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.

Introduction

The pancreas is a glandular organ with both endocrine and exocrine functions.1, 2 Its overall purpose is to maintain metabolic homeostasis by producing hormones that regulate blood glucose levels as well as enzymes that aid in digestion. The pancreas is derived from the embryonic foregut of the endodermal germ layer.³ During embryonic development, two buds that ultimately give rise to the dorsal and ventral pancreas emerge from the foregut. As these buds expand, they are gradually repositioned over time until they come into contact and fuse together, forming the mature pancreas. Under the control of various developmental cues, pancreatic progenitor cells become acinar, endocrine, or ductal in function. Endocrine cells (α, β, and δ) secrete hormones-like insulin, glucagon, and somatostatin into the circulatory system to modulate blood glucose levels.¹ This homeostatic function ensures that the metabolic demands of various tissues and organs are met. Acinar cells in the ducts secrete enzymes like trypsinogen, chymotrypsinogen, lipase, and amylase into the pancreatic duct.² These enzymes subsequently enter into the small intestine, where they aid in the digestion of various dietary macromolecules such as proteins, carbohydrates, and lipids.

Pancreatic dysfunction can lead to a number of common diseases including diabetes, pancreatitis, and cancer.4, 5, 6 Diabetes is the most prevalent of these diseases. However, cancer of the pancreas is by far the deadliest, and its etiology is often linked to other pancreatic disorders, including diabetes. Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and is associated with a particularly poor prognosis.⁷ Patients diagnosed with this disease exhibit a median overall survival of less than 6 months and a 5-year survival rate of roughly 8%. The poor prognosis associated with pancreatic cancer is attributed in part to poor methods of early detection.⁸ Patients often remain asymptomatic until the disease has disseminated throughout the body. Additionally, the therapeutics used to treat pancreatic cancer are relatively ineffective, as they fail to extend patient survival more than several months.⁹ Overcoming these challenges will be critical in the future treatment of the disease, as it is expected to become the second leading cause of cancer-related deaths in the United States by 2030.¹⁰

Pancreatic cancers can arise from either endocrine or exocrine cells. Thus, endocrine and exocrine tumors can be distinguished by histological appearance. Endocrine tumors are relatively uncommon and constitute less than 5% of all pancreatic cancers. They are associated with a median survival of 27 months and a 0.28-fold lower risk of mortality in comparison to the much more common pancreatic adenocarcinoma.¹¹ Endocrine tumors are commonly derived from pancreatic islet cells and often produce constitutively high levels of pancreatic hormones. They can be further categorized into insulinomas, glucagonomas, and gastrinomas depending on their cell of origin and the hormones that they secrete. Pancreatic endocrine tumors can be readily diagnosed due to their excessive hormone secretion, which leads to dramatic symptoms such as hypoglycemia or necrolytic migratory erythema (skin rash).¹² Pancreatic cancers derived from exocrine cells are much more common than endocrine tumors and can typically be classified into two histological subtypes. The pancreatic ductal adenocarcinoma (PDAC) subtype accounts for the majority of exocrine tumors and constitutes more than 90% of all pancreatic malignancies. PDACs are derived from epithelial cells that line the pancreatic duct and appear gland-like due to their origin.¹¹ These cancers frequently metastasize to the liver or lymph nodes.¹³ Due to their lack of symptoms at the early stages of cancer development, PDACs are often diagnosed at a late stage, potentially after the cancer has already metastasized. As a result, anticancer therapeutics tend to be weakly effective due to the cancers having acquired strong cytoprotective mechanisms that promote drug resistance. Because of this aggressiveness and drug resistance, estimated median survival for PDAC can be as short as 4 months.¹¹

PDACs are preceded by the development of hyperplastic lesions known as pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs) that are precancerous and exhibit a propensity to develop into cancer (Fig. 1). IPMNs look like papillae (finger-like structures) that protrude into the pancreatic duct.¹⁴ Mucinous tumors are the second most common histological subtype of pancreatic cancer, constituting less than 10% of cases. These tumors are usually much less invasive than adenocarcinomas at the time of diagnosis and have a 0.88-fold lower risk of mortality by comparison.¹¹ Mucinous tumors also originate from the pancreatic ductal epithelium, but secrete mucin, which can be seen in and around the cells, causing them to appear like they are “floating.”15, 16 There are many other subtypes of pancreatic cancer, such as those that arise from acinar cells, which are undifferentiated and resemble liver cancers. However, these subtypes are rare and will not be discussed in this chapter.

This chapter will focus on the molecular etiology of PDAC, the most prevalent form of pancreatic malignancy. The core genetic alterations that contribute to PDAC pathogenesis will be discussed. Furthermore, the molecular subtypes of PDAC will be presented with a focus on their cellular origin and the genetic alterations associated with them. The diverse and deregulated signaling pathways that contribute to PDAC pathogenesis will also be described in detail. To conclude, the molecular characteristics of PDAC will be discussed in relation to the current therapeutic strategies employed to manage the disease in the clinic and future approaches that may further improve patient prognosis.