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Dissertation
The role of neurotrophin-trk receptor interactions in the development of pancreatic ductal adenocarcinoma
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
Sep 1998
DOI:
https://doi.org/10.17918/00007267
Abstract
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the aberrant expression of many growth factors and their corresponding receptors. This study examined the expression and the potential involvement of a novel growth factor-receptor axis (neurotrophins and Trk receptors) in the development of PDAC and the consequences of uncoupling this interaction. Using immunohistochemical and in situ hybridization analyses, we localized the expression of Trks A, B, and C mainly to the ducts of both normal and neoplastic specimens. In addition, there was an increased expression of the Trk receptors in PDAC specimens as compared to the normal controls. Conversely, NT (BDNF, NT-3, and NT-4/5) expression was mainly localized to the stromal compartment, with some expression observed in the normal acinar cells within the tumor. As determined using a modified Boyden chamber assay, in vitro invasiveness of four of six PDAC derived cell lines was significantly inhibited when the cells were incubated with 100 ng/ml NT. However, when select cell lines (Panc1, CFPAC, and ASPC1) were incubated with lower concentrations of NT-3 or BDNF invasiveness was stimulated significantly. These studies demonstrated a dose-dependent, biphasic response to specific NTs on the in vitro invasive behavior of select PDAC derived cells, and further confirmed that the Trk receptors present on PDAC are in fact functional biologically. The consequences of inhibiting NT-Trk receptor interactions on the development of PDAC was evaluated using several preclinical models (subcutaneous (s.c.) and rat trachea xenografts) of human PDAC in athymic nude mice and the BOP-induced PDAC model in Syrian golden hamsters. Treatment of s.c. xenografts with CEP-701 (10 mg/kg s.c. BID, five days/week; 21 to 28 days) revealed a statistically significant reduction in tumor growth volume in five of the six PDAC xenografts. These data were corroborated using the rat trachea model of in vivo invasiveness, which showed that at the identical dose of CEP-701 in the same xenografts, tumor cell invasiveness through the tracheal wall was inhibited as compared to vehicle controls. In further support of the antitumor efficacy of CEP-701, the incidence of BOP-induced pancreatic tumors in Syrian golden hamsters was significantly reduced when CEP-701 was administered (10 mg/kg s.c. qd) during the post-initiation phase of PDAC development. These collective data suggest that NT-Trk interactions play a role in the development of PDAC and indicate that further studies are warranted to evaluate CEP-701 as a potential therapeutic agent in the treatment and management of PDAC.
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Details
- Title
- The role of neurotrophin-trk receptor interactions in the development of pancreatic ductal adenocarcinoma
- Creators
- Sheila Jean Miknyoczki
- Contributors
- Bruce A. Ruggeri (Advisor) - Drexel University, Allegheny University of the Health Sciences (1996-1998)
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- x, 138 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Allegheny University of the Health Sciences (1996-1998); School of Medicine (1996-1998); Pathology (and Laboratory Medicine) [Historical]
- Other Identifier
- 991021888911604721