The Role of the Tumor Microenvironment in Invasion and Metastasis of Pancreatic Cancer

Abstract

Pancreatic cancer, a devastating disease with a median overall survival of six months, is unique because the vast majority of the tumor is composed of stromal cells. The stroma, primarily composed of fibroblast cells, immune cell, and extracellular matrix proteins, has proven to be a major obstacle in the treatment of pancreatic cancer because the signaling pathways that promote metastasis are poorly understood. Recently, the hedgehog (Hh) and semaphorin signaling pathways have been identified as playing important roles in pancreatic cancer metastasis. The hedgehog pathway has been shown to regulate both cancer stem cell (CSCs) maintenance as well as growth factor secretion by stromal cells. Inhibition of the Hh pathway has been proven to be an effective therapeutic strategy that results in not only a decrease in the therapeutically problematic CSCs but also a decrease in the stromal compartment, which results in increased tumor vascularization and pharmacodelivery. Additionally, the semaphorin genes undergo frequent copy number alterations in pancreatic cancer. In other epithelial-derived cancers, semaphorin signaling has been shown to mediate tumor cell invasion into the nerves and blood vessels, as well as increase the density of nerves within the tumor. Because of the frequency of perineural invasion and associated pain in pancreatic cancer, the role of semaphorin signaling in pancreatic cancer metastasis should be further explored. Further understanding of the invasion-promoting pathways in the tumor microenvironment will aid in our understanding of how the tumor microenvironment regulates pancreatic cancer progression and will help to identify novel targets for improving therapies.