Pancreatic stellate cell activation in pancreatitis and cancer Potential targets for the treatment of pancreatic fibrosis
Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, Germany
Pancreatic cancer (PC) constitutes the fourth leading cause of cancer death in Western countries for both sexes (1). Despite tremendous scientific efforts and much gain in know-ledge regarding the role of genetic alterations in pancreatic cancer, prognosis still remains dismal. Thus, the 5-year survi-val rate (< 5 %) (2) is worse than for any other kind of malig-nant tumour. A central pathological feature of PC and chronic pancreatitis (as a major risk factor of pancreatic cancer) is the extended fibrosis, which has been linked to the activation of pancreatic stellate cells (PSCs) (3, 4). PSCs are fibroblast-like cells comprising only 4 % of all pancreatic cells in the healt-hy organ. In response to pro-fibrogenic mediators, such as o-xidant stress, various cytokines and, in chronic pancreatitis, et-hanol metabolites, PSCs undergo morphological and functio-nal changes known as PSC activation. This process includes proliferation, excessive secretion of extracellular matrix prote-ins (such as collagens, fibronectin and laminin) as well as ex-hibition of a myofibroblast-like phenotype that is characteri-sed by enhanced expression of α-smooth muscle actin (5-7).
2. Desmoplasia in pancreatic cancer: pathop-hysiological and molecular aspects
Recent studies in various models of human cancers revea-led that stromal fibroblasts have a more profound effect on de-velopment and progression of carcinomas than was previous-ly appreciated. As one fundamental principle of fibroblast-me-diated cancer progression, secretion of paracrine factors sti-mulating proliferation and suppressing apoptosis has emerged. Typical mediators of such effects include the fibroblast growth factor (FGF) family, hepatocyte growth factor, the epithelial growth factor family and some Wnt proteins. Furthermore, in carcinoma cells with defective anti-proliferative transforming growth factor-beta (TGF-β) signalling (such as most human pancreatic cancer cells ), TGF-β-dependent pathways me-diating loss of adherens junctions and increased motility may be retained, favoring invasion and metastasis (9). PSCs have been shown to be a source of TGF-β (10). In addition to cyto-kines, extracellular matrix components themselves and mat-rix-degrading enzymes (which are also secreted by PSCs) eFig. 1 - Effects of stroma cells on pancreatic cancer cells and tumourpro-gression
Fig. 2 - Effects of pancreatic cancer cells on stroma cells xert direct effects on cancer cells. Stroma cell-derived media-tors are also likely to play a role in the induction of tumour re-sistance towards chemotherapy, suppression of tumour cell a-poptosis, and promotion of cancer cell invasion. Figure 1 sum-marises selected mediators of stroma cell effects on pancrea-tic cancer cells.
In PC and other stroma-rich human tumours, there is also another side of the coin: the cancer cells do not simply respond to fibroblast-derived mediators, but also actively stimulate fib-rogenesis. Thus, it has recently been shown by Bachem et al. (3) that pancreatic adenocarcinoma cells induce PSC activati-on by secreting growth factors including fibroblast growth fac-tor 2 and platelet-derived growth factor, as well as stimulators of ECM synthesis such as TGF-β1. Furthermore, cancer cell-derived mediators also promote exhibition of an activated my-ofibroblast-like PSC phenotype, as indicated by the enhanced expression of the actication marker α-smooth muscle actin (4). Based on studies in nude mice, Bachem et al. (3) also pro-vided direct evidence that PSCs in vivo strongly stimulate PC growth. Thus, a larger tumour volume was observed when tu-mour cells were injected not alone but in combination with pancreatic stellate cells into the animals. An overview of me-chanisms involved in stroma cell activation by cancer cells is given in figure 2.
Limitations of the current knowledge
Most data addressing the role of fibrosis in pancreatic can-cer are derived from cell culture studies and animal experi-ments. In one of the rare clinical studies, Watanabe et al. (19) found a strong correlation between the presence of a fibrotic focus, and reduced overall- as well as liver metastasis free survival of the patients. On the other hand, not all observations fit the picture of fibrosis as a progression factor of the tumour di-sease. Thus, Hartel et al. (20) recently reported high connecti-ve tissue growth factor levels in tissue samples to be correla-ted with better tumor differentiation and patient survival. Clearly, follow-up studies are required.
The molecular basics of PC cell – PSC interaction are in-completely understood. Specifically, neither PSC/PC-cell-de-rived mediators, nor their intracellular signalling cascades and target genes have been studied in a systematic manner, apply-ing recent methods of transcriptome and proteome analysis.
