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Characterizing dsRNA-induced inflammation in ovarian cancer cells
Muccioli, Maria

2014, Doctor of Philosophy (PhD), Ohio University, Molecular and Cellular Biology (Arts and Sciences).
The involvement of inflammation in cancer progression is well-established. The immune system can play both tumor-promoting and suppressive roles, and efforts to harness the immune system to help fight tumor growth are at the forefront of research. Of particular importance is the inflammatory profile at the site of the tumor, with respect to both the leukocyte population numbers and the phenotype of these cells. In this regard, the pro-inflammatory effects of pattern-recognition receptor expression and activation in tumor cells have emerged to be very relevant to disease outcome, but detailed characterization studies of these pathways in specific cancer types are lacking. Importantly, it has been reported that overexpression of TLR3, a dsRNA receptor, in ovarian cancer appears to increase metastasis and quickens disease progression. Herewith, we characterize the effects of dsRNA-activated pathways on pro-inflammatory cytokine production in epithelial ovarian carcinoma cancer cell lines. It is hypothesized that the activation of TLR3 in tumor cells can alter the inflammatory cytokine profile of the tumor, which may result in enhanced recruitment and/or alternative activation of immune cells that can promote tumor growth. Consistently, we report that treatment of mouse and human ovarian cancer cells with synthetic dsRNA molecules results in the increased production of numerous inflammatory cytokines. We also evaluated the contribution of distinct dsRNA receptors to the cytokine secretion profile, and found that different ovarian cancer cell lines vary in their utilization of dsRNA receptors. Furthermore, as dsRNA-activated pathways have been reported to support tumor growth in certain contexts, while causing apoptosis in other studies, we investigated the effects of dsRNA treatment on cell death in ovarian cancer cells. Indeed, we found that at sufficient concentrations of dsRNA treatment, concentration-dependent cell death occurs, although activation with high concentrations of dsRNA in patients is toxic, preventing its use in cancer therapy. Thus this work provides a detailed characterization of dsRNA-activated inflammatory response in several (mouse and human) ovarian epithelial carcinoma cell lines, and provides insight into which molecules and pathways may offer the best potential for therapeutic targeting. Future studies utilizing immune-competent animal models will be useful to evaluate the physiological significance of the expression and activation of dsRNA receptors in ovarian tumor cells.
Fabian Benencia, Ph.D. (Advisor)
Marcia Kieliszewski, Ph.D. (Committee Member)
John Kopchick, Ph.D. (Committee Member)
Ramiro Malgor, M.D. (Committee Member)
138 p.

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Muccioli, M. (2014). Characterizing dsRNA-induced inflammation in ovarian cancer cells. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Muccioli, Maria. "Characterizing dsRNA-induced inflammation in ovarian cancer cells." Electronic Thesis or Dissertation. Ohio University, 2014. OhioLINK Electronic Theses and Dissertations Center. 22 Nov 2017.

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Muccioli, Maria "Characterizing dsRNA-induced inflammation in ovarian cancer cells." Electronic Thesis or Dissertation. Ohio University, 2014. https://etd.ohiolink.edu/

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