4.2 Intrinsic Pathways Within Pancreatic Cancer Ce...
Previous studies have reported that each pancreatic cancer case contain an average of 63 genetic alterations，most of which are point mutations.These alterations define a core set of 12 cellular signaling pathways（Jones et al.2008）.However，the rates of spontaneous mutations within normal pancreatic cells are very low.Compared with normal pancreatic cells，the widespread destabilization of gene copy number and nucleotide sequence assure us that instability of the genome is universally inherent within pancreatic cancer cells（Hanahan and Weinberg 2011）.In normal cells，there is extraordinary ability of genome maintenance systems to detect and resolve defects in the DNA，whereas in cancer cells，the protection mechanisms are defected and enable these cells to accumulate more genetic alterations and advantageously develop into a tumor（Hanahan and Weinberg 2011）.(https://www.daowen.com)
Evidently，inflammatory microenvironment participates in genome instability of pancreatic cancer cells.For example，Bielas et al.have reported that the mutation rate in the inflamed microenvironment is higher than in normal tissues，with a mutation frequency of 4 × 10-8 and＜1 × 108 per base pair，respectively（Bielas et al.2006）.The hallmark suppressor p53，critical in protecting genomes from instability，shows high frequency of mutations in chronic pancreatitis（Gansauge et al.1998）.Higher incidence of mutations within pancreatic cancer cells is largely attributed to the deregulate DNA repair systems and altered cell cycle checkpoints，whereas derivatives generated by inflammatory cells are also responsible for the destruction against these genome maintainers.For example，inflammatory cytokines，e.g.，TNF and IL-1p，could induce HIF-α in pancreatic cancer cells，which may destruct the mismatch repair mechanisms and leads to instability of genomes（Akakura et al.2001）.Nitrogen oxide（NO），another important mediator derived from inflammation microenvironment，could induce upregulation of DNA methyltransferase and result in promoter silencing and loss of gene expression of the mismatch repair member hMLH1（Fleisher et al.2000）.NO and its derivatives could also inhibit the function of p53 and are associated with p53 mutations（Jaiswal et al.2001），which will significantly attenuate its detection and repair ability against genome instability.Other inflammatory elements，including COX-2，reactive oxygen species，and MMPs can also tamper the genome surveillance machinery（Hanahan and Weinberg 2011）.Through these different mechanisms，inflammatory elements render the cancer genomes instable，which leads to a genomically heterogeneous population of expanding cells naturally selected for their ability to proliferate，invade and metastasize to distant tissues，and evading host defenses（Hanahan and Weinberg 2011）.