Abstract
Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is an early molecular event during progression of pancreatic cancer; it is followed by the accumulation of additional genetic abnormalities. This model has been supported by animal studies in which activated K-ras and p53 mutations produced metastatic pancreatic ductal adenocarcinoma in mice. According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage. However, when these mice are subjected to caerulein treatment, which induces a chronic pancreatitis-like state and inflammatory response, PanINs rapidly progress to invasive carcinoma. These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC. In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses. In this review we discuss the implications of increased TG2 expression in initiation, progression, and pathogenesis of pancreatic cancer.
Highlights
Pancreatic cancer (PC) is among the deadliest malignancies with the worst prognosis
Recent evidence suggests that endotoximia, which is due to increased gut permeability in alcoholics, may trigger inflammation in the pancreas tissue and contribute to the progression of chronic pancreatitis by activating pancreatic stellate cells (PSCs)
Recent observations that activated PSCs, pancreatic intraepithelial lesions (PanINs) [10] and advanced-stage pancreatic cancer [11,12] express elevated levels of the pro-inflammatory protein tissue transglutaminase (TG2), in conjunction with the earlier observations that TG2-catalyzed protein crosslinking reactions play an important role in extracellular matrix (ECM) stabilization [13], are of particular importance
Summary
Pancreatic cancer (PC) is among the deadliest malignancies with the worst prognosis. Worldwide, nearly 230,000 new cases of PC are diagnosed every year, and almost the same number of patients die of the disease, underscoring the aggressive nature of this cancer [1]. Several signaling pathways (e.g., JAK-STAT, MAPK, NF- B, AP-1, etc.) have been implicated in PSCs activation [9] In this context, recent observations that activated PSCs, PanINs [10] and advanced-stage pancreatic cancer [11,12] express elevated levels of the pro-inflammatory protein tissue transglutaminase (TG2), in conjunction with the earlier observations that TG2-catalyzed protein crosslinking reactions play an important role in ECM stabilization [13], are of particular importance. TG2 exists as a catalytically inactive intracellular protein due to low Ca2+ and high inhibitory concentrations of GTP/GDP [20] In this form, TG2 acts as a scaffold protein and results in the activation of some critical cell survival signaling pathways (NF- B, Akt, focal adhesion kinase) [16,19,21,22]. (compact versus extended) in a cell may be a reflection of the fact that TG2 functions as a double-edged sword in cancer cells, conferring advantage or disadvantage to the tumor
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