Pancreatic cancer, and specifically pancreatic ductal adenocarcinoma (PDAC), is among the five leading causes of cancer death in Western countries including the United States. Despite advances in diagnostic imaging and surgical techniques, mortality still approaches incidence as non-specific and often late symptoms complicate early detection and the frequent spread limit chances of cure. One of the important clinical manifestations of pancreatic cancer is pain. The often intense pain is thought to arise from invasion of tumor cells into the pancreatic nerves. This nerve-cancer interaction may also contribute to the aggressive behavior of pancreatic neoplasms. Together these findings suggest an intimate relationship between the peripheral nervous system and pancreatic cancer, wherein tumor-produced growth factors induce nerve sprouting and hypertrophy, increasing nerve-cancer interactions, which in turn promote cancer growth and invasion. We have begun to breed a transgenic mouse model that expresses the most common genetic lesions seen in human pancreatic cancer (a gain-of-function Kras mutations and loss of the p53 tumor suppressor gene) and develop tumors with virtually all of the features seen in the human disease. But before we develop a comprehensive program to exploit these mice for the study of cancer pain we need to determine if in fact they exhibit quantifiable pain behaviors, and whether these behaviors are correlated with changes in the peripheral sensory nervous system as has been seen in humans. Our hypothesis is that pancreatic cancer in Kras/p53 mice will produce pain behaviors that are correlated with tumor growth and the production of neurotrophic factors that have been shown to regulate anatomy and function of adult nociceptors (e.g., NGF and artemin). To test this hypothesis we will complete the following aims: SA1: Phenotype pain behaviors in Kras/p53 mice during progression of PDAC. a) Using Kras/p53 and control mice, we will conduct longitudinal studies of behaviors that should be affected by ongoing pain, including open field behavior, gait analysis, and hunching, as well as testing for the development of referred hypersensitivity (e.g., to abdominal skin). SA2: Test the hypothesis that PDAC increases neurotrophic factors (e.g. NGF, artemin, GDNF) and induces hypertrophy of visceral afferents . This hypothesis will be examined by: a) Determining changes in growth factor and growth factor receptor expression in pancreatic tumors (via real- time PCR, Western blots). b) Documenting changes in pancreatic innervation for growth factor dependent afferent fibers during the course of PDAC.
Pancreatic cancer remains a common and extremely painful disease, affecting about 40,000 individuals in the United States each year. This proposal will determine if a mouse model of pancreatic cancer, one that has many of the genetic, anatomical and biochemical features of the human disease, also experiences ongoing pain. These studies have to potential to lay the foundation for future experiments that will elucidate the mechanisms that cause pancreatic cancer pain, with the goal of developing novel therapies for cancer pain.
|Stopczynski, Rachelle E; Normolle, Daniel P; Hartman, Douglas J et al. (2014) Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res 74:1718-27|