Pancreatic ductal adenocarcinoma (PDAC), like many cancers, has a major inflammatory component that is integral to disease progression. In humans, patients with familial chronic pancreatitis (CP) have a 53-fold increase in their risk for PDAC [92] and 40% go on to develop pancreatic cancer [63]. The link between CP and PDAC is so strong that physicians often recommend prophylactic pancreatectomy for patients with severe CP. The mechanistic link between pancreatic inflammation and cancer is not known. However, studies by our laboratories and others indicate that inflammation accelerates the disease, driving maturation of precancerous lesions into frank cancer [40, 41]. Furthermore, in a genetically engineered mouse model (GEM) of PDAC, pancreatic inflammation increased dissemination of pancreatic cells into the blood and liver [78]. Experiments in our labs show that pancreatic inflammation can be regulated by the nervous system. The importance of "neurogenic inflammation" is supported by studies that show ablation or silencing of pancreatic afferents attenuates/prevents acute and chronic pancreatitis [45, 67, 81, 82]. PDAC converts the pancreas into a tissue that produces pathological levels of neurotrophic factors that cause hypersensitivity and sprouting of sensory neuron terminals and this likely underlie disease-related neurogenic inflammation. Importantly, preliminary data from our lab indicate that growth factor upregulation begins early in the disease process, even before the appearance of frank cancer (Preliminary Data). These observations in combination with the role that inflammation appears to play in progression of PDAC leads to the central hypothesis of this application: PDAC-generated neurotrophic factors induce neurogenic inflammation that drives PDAC progression. This hypothesis will be tested in the following specific aims:
Aim 1 : Determine the effect of PDAC-produced neurotrophic factors on pancreatic afferents (dorsal root and nodose ganglion neurons) and whether blocking these growth factors attenuates the release of neurogenic inflammatory molecules.
Aim 2 : Determine the contribution of neurogenic inflammation to PDAC progression and tumor growth. These studies will directly test the role of the nervous system in PDAC. Three different methodologies will be tested for their ability to block neurogenic inflammation and slow/halt disease progression. Each of these methods is either currently available or in development for use in the clinical setting. If successful, any of these approaches could be used for patients with high-risk for PDAC or those in which the disease is already diagnosed.

Public Health Relevance

Pancreatic cancer remains a common and mostly deadly disease, affecting about 40,000 individuals in the United States each year. Inflammation is a critical feature of this disease and may be responsible for many of its aggressive features. This proposal will examine how the nervous system regulates cancer-associated inflammation, whether blocking nervous system activity can reduce/prevent inflammation and how this affects disease progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA177857-01
Application #
8559041
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
2013-08-15
Project End
2018-06-30
Budget Start
2013-08-15
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$409,211
Indirect Cost
$83,075
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Rhim, Andrew D; Oberstein, Paul E; Thomas, Dafydd H et al. (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735-47
Coleman, Stacey J; Rhim, Andrew D (2014) Molecular biology of pancreatic ductal adenocarcinoma. Curr Opin Gastroenterol 30:506-10