Reactive species promotion of head and neck squamous cell carcinoma
Head and neck squamous cell carcinoma (HNSCC) is the most common form of oral cancer. Current standard therapy involves surgical resection of the primary tumor followed by radiotherapy and/or chemotherapy. Each year 3-7% patients succumb to a second primary tumor at. Clinical evidence supports a contribution of sustained inflammation, reactive species (RS) and their sequelae in carcinogenesis. Studies in Chapter 2 focused on elucidating mechanisms by which RS facilitate HNSCC tumorigenesis. The purpose of this investigation was to assess the effects of reactive oxygen and nitrogen species on selected parameters of the HNSCC tumorigenic phenotype i.e. nuclear factor (NF)kappaB activation, sustained cell proliferation, and production of proinflammatory and proangiogenic proteins. Results showed that reactive oxygen (H2O2) and for the first time reactive nitrogen (SIN1) activated NFkappaB in HNSCC cells. Notably, TNF, H2O2, NOC18 and SIN1 increased IL-8, VEGF and EGFR protein levels. Our results indicate RS mediate HNSCC development by activation of NFkappaB followed by increased growth factor production. N-acetyl-cysteine (NAC) has previously been identified as a potentially effective chemopreventative agent. As a precursor to L-cysteine, the rate limiting reactant in glutathione (GSH) synthesis, it possesses ability to increase cellular stores of the antioxidant GSH, and inhibit matrix metalloproteinases (MMPs). MMPs are a family of enzymes noted for their ability to degrade the extracellular matrix (ECM) and their overexpression has been linked to the ability of tumors to invade, metastasize and release growth factors. Chapter 3 studies evaluate the effect of NAC treatment on RS induced activation of NFkappaB and activator protein (AP)-1 transcription factors and on the induction of MMP-2, MMP-9, tissue inhibitors of MMPs (TIMP)-1 and TIMP-2. Results demonstrated no significant response with respect to the transcription factors NFkappaB or AP-1, MMP-2 and -9 mRNA or protein, and TIMP-1 and -2 protein. In contrast, NAC pretreatment increased TIMP-1 and -2 mRNA. Results, from both Chapters 2 and 3, aid in understanding how RS promote tumorigenesis in HNSCC and how might antioxidants be used to reduce their impact.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:ap 1 epidermal growth factor receptor interleukin 8 vegf hnscc tumor necrosis matrix metalloproteinase reactive species oxygen nitrogen nfkappab
Date of Publication:01/01/2007