Cancer research is evolving. Historically concerned with the mechanisms by which malignant cells circumvent cell death signaling and maintain unchecked proliferation, focus has shifted to the complex interactions between the tumor cell and the surrounding microenvironment. Ovarian cancer has one of the highest incidence-to-death ratios of all cancers, and is typically asymptomatic until the later stages, often resulting in metastasis prior to discovery. Naturally occurring phenotypes like lactation and child-bearing (parity) reduce ovarian cancer incidence, but the mechanisms are not understood. As the primary site for ovarian cancer metastasis, and a secondary lymphoid organ capable of mounting potent innate and adaptive immune responses, we believe the omental fat band (OFB) provides a unique opportunity to study complex interactions within the tumor microenvironment. Additionally, we hypothesize that once understood, leukocyte populations within the OFB could be modulated to disrupt the pro-tumorigenic cascade. Using fluorescence-activated cell sorting (FACS) and quantitative realtime PCR (qRT-PCR), we comparatively evaluated the changes in the compositional immune profile of the OFB as a result of parity and cancer. Parous mice were associated with a reduction in macrophages and neutrophils in the OFB, resulting in an inherent "protective state" that was refractory to metastatic cancer cell growth after intraperitoneal implantation. This indicates that the leukocyte populations within the
OFB play an important role in tumor development. Therefore we utilized the potent TH1-type immunomodulatory cytokine IL-12 in a membrane-bound form to circumvent reported side effects, such as hepatic and renal damage, cardiotoxicity and death. Targeted IL-12 delivery to the OFB resulted in delayed disease development, although not protection from subsequent challenge. This was also associated with a reduction tumor-associated macrophages (TAMs) and neutrophils (TANs) within the OFB. Kinetic studies demonstrated that these changes were induced by a significant reduction in neutrophil and macrophage chemoattractants early on in the pro-tumorigenic cascade (7 days post-implantation). This work demonstrates that the OFB is a functionally plastic tissue that can be harnessed and re-mobilized to display an anti-tumorigenic microenvironment. / Ph. D.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/50968 |
| Date | 11 June 2013 |
| Creators | Cohen, Courtney A. |
| Contributors | Veterinary Medicine, Roberts, Paul C., Swecker, William S., Schmelz, Eva M., Bevan, David R., Li, Liwu |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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