Glioblastoma Multiforme (GBM) is the most common brain cancer and one of the most fatal forms of cancer overall. The average survival time is 10-14 months, and less than 10% of patients survive more than 5 years after diagnosis. It is characterized by extreme vasculature, chemo/radioresistance, and invasiveness into the normal brain. The current standard of care, which includes surgical removal of tumor, radiation, and the chemotherapeutic agent temozolomide, initially stunt tumor growth. Nevertheless, the tumor invariably rebounds and the patient succumbs to the disease. Therefore, there is an urgent need to develop new therapies for this devastating disease.
YKL-40 is one of the most over-expressed proteins by GBM cells, and is elevated in the serum of patients with GBM. YKL-40 is implicated in a host of inflammatory diseases and has been shown to play a major role in the maturation of some cells of the immune system, especially macrophages. Thus, it has been suggested that YKL-40 may act as a prognostic biomarker for cancer and inflammatory disease. However, little is known about the role of YKL-40 in relation to cancer development and progression, and more work needs to be done to validate it as a biomarker or as a therapeutic target.
It was the goal of the work described herein to uncover some of the key molecular mechanisms of GBM development and progression in the hopes of offering new therapeutic targets. Using a wide variety of in vitro and in vivo techniques, the role of a secreted glycoprotein YKL-40 in GBM was probed. It was demonstrated that YKL-40 enhanced angiogenesis, radioresistance, and progression of GBM cells. Moreover, inhibition of YKL-40 in mouse models markedly arrested tumor growth and vascularization, lending support to the idea of YKL-40 as a therapeutic target. Finally, YKL-40 drove GBM cells into a mesenchymal phenotype, where the tumor cells act as mural-like cells, supporting tumor vasculature networks. Hopefully, the results from these studies will offer the rationale to develop drugs against YKL-40 and potentially extend the lives of patients with this terrible disease.
| Identifer | oai:union.ndltd.org:UMASS/oai:scholarworks.umass.edu:open_access_dissertations-1798 |
| Date | 01 September 2013 |
| Creators | Francescone, Ralph Anthony |
| Publisher | ScholarWorks@UMass Amherst |
| Source Sets | University of Massachusetts, Amherst |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Open Access Dissertations |
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