Amplification of the Urokinase-Type Plasminogen Activator Receptor (uPAR) Gene in Ductal Pancreatic Carcinomas Identifies a Clinically High-Risk Group

Abstract

The serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are known to be involved in the invasion and metastasis of many solid tumors. In this study, we analyzed the role of the uPAR/uPA system in both the development and progression of pancreatic cancer in invasive ductal adenocarcinomas of the pancreas (PDA) and their premalignant precursors (PanIN lesions) in 50 patients with long-term clinical follow-up. We found overexpression of the uPAR in 48 of 50 invasive carcinomas as well as in a large proportion of high-grade PanIN lesions by immunohistochemistry and in situ hybridization. Fluorescence in situ hybridization analysis showed both high-and low-level amplification of the uPAR gene in ϳ50% of cases with strictly identical patterns between invasive cancers and their accompanying precursor lesions. These results suggest that PDA may develop from PanIN lesions along an alternative rather than a sequential molecular pathway. The detection of the gene amplification of uPAR was a highly significant, adverse prognostic parameter (P < 0.001) because it likely renders the tumors more sensitive to uPA and its proproliferative and anti-apoptotic signals. We conclude that the activation of the uPAR/uPA system is an early event in the development of PDA and that uPAR gene amplifications identify a subgroup of particularly aggressive tumors, making the uPAR/uPA system a critical and highly promising target for therapeutic in- Invasive ductal adenocarcinoma of the pancreas (PDA) represents the fourth most common cause of cancerrelated death and its incidence is still increasing.1 With an estimated number of 232,000 new cases per year, pancreatic cancer is among the most common malignancies worldwide.2 Moreover, it is one of the most lethal cancers, as indicated by a mortality incidence ratio of 98%.2 Once pancreatic cancer is clinically evident, it progresses at a rapid rate, and metastasis is often present already at the time of diagnosis.3 The mechanisms that regulate this aggressive growth behavior in pancreatic cancer are still poorly understood.Several studies indicate that during cancer cell invasion and metastasis proteolytic enzymes participate in the degradation of extracellular matrix components. The serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR, CD87) are involved in the control of extracellular matrix turnover, cell migration, invasion, and cell signaling leading to a variety of different responses under both physiological and pathological conditions. 4 -6 uPAR is a highly glycosylated 45-to 60-kDa protein that is attached to the cell membrane via glycosylphosphatidylinositol anchor. It consists of three

Suppression of the uPAR–uPA System Retards Angiogenesis, Invasion, and In Vivo Tumor Development in Pancreatic Cancer Cells

“…Other studies have showed similar results and have shown the importance of the uPAR-uPA system in pancreatic carcinoma cell migration (7). Invasion studies also suggest that uPAR is a potential target for therapy in patients with pancreatic cancer (1,(6)(7)(8)(9)(10). In addition, studies have shown the influence of the insulin-like growth factor (IGF) system on tumor progression from benign mucinous cystadenomas to pancreatic ductal adenocarcinoma (PDAC; ref.…”

“…expression of uPAR was always correlated with the expression of its ligand uPA. Researchers have shown that activation of the uPAR-uPA system is an early event in the development of pancreatic ductal adenocarcinoma and that uPAR gene amplifications identify a subgroup of particularly aggressive tumors, thereby making the uPAR-uPA system a critical and highly promising target for therapeutic interventions (10).…”

Stabilizing a Flexible Interdomain Hinge Region Harboring the SMB Binding Site Drives uPAR into Its Closed Conformation

“…In pathophysiology, uPAR expression is, however, often up-regulated in lesions associated with active tissue remodeling, cell migration, and chronic inflammation as exemplified by malignant pancreatic carcinomas [41], rheumatoid arthritis [42], and neuronal remodeling after spinal cord injury [43]. High levels of circulating shed uPAR are accordingly predictive biomarkers of poor prognosis in cardiovascular diseases [44], infectious diseases [45], and many solid carcinomas including those of colon, breast, lung, ovary, and prostate [46].…”

Conditionally immortalized human pancreatic stellate cell lines demonstrate enhanced proliferation and migration in response to IGF-I

“…uPA is known to modulate cell adhesion and enhance both cell proliferation and migration of many tumors. Amplification of the uPA receptor gene, thus rendering tumors more sensitive to uPA, has been implicated in pancreatic cancer progression [18].…”