Publication Date
2020
Document Type
Thesis
Committee Members
Ravi P. Sahu, Ph.D. (Advisor); Anita Thyagarajan, Ph.D. (Committee Member); Ji Chen-Bihl, M.D., Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Lung cancer is one of the world’s leading causes of cancer-related deaths with poor prognosis, and difficult to treat malignancy. Several genetic, and environmental factors including cigarette smoking and hypertension have been linked as the common risk factors for lung cancer. To that end, multiple mechanisms have been proposed in regulating tumor growth, angiogenesis, and metastasis, as well as the efficacy of cancer therapy in experimental lung cancer models. Importantly, studies including ours, have shown that exposure to reactive oxygen species (ROS)-generating stimuli such as cigarette smoking, and cancer therapy produced oxidized lipids with platelet-activating factor (PAF) agonistic activity from cell types including tumor cells. These PAF agonists via activating PAF-receptor (PAF-R) can augment the growth and metastasis of experimental tumor types or impede the efficacy of cancer therapy via targeting cellular signaling pathways, enzymes/growth factors, and immune-suppressive cells. Importantly, our recent studies have demonstrated that PAF-agonists mediate its effects via microvesicle particles (MVPs), released from various cell types in response to stimuli including cancer therapy. MVPs are nanosize extracellular vesicles that are involved in cell-to-cell communication, and thus, are being explored for its potential to be used as biomarkers or therapeutic targets due to their ability to carry bioactive contents including lipids, and microRNAs (miRs). While studies, including ours, have shown the involvement of the PAF-R pathway in lung tumorigenesis, its association with hypertension has not been studied. Given that anti-hypertensive drugs failed to elicit an anti-tumor response in experimental lung cancer models, we sought to study the effects of the PAF-R in this context. Using a murine PAF-R-deficient lewis lung cancer LLC1 model, our in vitro studies tested the response of two anti-hypertensive drugs, valsartan and losartan on MVP release. We observed that the treatment with both these drugs induce MVP release in a dose-dependent manner. Given that the biosynthesis of MVPs involves acid sphingomyelinase (aSMase) enzyme, our next studies determined that valsartan and losartan-mediated release of MVPs is via aSMase. We found that the inhibition of aSMase via its specific inhibitor, imipramine significantly blocked these anti-hypertensive drugs-induced MVP release. We next tested the effects of the PAF-R pathway on valsartan (used as a model)-mediated anti-tumor effects using PAF-R-expressing C57BL/6-wild type (WT) mice. LLC1 cells were subcutaneously implanted into the dorsal flanks of WT mice, and upon the development of palpable tumors, they were intraperitoneally treated with vehicle (for control), valsartan, PAF-R antagonist WEB2086 compound, and the combination of valsartan and WEB2086 followed by the measurement of tumor growth. Similar to the published reports, we observed that valsartan did not elicit an anti-tumor response as compared to the control group. Importantly, WEB2086 treatment not only resulted in decreased growth of LLC1 tumor xenografts but also enhanced valsartan anti-tumor efficacy. Consistent with our hypothesis, we noticed increased levels of MVP release in tumors, and plasma samples collected from the valsartan-treated mice group compared to the control group, and decreased MVP levels in WEB2086 and valsartan group. In summary, our studies provide the possible role of the PAF-R in modulating the anti-tumor response of anti-hypertensive drug via MVP release, and that PAF-R blockade can enhance its anti-tumor efficacy. Future studies are warranted to define the mechanistic insight of PAF-R and hypertension in lung cancer.
Page Count
33
Department or Program
Department of Neuroscience, Cell Biology and Physiology
Year Degree Awarded
2020
Copyright
Copyright 2020, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
