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Invasive Predictive Biomarker for Malignant Transformation of Oral Epithelial

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Invasive Predictive Biomarker for Malignant Transformation of Oral Epithelial CD31: Invasive Predictive Biomarker for Malignant Transformation of Oral Epithelial Dysplasia THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Jeffrey M. Hagen Graduate Program in Dentistry The Ohio State University 2013 Master's Examination Committee: Susan R. Mallery, D.D.S., Ph.D., Advisor Gregory Ness, D.D.S. Henry Fields, D.D.S., M.S., M.S.D. Copyright by Jeffrey M. Hagen 2013 Abstract While not all oral epithelial dysplasia (OED) lesions will transform, approximately one third of OED lesions progress to oral squamous cell carcinoma (OSCC). Provided the poor overall prognosis for OSCC patients, intervention at the premalignant stage of OED is an attractive clinical strategy. We do not, however, currently have biomarkers to identify the most aggressive premalignant lesions. Identification of such biological indicators would allow for targeting of OED lesions with high transformation risk and direct lesional-specific management e.g. anti-angiogenic compounds. A wealth of translational and clinical research supports the key role of angiogenesis during malignant transformation. Past human studies involving pre- neoplastic lesions of breast and cervical tissue have revealed a positive correlation between angiogenesis and the progression, prognosis and metastasis of ductal carcinoma in situ and cervical intraepithelial neoplasia. In addition to studies involving human breast and cervical tissue, numerous studies have been carried out to examine the association of between angiogenesis and progression of OED. These data present compelling evidence regarding MVD’s importance in carcinogenesis. A site-matched longitudinal assessment was conducted to determine if increased microvascular density positively correlates with malignant transformation. The clinical basis of this current study: i) identifiy oral epithelial dysplastic lesions likely to progress ii to OSCC, thus, dictating a more aggressive treatment modality and ii) establish reliable clinically relevant biomarkers for OSCC chemoprevention. iii Vita 1998 Columbia Station High School 2002 B.S. Biology, Bowling Green State University 2006 D.M.D. University of Pittsburgh School of Dental Medicine 2013 Oral Maxillofacial Surgery Certificate, The Ohio State University Fields of Study Major Field: Dentistry iv Table of Contents Abstract ............................................................................................................................... ii Vita ..................................................................................................................................... iv List of Tables .................................................................................................................... vii List of Figures .................................................................................................................. viii Chapter 1: Introduction ...................................................................................................... 1 Epidemiology of Oral Squamous Cell Carcinoma...................................................1 Tumor-Associated Angiogenesis.............................................................................2 Angiogenic Switch in Neoplasia.............................................................................3 Angiogenesis and Transformation of Oral Epithelial Dysplasia...…......................5 Shortcomings of Previous Oral Cavity Studies.......................................................8 Design Novelties Available...................................................................................10 Inhibition of Angiogenesis as a Therapeutic Strategy...........................................12 Clinical Implications of Current Study..................................................................12 Specific Aims.........................................................................................................13 Null Hypothesis.....................................................................................................13 Chapter 2: Materials and Methods ................................................................................... 14 Rational for selection of CD31..............................................................................14 Justification for automated image analysis............................................................14 v Sample Identification and Selection......................................................................15 Histological Grading of OED................................................................................16 Immunohistochemical Staining.............................................................................17 Quantification of Vascularity.................................................................................19 Statistical Analysis.................................................................................................25 Chapter 3: Results.............................................................................................................27 Chapter 4: Discussion and Conclusion.............................................................................42 Conclusion.............................................................................................................48 References..........................................................................................................................50 vi List of Tables Table 1. Patient Profiles ................................................................................................... 28 Table 2. Correlation between MVD and progression over time.......................................30 Table 3. Correlation between MVD and nonprogression over time.................................31 Table 4. Nonprogressive association between MVD and histologic grade......................35 Table 5. Progressive association between MVD and histologic grade.............................39 Table 6. MVD analysis between progressive and nonprogressive groups.......................41 vii List of Figures Figure 1. Western blot analysis of HUVEC ..................................................................... 19 Figure 2. CD31 IHC stained specimens ........................................................................... 22 Figure 3. Image analysis.. ................................................................................................ 23 Figure 4. 40x scanned image ........................................................................................... 24 Figure 5. Vessel detection. ............................................................................................ 24 Figure 6. Lumen detection ............................................................................................... 25 Figure 7. Progressive timeline correlation ....................................................................... 30 Figure 8. Nonprogressive timeline correlation ................................................................ 31 Figure 9. Nonprogressive association between total MVD and histological grade ......... 32 Figure 10. Nonprogressive association between small vessel MVD and histological grade .................................................................................................................................. 33 Figure 11. Nonprogressive association between medium vessel MVD and histological grade .................................................................................................................................. 34 Figure 12. Nonprogressive association between large vessel MVD and histological grade .................................................................................................................................. 35 Figure 13. Progressive association between total MVD and histological grade .............. 36 Figure 14. Progressive association between small vessel MVD and histological grade .................................................................................................................................. 37 viii Figure 15. Progressive association between medium vessel MVD and histological grade .................................................................................................................................. 38 Figure 16. Progressive association between large vessel MVD and histological grade .................................................................................................................................. 39 Figure 17. MVD analysis ……………………………………………………………....40 ix Chapter 1: Introduction Epidemiology of Oral Squamous Cell Carcinoma Head and Neck squamous cell carcinoma (HNSCC) is the sixth most common human cancer worldwide with a long-term survival rate of less than 50% (1). Similar to other carcinomas, HNSCC’s arise from malignant transformation of a recognized precursor lesion known as oral epithelial dysplasia (OED) (2,3). Although up to 36% of these precursor lesions will progress to oral squamous cell carcinoma (OSCC), we are currently unable to predict which lesions will undergo malignant transformation (2,3). Conventional management of oral epithelial dysplasia is based on histologic grading into mild, moderate, severe dysplasia and carcinoma in situ (4). Complete excision with close clinical follow-up is standard for moderate or higher grade OEDs (5). Despite surgically clear margins, local OED recurrences are common
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