Pancreatic Cancer Is Inflammatory Malignancy
Extensive histopathological studies have identified different precursor lesions as having the potential to evolve into highly malignant and invasive pancreatic cancer，including chronic pancreatitis，pancreatic intraepithelial neoplasia（PanIN），mucinous cystic neoplasms，and intraductal papillary mucinous neoplasms（Brugge et al.2004；Maitra et al.2005）.PanINs are the most common precancerous lesions in pancreas，constituting the development course of pancreatic cancer（Costello et al.2012），which is somewhat similar to that of adenoma-carcinoma sequence in the development of colon cancer（Vogelstein et al.1988）.
It have now well documented concerning the genetic and epigenetic alterations accompanying the sequential course of cellular transformation from normal pancreas to pancreatic cancer（Bardeesy and DePinho 2002）.Multi-modality analyses with clinic-pathological parameters have further characterized the clinical significance of those alterations in detection and diagnosis，prognostic prediction，treatment selection，and etc.K-ras is the most notable and prevalent oncogene identified in pancreatic cancer cells.Although occasionally occurring in normal pancreatic tissue and only 30%of pancreatic lesions at the earliest stage of histopathological disturbance（Klimstra and Longnecker 1994），the frequency of K-ras activation increases as the disease progresses and is found in almost all PDAC cases，making this mutational activation virtually essential for PDAC pathogenesis（Rozenblum et al.1997）.Identification of K-ras mutation as the first notable genetic alteration led to much better understanding of pancreatic cancer genetics，which are including inactivation of tumor-suppressive genes，e.g.，p16/CDKN2A，TP53，and SMAD4（Bardeesy and DePinho 2002）.A recent landmark study of sequencing of 23，219 transcripts reveals 20，661 protein-coding genes in 24 PDAC cases.This detailed global genomic study has identified a large number of genetic alterations，among which a core set of 12 signaling pathways and processes are shown to have an altered gene expression in 67-100%of pancreatic cancer cases（Jones et al.2008）.(https://www.daowen.com)
Apparently，pancreatic cancer takes 20 years to grow into a detectable tumor，and during this time course，an average of 63 genetic alterations happen in each case（Jones et al.2008）.Two prerequisites for pancreatic cancer are proposed:first，there must be immortal pancreatic cells to accumulate these genetic events；second，there must be harsh milieu to efficiently induce the genetic events to happen.Existence of cancer stem cells meets the first prerequisite，whereas the second prerequisite may largely be attributed to chronic inflammation surrounding pancreatic cells（Cooks et al.2014）.Lessons from ulcerative colitis show that the inflammation process will lead to repeated cycles of epithelial cell damage and regeneration，which presumably increase the possibility of somatic mutations and favor cellular transformation and tumorigenesis（Itzkowitz and Yio 2004）.Chronic pancreatitis may follow a similar path to pancreatic cancer.
On the other hand，the entire process of pancreatic cancer development and progression is full of inflammation.The inflammatory response is observed at the early stages of pancreatic cancer initiation.For example，we have recently found that active infiltration of inflammatory cells and immune cells is observed during acinarto-ductal metaplasia phase and KLF4 plays a critical role in inflammatory response，which appears to be important for PanIN formation and progression to late-stage invasive pancreatic cancer.The inflammation is also important to pancreatic desmoplasia.Therefore，pancreatic inflammation could be a cause of pancreatic cellular transformation and cancer initiation，and also could be a driver force of pancreatic cancer promotion and progression.