Pancreatic stellate cell activation in pancreatitis and cancer Potential targets for the treatment of pancreatic fibrosis

Robert Jaster

Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, Germany

1. Introduction

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 [8]), 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].

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Address for correspondence:
Dr. Robert Jaster
Department of Medicine, Division of Gastroenterology
Medical Faculty, University of Rostock, E. Heydemann Str. 6,
18057 Rostock, Germany
Phone: +49-381-4947349
Fax: +49-381-4947482
E-mail: jaster@med.uni-rostock.de