institute of pathology

Research interests:
The laboratory’s main focus is to investigate the interactions between epithelial and mesenchymal cells in the process of pancreatic carcinogenesis. Pancreatic cancer is a very aggressive disease with a dismal prognosis. With its median survival time of 6-8 months after diagnosis and its 5-year survival rate of less than 1%, pancreatic cancer has one of the worst prognoses of all neoplastic diseases. This aggressive behaviour is related to a specific pattern of genetic changes that characterize pancreatic cancer during its development from precursor lesions (pancreatic intraepithelial neoplasia, PanIN) and affect its propensity for local and distant spreading. However, the reason for the extraordinary invasive ability of pancreatic ductal adenocarcinoma also resides in the relationship that the tumor cells establish with the surrounding tissue. Pancreatic cancer is characterized by a dense desmoplastic stroma, which is not found in other pancreatic primary or secondary tumors (Figure 1). This suggests an active role played by ductal adenocarcinoma cells in influencing the modification of the surrounding host tissue elements, in order to create a favourable microenvironment for their growth and spreading.

 In recent studies we have shown that:
1) Mast cells and macrophages, the main components of the inflammatory cell infiltrate in pancreatic cancer, are a source of VEGF-A, bFGF and VEGF-C, proangiogenic factors that are also widely expressed by the tumor cells. A correlation was demonstrated between the number of infiltrating inflammatory cells and the intratumoral microvessel density (IMD). Moreover, tumors with higher IMD and higher number of infiltrating inflammatory cells showed a tendency for a worse prognosis.

2) Mast cells accumulate in pancreatic cancer stroma and are the main source of stem cell factor (SCF) in pancreatic tissues. Pancreatic cancer cells express c-kit, the SCF-receptor, and to a lower extent, SCF itself. SCF had no effect on the growth of pancreatic cancer cells, whereas it inhibited the growth of the normal pancreatic ductal cell line TAKA-1. A growth-modulating role of mast cell-derived SCF in pancreatic ductal cells was then proposed, as also suggested by the selective accumulation of mast cells around ducts in pancreatic tissues.

3) Activated myofibroblasts, so called pancreatic stellate cells (PSC) play a major role in the generation of the desmoplastic stroma in pancreatic cancer and affect biological properties of pancreatic cancer cells (Figure 2). For example, PSC express Tenascin C (TNC), an oligomeric ECM glycoprotein that exerts pro- and anti-adhesive functions, acts as a growth and survival factor for normal and transformed cells but can also inhibit cell proliferation through its effects on intracellular pH and cellular rounding.
We showed that the expression of Tenascin C by PSC can be regulated by soluble factors, such as TNF-alpha and TGF-β1 that are released by the cancer cells. Another important result of this study was the detection of Tenascin C expression with increased frequency in the progression from PanIN-1 lesions to pancreatic cancer, and a parallel switch from cytoplasmic to cell surface expression of annexin II. This finding points to a possible interaction of Tenascin C and annexin II in the process of pancreatic carcinogenesis. Other proteoglycans that are expressed by PSC in the stroma of pancreatic cancer and influence some biological properties of pancreatic cancer cells are Decorin, Lumican and Versican, whose levels of expression are affected by soluble factors released by the cancer cells. Moreover, Osteopontin (OPN) and Periostin (POSTN) are additional stromal proteins that - through multiple mechanisms - contribute to the growth and promote the invasion of pancreatic cancer cells.

4) Since newly generated microvessels are an important component of the peritumoral stromal reaction, in another study the expression and localization of SPARC-like protein 1 (SPARCL1), a member of the SPARC family of proteins primarily expressed by endothelial cells, was analyzed in a wide range of non-tumorous and neoplastic pancreatic tissues. Functional aspects were investigated in cultured pancreatic cancer cells. Pancreatic ductal adenocarcinoma, acinar cell carcinoma, as well as serous and mucinous cystadenoma, exhibited increased SPARCL1-mRNA levels compared to the normal pancreas. SPARCL1 expression was observed in small capillaries in areas of inflammation/tumor growth and in some islet cells. However, the percentage of SPARCL1-positive vessels was higher in chronic pancreatitis, as well as in benign and borderline pancreatic tumors than in pancreatic cancer. This finding, together with the anti-invasive effects of recombinant SPARCL1, suggests a tumor-suppressor function of this protein in pancreatic cancer.

5) A comprehensive analysis of the angiogenic machinery in pancreatic cancer showed that a shift of the angiogenic balance to the proangiogenic state, termed the "angiogenic switch," is a hallmark of cancer progression. A global network pattern for vascular homeostasis connecting known angiogenesis-related genes with previously unknown signalling components was demonstrated and validated in pancreatic cancer. The targeted removal of a hub node (peroxisome proliferative-activated receptor delta) of the angiogenic network in knock-out mice markedly impaired angiogenesis and tumor growth. The expression levels of peroxisome proliferative-activated receptor delta expression in pancreatic cancer specimens were correlated with advanced pathological tumor stage, increased risk for tumor recurrence, and distant metastasis. These results may contribute to the rational design of antiangiogenic cancer agents that selectively target and remove angiogenic "hub" nodes.

Based on the previous results a model of pancreatic cancer progression where PSC, inflammatory cells and endothelial cells act in synergy to affect and promote the subsequent steps of tumor development has been proposed (Figure 3).