, Bell RH, Denham W (2004) Pancreatic cancer stimulates pancreatic stellate cell proliferation and TIMP-1 production through the MAP kinase pathway. Biochem Biophys Res Commun 323:1241–1245
Bachem MG, Schünemann M, Ramadani M, Siech M, Berger H, Buck A, Zhou S, Schmid-Kostas A, Adler G (2005) Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128:907–921
Friedman SL (2004) Stellate cells: a moving target in hepatic fibrogenesis. Hepatology 40:1041–1043
Eng FJ, Friedman SL (2000) Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex. Am J Physiol Gastrointest Liver Physiol 279:G7–G11
Gressner AM, Bachem MG (1995) Molecular mechanisms of liver fibrogenesis—a homage to the role of activated fat-storing cells. Digestion 56:335–346. Review
Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS (1998) Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43:128–133
Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Berger H, Grünert A, Adler G (1998) Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115:421–432
Saotome T, Inoue H, Fujimiya M (1997) Morphological and immunocytochemical identification of periacinar fibroblast-like cells derived from human pancreatic acini. Pancreas 14:373–382
Buchholz M, Kestler HA, Holzmann K, Ellenrieder V, Schneiderhan W, Siech M, Adler G, Bachem MG, Gress TM (2005) Transcriptome analysis of human hepatic and pancreatic stellate cells: organ-specific variations of a common transcriptional phenotype. J Mol Med 83:795–805
Schneiderhan W, Diaz F, Fundel M, Zhou S, Siech M, Hasel C, Moller P, Gschwend JE, Seufferlein T, Gress T, Adler G, Bachem MG (2007) Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay. J Cell Sci 120:512–519
Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H, Nabeshima K (1995) The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 55:434–439
Caudroy S, Polette M, Nawrocki-Raby B, Cao J, Toole BP, Zucker S, Birembaut P (2002) EMMPRIN-mediated MMP regulation in tumor and endothelial cells. Clin Exp Metastasis 19:697–702
Kanekura T, Chen X, Kanzaki T (2002) Basigin (CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. Int J Cancer 99:520–528
Sameshima T, Nabeshima K, Toole BP, Yokogami K, Okada Y, Goya T, Koono M, Wakisaka S (2000) Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane type matrix metalloproteinase and activated gelatinase A in co-cultures with brain derived fibroblasts. Cancer Lett 157:177–184
Taylor PM, Woodfield RJ, Hodgkin MN, Pettitt TR, Martin A, Kerr DJ, Wakelam MJ (2002) Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway. Oncogene 21:5765–5772
Zucker S, Hymowitz M, Rollo EE, Mann R, Conner CE, Cao J, Foda HD, Tompkins DC, Toole BP (2001) Tumorigenic potential of extracellular matrix metalloproteinase inducer. Am J Pathol 158:1921–1928
Marieb EA, Zoltan-Jones A, Li R, Misra S, Ghatak S, Cao J, Zucker S, Toole BP (2004) EMMPRIN promotes anchorage-independent growth in human mammary carcinoma cells by stimulating hyaluronan production. Cancer Res 64:1229–1232
Sidhu SS, Mengistab AT, Tauscher AN, LaVail J, Basbaum C (2004) The microvesicle as a vehicle for EMMPRIN in tumor–stromal interactions. Oncogene 23:956–963
Haug C, Lenz C, Diaz F, Bachem MG (2004) Oxidized low-density lipoproteins stimulate extracellular matrix metalloproteinase inducer (EMMPRIN) release by coronary smooth muscle cells. Arterioscler Thromb Vasc Biol 24:1823–1829
Ellenrieder V, Alber B, Lacher U, Hendler SF, Menke A, Boeck W, Wagner M, Wilda M, Friess H, Büchler M, Adler G, Gress TM (2000) Role of MT-MMPs and MMP-2 in pancreatic cancer progression. Int J Cancer 85:14–20
Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174
Liotta LA, Kohn EC (2001) The microenvironment of the tumour–host interface. Nature 411:375–379
Zucker S, Cao J, Chen WT (2000) Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19:6642–6650
Itoh T, Tanioka M, Matsuda H, Nishimoto H, Yoshioka T, Suzuki R, Uehira M (1999) Experimental metastasis is suppressed in MMP-9-deficient mice. Clin Exp Metastasis 17:177–181
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Grant support: Deutsche Forschungsgemeinschaft (SFB 518, project A7 to M.G.B. and WS).
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Bachem, M.G., Zhou, S., Buck, K. et al. Pancreatic stellate cells—role in pancreas cancer. Langenbecks Arch Surg 393, 891–900 (2008). https://doi.org/10.1007/s00423-008-0279-5
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DOI: https://doi.org/10.1007/s00423-008-0279-5