Common Alterations Involved in Pancreatic Cancer...
Epidemiologic data identified inflammation as a significant risk factor for solid tumors.Both hereditary and sporadic forms of chronic pancreatitis are associated with increased risk of pancreatic cancer.In such context，the focus of cancer research have recently shifted from pancreatic cancer cells to the inflammatory milieu surrounding them，and identified a list of notable targets involved in inflammation-associated carcinogenesis.Targeted therapy against certain molecules generates promising effects in clinic.Novel therapeutics targeting the extrinsic and intrinsic pathways linking chronic pancreatitis and pancreatic cancer would decrease the levels of tumor-promoting properties of the inflammatory cells，and ultimately balance the inflammatory network to regain a normal homeostasis.
Cytokines The progressive and irreversible desmoplasia within chronic pancreatitis are largely attributed to the cytokines existing in stroma（Cavestro et al.2003）.Many cytokines have been identified within chronic pancreatitis，including TNF-α，IL-1，IL-6，IL-8，PDGF，TGFβ，and etc.A similar expression pattern of chemokines is found in pancreatic cancer（Farrow and Evers 2002）.As pancreatic inflammation represents an early step in the development of pancreatic cancer（McKay et al.2008），it is logical to believe that these cytokines are engaged in pancreatic carcinogenesis.Numerous studies have demonstrated the tumor-promoting roles of these cytokines in pancreatic carcinogenesis（Yu and Kim 2014）.For example，TNF-α is normally expressed under the context of pancreatic acinar cell injury，whereas in chronic pancreatitis，TNF-α could upregulate PDGF expression，which is known to strongly stimulate fibrogenesis（Friess et al.1999）.PDGF，as well as other TNF-α downstream targets，e.g.，EGFR and TGF-α，are all well-known oncogenes in pancreatic carcinogenesis（Kalthoff et al.1993）.Through NF-κB activation，TNF-α may also inhibit apoptosis of pancreatic cancer cells（McDade et al.1999）.These data suggest that abnormal cytokine expressions in chronic pancreatitis are significantly associated with pancreatic carcinogenesis.A new generation of vaccines directed against cytokine activity could be beneficial in future treatment of cancer（Zagury et al.2001）.
Nuclear factor kappa B Nuclear factor kappa B（NF-κB）is an important transcription factor proved to be involved in multiple cellular activities（Suzuki et al.2011）.The functional NF-κB in pancreas is a p65/p50 heterodimer.Under normal conditions，NF-κB dimers are bound to inhibitory proteins，IκBs，which block nuclear localization sequences and thus trap the dimers within the cytoplasm where they were inactive（DiDonato et al.1997）.However，in inflammatory response，e.g.，pancreatitis，IκBs are degraded and NF-κB subsequently translocate into the nucleus，where it interacts with other transcription factors and binds to its consensus sequence on promoters of target genes（Huang et al.2013）.Enhanced NF-κB activity is associated with increased severity of acute and chronic pancreatitis（Huang et al.2013）.NF-κB activity is ubiquitously unregulated in many cancer types.It has been suggested that NF-κB plays its role in carcinogenesis through its inhibition of apoptosis of preneoplastic cells and the maintenance of a pro-neoplastic microenvironment rich in proinflammatory mediators（McKay et al.2008）.Targeted therapy against NF-κB could induce apoptosis and increase gemcitabine effectiveness in a subset of pancreatic cancer cells（Pan et al.2008）.Due to the critical role that NF-κB plays in linking chronic pancreatitis and pancreatic cancer，restoration of its expression and function may decrease the tumor-promoting effects of inflammatory cells，with hope to orchestrate the homeostatic relationship between inflammation and pancreatic cells.(https://www.daowen.com)
Peroxisome proliferator-activated receptor-y Peroxisome proliferator-activated receptor-y（PPARy）is a nuclear receptor and transcription factor，which can repress inflammatory genes and orchestrate inflammation homeostasis（Glass and Saijo 2010）.Ligands of PPAR7 play important roles in preventing the out-of-control inflammation in various tissues.For examples，different PPARy agonists could reduce the severity of cerulein-induced acute pancreatitis（Hashimoto et al.2003；Cuzzocrea et al.2004）.PPARy agonists could inhibit the proinflammatory cytokine gene expression within macrophages to prevent the development of chronic pancreatitis（Shimizu et al.2002）.Also，PPARy overexpression could inhibit pro-fibrogenic activities of immortalized rat pancreatic stellate cells to suppress chronic inflammation process（Jaster et al.2005）.Furthermore，the impact of PPARy on pancreatic cancer development and progression has support the notion that chronic pancreatitis is strongly associated pancreatic cancer.For examples，PPARy ligand could suppress cancer growth（Elnemr et al.2000）.A list of targets，including cyclin D1，p27KiPl，and PTEN are implicated in its anti-tumor effects（Diao and Chen 2007）.Troglitazone is a wellknown PPARy ligand，and clinical studies have shown that troglitazone could significantly lower PSA levels in prostate cancer patients（Mueller et al.2000）.However，its therapeutic efficacy against pancreatic cancer have not been evaluated in clinics.
Reactive oxygen species Reactive oxygen species are generated by activated neutrophils and macrophages during inflammation.Reactive oxygen species has been implicated in the pathogenesis of acute and chronic pancreatitis，and antioxidants could be potentially effective against the development of pancreatic fibrosis in patients with chronic pancreatitis（Asaumi et al.2007）.Furthermore，highly reactive oxygen species could promote repeated tissue damage and regeneration during chronic pancreatitis.In this process，reactive oxygen species can induce genotoxic effects，including DNA strand breaks，sister chromatid exchanges，and formation of adducts with DNA（Jackson and Loeb 2001）.Repeated damage-regeneration stimuli could impose permanent genomic alterations into pancreatic cells，which further accelerate the mutation accumulation，and subsequently the carcinogenesis process（Campisi and d'Adda di Fagagna 2007）.Though the anti-tumor effects of those compounds with anti-oxidant activity have not been validated in clinic，epidemiologic studies show that intake of fresh fruit and vegetables appears to be inversely correlated with pancreatic cancer（Wiseman and Halliwell 1996）.Eradication of reactive oxygen species from chronic inflammatory milieu will protect pancreatic cells DNA from genotoxic damage，and could perhaps lower the incident of transformation of these cells.