• Elucidating the Role of Fatty Acid Synthase in Oral Carcinogenesis and Potential Therapeutics

      Wisniewski, David John; Schneider, Abraham; 0000-0002-7514-7918 (2018)
      The 5-year overall survival rate in oral squamous cell carcinoma (OSCC) has remained relatively unchanged over decades, due to late stage diagnosis and high recurrence rates. This work investigates two potential contributing risk factors associated with OSCC development: nicotine, present in traditional combustible tobacco cigarettes and electronic nicotine delivery systems, and high glucose as associated with Type II diabetes and hyperglycemia. A novel therapeutic, TVB-3166, for OSCC treatment was also studied through in vitro experiments, which may help improve clinical treatments for fully developed, often late-stage OSCC. Through cell viability and growth assays, scratch assays to mimic in vitro migration, and western blotting, we determined that both nicotine and high glucose caused oral dysplastic keratinocytes to exhibit an increase in malignant-like behavior. High expression levels of fatty acid synthase (FASN), a key de novo lipogenic enzyme, have been implicated in OSCC, and this work presents the first evidence that both nicotine and high glucose markedly increase oral dysplastic keratinocyte FASN expression, which drives epidermal growth factor receptor (EGFR) signaling, a key pro-oncogenic signaling pathway commonly associated with oral carcinogenesis. We also demonstrate that TVB-3166, a novel selective FASN inhibitor, induces apoptosis and reduces in vitro OSCC cell migration. Moreover, TVB-3166 inhibits basal EGFR activity and several other oncogenic signaling proteins. This further establishes a potential role for FASN and EGFR not only in the progression of oral epithelial dysplastic pre-malignant lesions, but in fully-developed OSCC tumors. Overall, this work suggests that both nicotine and high glucose play a role in OSCC progression, specifically as it relates to FASN-dependent EGFR activation. Further, the novel drug TVB-3166 should be investigated in future pre-clinical animal models as a potential adjunct to OSCC therapeutics. Through an improved understanding of risk factors for OSCC development, as well as determination of novel therapeutic strategies, this work aims to improve overall patient survival through prevention of OSCC development, as well as discovery of new adjunctive treatments for fully established tumors.
    • The Diagnostic Utility of Cancer Stem Cell Marker CD44 in Early Detection of Oral Cancer

      Alsalem, Bader; Meiller, Timothy F. (2019)
      The incidence of Oral Squamous Cell Carcinoma (OSCC) is expected to increase in the coming decades. In recent years, cancer biomarkers have emerged as a promising diagnostic and prognostic tool for various cancers. The cluster differentiation antigen (CD44) is among the most frequently identified cancer stem cell markers in solid tumors. Using immunohistochemistry labeling in previously diagnosed specimens, we aimed to analyze the utility of CD44 in early diagnosis of OSCC. Biopsy specimen subgroups of lateroventral tongue revealed an increased proportion of cells staining positive for CD44 in the epithelial samples of OSCC compared with erosive lichen planus and oral dysplastic lesions. CD44, in combination with other oral biomarkers, therefore, has the potential to assist in the early diagnosis of OSCC. Future studies with larger sample sizes and multiple biomarkers should be carried out, utilizing a pre-determined IHC staining and interpretation strategy to promote reproducibility of evidence.