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Neuroplastic changes in a mouse model of pancreatic ductal adenocarcinoma

Stopczynski, Rachelle Eve (2013) Neuroplastic changes in a mouse model of pancreatic ductal adenocarcinoma. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Tumor-nerve interactions including tumor invasion of intra- and extra-pancreatic nerves and pain have been extensively documented in pancreatic malignancies. However, little is known about the relationship between tumor development and neuroplastic changes in the pancreas. Studies of human tissue demonstrate increased neurotrophic factor expression in pancreatic ductal adenocarcinoma (PDAC), and neurotrophic factors are known to enhance nerve sprouting and sensitization in peripheral afferents. Furthermore, animal studies show that chronic pancreatic inflammation produces hypertrophy and hypersensitivity of pancreatic afferents and that sensory fibers may themselves drive inflammation via neurogenic mechanisms. These observations led us to hypothesize that PDAC-related pain is due to changes in sensory afferent gene expression, driven by tumor-derived neurotrophic factors, and that sensitized afferents accelerate the transition from precancerous lesions to cancer via neurogenic inflammation. Using a genetically engineered mouse model of PDAC we found that although disease time course varied, pancreatic cancer typically developed by 16 weeks of age, however pancreatic neurotrophic factor mRNA expression was up-regulated and pancreatic innervation increased dramatically prior to this time point. These changes correlated with pain-related decreases in exploratory activity and increased expression of nociception-related genes in sensory ganglia. Cells of pancreatic origin could also be found invading the celiac or sensory ganglia. These results demonstrate that the nervous system participates in all stages of PDAC, including those that precede appearance of cancer.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Stopczynski, Rachelle Everes63@pitt.eduRES63
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRinaman, Linda M.rinaman@pitt.eduRINAMAN
Thesis AdvisorAlbers, Kathryn M.kaa2@pitt.eduKAA2
Committee MemberDavis , Brian M.bmd1@pitt.eduBMD1
Committee MemberMolliver, Derek C.dcm12@pitt.eduDCM12
Committee MemberWhitcomb, David C.whitcomb@pitt.eduWHITCOMB
Committee MemberRhim, Andrew D. arhim@med.umich.edu
Date: 19 July 2013
Date Type: Publication
Defense Date: 10 June 2013
Approval Date: 19 July 2013
Submission Date: 18 July 2013
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 143
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Neurotrophic Factors, Pain, Peripheral Nervous System, Perineural Invasion, Metastases
Date Deposited: 19 Jul 2013 18:13
Last Modified: 15 Nov 2016 14:14
URI: http://d-scholarship.pitt.edu/id/eprint/19385

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