Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward

Abstract

Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.

Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival

“…In MiaPaCa cells (Figure 2A), LEV showed a decrease on average size under moderate hypoxia (616.9 ± 217.9 nm), which increased somewhat under extreme hypoxia (751.6 ± 129.9 nm), compared to that under normoxic condition (732. 6 (Figure 2A and 2B).…”

“…However, under both moderate and extreme hypoxia, their levels kept on increasing in the CM ( Figure 1C, left panel). 6 normoxia. In AsPC1 cells, LEV and MEV release remained largely similar under normoxia and hypoxia except for significant difference recorded in MEV release at 24 hours.…”

“…[5][6][7] Pancreatic tumors are highly desmoplastic characterized by extensive deposition of extracellular matrix and poor vasculature. [5][6][7] Pancreatic tumors are highly desmoplastic characterized by extensive deposition of extracellular matrix and poor vasculature.…”

Transcriptome‐wide association study identifies multiple genes and pathways associated with pancreatic cancer

“…Genetic factors play important roles in the development of pancreatic cancer. Multiple genetic studies have been implemented and identified some susceptibility genes for PC, such as KRAS, BRCA1, BRCA2, PALB2, FANCC, FANCG, ATM, CDKN2A, PRSS1, SPINK1, TERT, NR5A2, ZNRF3, and SMC2 . However, the genetic risk of PC explained by the reported candidate loci was limited, indicating the existence of undiscovered susceptibility loci for PCs.…”

“…for PC, such as KRAS, BRCA1, BRCA2, PALB2, FANCC, FANCG, ATM, CDKN2A, PRSS1, SPINK1, TERT, NR5A2, ZNRF3, and SMC2. 3 However, the genetic risk of PC explained by the reported candidate loci was limited, indicating the existence of undiscovered susceptibility loci for PCs.…”