3. Therapeutic implications
Given the growing body of evidence suggesting fibrosis as an aggravating factor of pancreatic cancer, stroma cells might be-come an attractive target for an adjuvant „antifibrotic therapy“. Unfortunately, there are currently no established approaches to prevent or even reverse stellate cell activation in the pancreas. Possible candidates that warrant further investigations are, for e-xample, interferon-γ (an inhibitor of stellate cell activation in vitro), and substances that induce a quiescent PSC phenotype through modulating intracellular signal transduction pathways (e.g., thiazolidinediones as ligands of the intracellular receptor peroxisome proliferators-activated receptor-γ) [21, 22].
1 - Todd KE, Reber HA: Pancreatic neoplasms. Curr Opin Gastroenterol, 1996, 12: 436 - 41
2 - Schneider G, Siveke JT, Eckel F et al: Pancreatic cancer: basic and clinical aspects. Gastroenterology, 2005, 128: 1606 - 25
3 - Bachem MG, Schunemann M, Ramadani M et al: Pancreatic carcinoma cells induce fibrosis by stimulating pro-liferation and matrix synthesis of stellate cells. Gastroenterology, 2005, 128: 907 - 21
4 - Apte M V, Park S, Phillips PA et al: Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 2004, 29: 179 - 87
5 - Apte M V, Haber PS, Applegate TL et al: Periacinar stella-te shaped cells in rat pancreas: identification, isolation, and culture. Gut, 1998, 43: 128 - 33
6 - Bachem MG, Schneider E, Gross H et al: Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology, 1998, 115: 421 - 32
7 – Jater R: Molecular regulation of pancreatic stellate cell function. Mol Cancer, 2004, 3: 26
8 - Real FX: A "catastrophic hypothesis" for pancreas cancer progression. Gastroenterology, 2003,124: 1958 - 64
9 - Bhowmick NA, Neilson EG, Moses HL: Stromal fibrob-lasts in cancer initiation and progression. Nature, 2004, 432: 332 - 7
10 - Shek FW, Benyon RC, Walker FM et al: Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chro-nic pancreatitis. Am J Pathol, 2002,160: 1787 - 98
11 - Armstrong T, Packham G, Murphy LB et al: Type I col-lagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res, 2004, 10: 7427 - 37
12 - Miyamoto H, Murakami T, Tsuchida K et al: Stroma in-teraction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas, 2004, 28: 38 - 44
13 - Koninger J, Giese NA, di Mola FF et al: Overexpressed decorin in pancreatic cancer: potential tumor growth inhibiti-on and attenuation of chemotherapeutic action. Clin Cancer Res, 2004, 10: 4776 - 83
14 - Muerkoster S, Wegehenkel K, Arlt A et al: Tumor stroma interactions induce chemoresistance in pancreatic ductal car-cinoma cells involving increased secretion and paracrine ef-fects of nitric oxide and interleukin-1beta. Cancer Res, 2004, 64: 1331 - 7
15 - Qian LW, Mizumoto K, Maehara N et al: Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fib-roblasts: fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production. Cancer Lett, 2003, 190: 105 -12
16 - Ohuchida K, Mizumoto K, Murakami M et al: Radiation to stromal fibroblasts increases invasiveness of pancre-atic cancer cells through tumor-stromal interactions. Cancer Res, 2004, 64: 3215 - 22
17 - Kuniyasu H, Abbruzzese JL, Cleary KR et al: Induction of ductal and stromal hyperplasia by basic fibroblast growth factor produced by human pancreatic carcinoma. Int J Oncol, 2001,19: 681 - 5
18 - Lohr M, Schmidt C, Ringel J et al: Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res, 2001, 61: 550 - 5
19 - Watanabe I, Hasebe T, Sasaki S et al: Advanced pancrea-tic ductal cancer: fibrotic focus and beta-catenin expression correlate with outcome. Pancreas, 2003, 26: 326 - 33
20 - Hartel M, Di Mola FF, Gardini A et al: Desmoplastic re-action influences pancreatic cancer growth behavior. World J Surg, 2004, 28: 818 - 25
21 - Baumert JT, Sparmann G, Emmrich J et al: Inhibitory ef-fects of interferons on pancreatic stellate cell activation. World J Gastroenterol, 2006, 12: 896 - 901
22 - Jaster R, Lichte P, Fitzner B et al: Peroxisome prolifera-tor-activated receptor _ overexpression inhibits pro-fibrogenic activities of immortalized rat pancreatic stellate cells. J Cell Mol Med, 2005, 3: 670 - 82.Address for correspondence:
Dr. Robert Jaster
Department of Medicine, Division of Gastroenterology
Medical Faculty, University of Rostock, E. Heydemann Str. 6,
18057 Rostock, Germany