Dissertation
COMPARATIVE CHARACTERIZATION OF HEPATOCYTE GROWTH FACTOR AND MACROPHAGE STIMULATING PROTEIN IN PANCREATIC AND GLIOBLASTOMA CANCER MODELS
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/16794
Abstract
Pancreatic cancer and glioblastoma (GB) are aggressive cancers with poor prognoses for which no curative treatment exists. Hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) along with their respective receptors Met and Ron are structurally and functionally similar growth factor systems suspected of driving the progression of many cancers, which has made them a focus of targeted anti-cancer drug development. Over-activation of the HGF/Met system in pancreatic cancer and GB is linked to poor patient outcomes. Although pre-clinical data suggests a role for the MSP/Ron system in driving pancreatic cancer and GB, the value of this system as a prognosticator of cancer aggressiveness and disease outcome is unclear. Given the similarities between the HGF/Met and MSP/Ron systems, many studies have drawn parallels between their pro-cancer effects. However, studies that directly compare these related systems are limited, which has led to a gap in understanding of how these systems may coordinately and uniquely contribute to a cancerous phenotype. A better understanding of the individual characteristics of these related systems will lead to more informed application of HGF/Met, MSP/Ron, and dual HGF/Met:MSP/Ron targeted therapeutics in cancers that exhibit over-activation of these systems. To begin to address this, a comparison of the in vitro effects of HGF and MSP treatment on a panel of cancer-related responses of both a human pancreatic cancer cell line and a cell model of GB were pursued. Results indicated that HGF induces a broad array of cancer-related signaling, behavioral, and transcriptional effects in pancreatic cancer cells. MSP mimicked a subset of those effects produced by HGF in pancreatic cancer cells and produced very few unique effects. The redundant cancer-related effects of HGF and MSP in this model suggest that dual inhibition of these systems may provide a more complete anti-cancer effect in pancreatic cancer. In a GB cell model HGF triggered several pro-cancer signaling and behavioral effects, further supporting its candidacy as a GB drug target. Despite the presence of Ron expression MSP did not produce a substantial effect on model GB cells, indicating that more study is needed to assess the role of the MSP/Ron system in GB pathobiology and to determine its value as a drug target in this cancer.
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Details
- Title
- COMPARATIVE CHARACTERIZATION OF HEPATOCYTE GROWTH FACTOR AND MACROPHAGE STIMULATING PROTEIN IN PANCREATIC AND GLIOBLASTOMA CANCER MODELS
- Creators
- Brett Vanderwerff
- Contributors
- Joseph W Harding (Advisor)Cliff E Berkman (Committee Member)Michael D Griswold (Committee Member)Jon M Oatley (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 114
- Identifiers
- 99900581816701842
- Language
- English
- Resource Type
- Dissertation