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Influence of Sphingosine 1-Phosphate receptor subtypes on glioblastoma multiforme malignant behavior

Young, Nicholas Adam
http://rave.ohiolink.edu/etdc/view?acc_num=osu1190142189

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science.
Cellular accumulation of Sphingosine 1-phosphate (S1P) stimulates cellular motility, invasion, proliferation, adhesion, and angiogenesis. S1P tranduces these cellular effects by signaling through one of a family of high affinity G-protein coupled receptors that include EDG-1/S1P1, EDG-5/S1P2, EDG-3/S1P3, EDG-6/S1P4, and EDG-8/S1P5. Upon receptor stimulation, unique and preferential G-protein signaling pathways are activated to varying degrees to elicit these cellular responses. Enzymatic production of S1P is a result of the activity of sphingosine kinase (SK). Expression of this protein has been shown to correlate to poor glioblastoma multiforme (GBM) patient prognosis. This deadly neoplasm is diagnosed through histologic criteria that include significant neovascularization, high mitotic index, and diffuse infiltrative appearance. Although progress has been made in the treatment of many cancers in recent years, the dismal patient prognosis for GBM patients has not. Mo lecular based therapies targeting the infiltrative nature of this tumor could ultimately improve patient outcome. This work focuses on GBM malignant behavior as influenced by S1P receptor subtype signaling. All the individual receptor subtypes were found to have unique influences over in vitro GBM proliferative, migratory, adhesive, and invasive responses. The S1P2 receptor subtype displayed novel S1P-induced pro-invasive, but anti-migratory effects, which were mediated through increased adhesion to the extracellular matrix. Invasiveness was promoted through CCN1, uPA, and uPAR, which have all been correlated to GBM tumorigenesis. S1P induced expression of CCN1 through S1P1-2 promoted invasion that was limited with antibody in a spheroid invasion assay. Enhanced activation of SK with receptor subtype S1P1 overexpression resulted in endogenous upregulation of uPA and uPAR expression as well as uPA activity. Additionally, antibody targeting uPA also limited total invasiv e distance of spheroids. The invasive mediators uPA and uPAR were shut down with the inhibition of SK and spheroid invasiveness was eliminated regardless of receptor subtype overexpression. The results of this work better delineate the complex S1P receptor subtype signaling pathways in GBM cells as well as their contributions to malignant behavior. The results on GBM invasiveness have illustrated the key role that SK plays and validated uPA and CCN1 as viable targets for molecular based approaches to therapy.
James Van Brocklyn (Advisor)
sphingosine 1-phosphate; glioma; glioblastoma multiforme; invasion; sphingolipids; cancer

Recommended Citations

Citations

  • Young, N. A. (2007). Influence of Sphingosine 1-Phosphate receptor subtypes on glioblastoma multiforme malignant behavior [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1190142189

    APA Style (7th edition)

  • Young, Nicholas. Influence of Sphingosine 1-Phosphate receptor subtypes on glioblastoma multiforme malignant behavior. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1190142189.

    MLA Style (8th edition)

  • Young, Nicholas. "Influence of Sphingosine 1-Phosphate receptor subtypes on glioblastoma multiforme malignant behavior." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1190142189

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.