Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC commonly invades into the lymph nodes and mandible, which correlate with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly, cause large amounts of bone destruction and require extensive surgeries. Unfortunately, the molecular mechanisms of OSCC invasion into the mandible are not well understood and survival rates have not significantly improved for over 30 years. In a syngeneic model of murine OSCC, Parathyroid Hormone-related Protein (PTHrP), has been shown to be required for OSCC invasion into the mandible. Existing studies have identified the Hedgehog (Hh) transcription factor, Gli2 as the regulator of PTHrP and our previous work in breast cancer metastasis to bone suggest that TGFB may regulate Gli2 transcription. Here we demonstrate that Hh and TGFB signaling concomitantly regulate Gli2 and subsequently PTHrP in OSCC. Additionally, we have elucidated a mechanical signaling mechanism that controls Gli2 activation levels, where extra-cellular matrix rigidities similar to bone, but not basement membrane, causes an increase in ciliogenesis. We also demonstrate the feasibility of targeting Gli2 in vivo using GANT58 loaded microspheres to prevent bone destruction.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11292016-100341 |
| Date | 30 November 2016 |
| Creators | Cannonier-Rudolph, Shellese Amanda |
| Contributors | Linda Sealy, Stephen Brandt, Scott Guelcher, Julie Sterling |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11292016-100341/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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