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.

Keywords: microRNA; molecular pathogenesis; mutations; non-coding RNAs; pancreatic ductal adenocarcinoma; tumor microenvironment.

Figure 1

Histopathological and molecular changes in the pathogenesis of pancreatic adenocarcinoma (PDAC). The illustration describes the multistep PDAC development, starting from normal epithelium to low-grade pancreatic intraepithelial neoplasia (PanINs) and on to high-grade PanIN and invasive carcinoma. During this progression, several alterations in key genes (KRAS, CDKN2, TP53, SMAD4/DPC4 and BRCA2) are accumulated. Apart from genetic alterations, deregulated signaling pathways, stromal associated factors and microRNAs serve as fuel for the development of aggressive pancreatic cancer. KRAS: Kirsten rat sarcoma oncogene homolog; Her-2/neu: Human epidermal growth factor receptor 2; EGFR: Epidermal growth factor receptor; CXCR4: C-X-C chemokine receptor type 4; SHH: Sonic hedgehog; MUC4: Mucin 4; PTEN: Phosphatase and tensin homolog; CDKN2A/p16^Ink4A: Cyclin dependent kinase inhibitor 2A; SMAD4/DPC4: Mothers against decapentaplegic homolog 4/ Deleted in pancreatic cancer-4; BRCA2: Breast cancer type 2 susceptibility protein; CXCL12: C-X-C motif chemokine 12.