Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies and remains difficult to treat. Pancreatic intraepithelial neoplasias (PanINs) represent the majority of the pre-cancer lesions in the pancreas. The PDAC microenvironment consists of activated pancreatic stellate cells (PSCs) and immune cells, which are thought to contribute to neoplastic transformation. However, the signaling events involved in driving the transition from the neoplastic precursor to the more advanced and aggressive forms in the pancreas are not well understood. Recepteur d’Origine Nantais (RON) is a c-MET family receptor tyrosine kinase that is implicated in playing a role in cell proliferation, migration and other aspects of tumorigenesis. Macrophage stimulating protein (MSP) is the ligand for RON and becomes activated upon proteolytic cleavage by matriptase (also known as ST14), a type II transmembrane serine protease. In the current study, by immunohistochemistry (IHC) analysis of human pancreatic tissues, we found that the expression levels MSP and matriptase are drastically increased during the transition from the preneoplastic PanIN stages to the more advanced and aggressive PDAC. Moreover, RON is highly expressed in both PDAC and in cancer-associated stellate cells. In contrast, MSP, RON, and matriptase are expressed at low levels, if any, in normal pancreas. Our study underscores an emerging role of MSP-RON autocrine and paracrine signaling events in driving malignant progression in the pancreas.
Highlights
Pancreatic cancer has extremely poor prognosis and is the fourth leading cause of cancer-related death (Hidalgo, 2010; Jemal et al, 2011; Siegel et al, 2013)
While Macrophage stimulating protein (MSP) expression is minimal in normal pancreas, it is significantly upregulated in the cancer cells of all 12 Pancreatic ductal adenocarcinoma (PDAC) specimens that we analyzed (Figures 1A,B)
We performed IHC staining on a tissue microarray (TMA) that includes 38 PDAC samples and found that high levels of MSP can be detected in 79% (30 of 38) of the specimens (Table 1)
Summary
Pancreatic cancer has extremely poor prognosis and is the fourth leading cause of cancer-related death (Hidalgo, 2010; Jemal et al, 2011; Siegel et al, 2013). Pancreatic ductal adenocarcinoma (PDAC) comprises more than 85% of all pancreatic cancer and has an overall 5-year survival rate of less than 5% (Hidalgo, 2010). A major challenge in the clinics is the lack of effective methods for early detection and treatment. Three types of “preneoplastic” lesions have been characterized as potential precursors of PDAC, including pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms (MCN) (Hruban et al, 2000; Maitra et al, 2005). PanINs represent the majority of early neoplastic lesions and are characterized by three morphologically defined stages, namely PanIN1, 2, and 3 (Hruban et al, 2000; Maitra et al, 2005). The signaling events involved in promoting the transition from the preneoplastic lesion to the more advanced and aggressive forms are still not fully understood
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