Molecular Pathogenesis of Pancreatic Cancer

Abstract

Pancreatic cancers arise predominantly from ductal epithelial cells of the exocrine pancreas and are of the ductal adenocarcinoma histological subtype (PDAC). PDAC is an aggressive disease associated with a poor clinical prognosis, weakly effective therapeutic options, and a lack of early detection methods. Furthermore, the genetic and phenotypic heterogeneity of PDAC complicates efforts to identify universally efficacious therapies. PDACs commonly harbor activating mutations in the KRAS oncogene, which is a potent driver of tumor initiation and maintenance. Inactivating mutations in tumor suppressor genes such as CDKN2A/p16, TP53, and SMAD4 cooperate with KRAS mutations to cause aggressive PDAC tumor growth. PDAC can be classified into 3-4 molecular subtypes by global gene expression profiling. These subtypes can be distinguished by distinct molecular and phenotypic characteristics. This chapter will provide an overview of the current knowledge of PDAC pathogenesis at the genetic and molecular level as well as novel therapeutic opportunities to treat this highly aggressive disease.

Keywords: KRAS; Pancreatic cancer; Pharmacogenomics; Signal transduction; Targeted therapeutics.

Figure 1.. Disease Progression Model of Pancreatic Cancer.

Pancreatic cancer arises from two histological types of precursor lesions: PanINs and IPMNs. Through progressive stages of pathogenesis, molecular changes occur, leading to increasing degrees of nuclear and cytoskeletal abnormalities. Genetic alterations commonly observed in these lesions are indicated with respect to the stages in which they most often occur.

Figure 2.. Deregulated Signaling Networks in Pancreatic Cancer.

A. RTK and cell cycle-regulatory signaling networks frequently altered in pancreatic cancer. Oncogenes exhibiting gain-of-function mutations are indicated by a dark dashed line. Tumor suppressor genes altered in the disease are indicated by a lighter dashed line. The frequencies at which these genes are altered are also included. Oncogenic KRAS mutation cooperates with the loss of various tumor suppressor genes to promote cellular proliferation, growth, survival, and stem cell renewal. B. Hippo signaling is frequently deregulated in pancreatic cancer. The ability of the pathway to restrict cell growth and induce apoptosis is mediated by a number of stimuli including cell density, glucose levels, serum levels, and cytoskeletal tension.