Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy due to the insufficient accurate screening programs for the early detection of EOC. To improve the accuracy of the early detection, there is a need to deeply understand the mechanism of EOC progression and the interaction between cancer cells with their unique microenvironment. Therefore, this work investigated the metabolic shift in the mouse model for progressive ovarian cancer, and evaluated the effects of hypoxic environment, spheroid formation as well as stromal vascular fractions (SVF) on the metabolic shift, proliferation rate, drug resistance and protein markers in functional categories. The results demonstrated an increasingly glycolytic nature of MOSE cells as they progress from a tumorigenic (MOSE-L) to a highly aggressive phenotype (MOSE-FFL), and also showed changes in metabolism during ovarian cancer spheroid formation with SVF under different oxygen levels. More specifically, the hypoxic environment enhanced glycolytic shift by upregulating the glucose uptake and lactate secretion, and the spheroid formation affected the cellular metabolism by increasing the lactate secretion to acidify local environments, modulating the expression of cell adhesion molecules to enhance cell motility and spheroids disaggregation, and up-regulating invasiveness markers and stemness makers to promote ovarian cancer aggressive potential. Hypoxia and spheroid formation decreased ovarian cancer cells growth but increased the chemoresistance, which leads to the promotion of aggressiveness and metastasis potential of ovarian cancer. SVF co-cultured spheroids further increased the glycolytic shift of the heterogeneous of ovarian cancer spheroids, induced the aggressive phenotype by elevating the corresponding protein markers. Decreasing the glycolytic shift and suppression of the proteins/pathways may be used to inhibit aggressiveness or metastatic potential of ovarian cancer heterogeneous of ovarian cancer spheroids, induced the aggressive phenotype by elevating the corresponding protein markers. Decreasing the glycolytic shift and suppression of the proteins/pathways may be used to inhibit aggressiveness or metastatic potential of ovarian cancer. / Master of Science / Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy due to the usually late detection when the cancer has already spread throughout the peritoneal cavity. Physical, cellular and chemical factors can contribute to EOC progression and metastasis. Critical physical factors are the low oxygen content in the peritoneal cavity (hypoxia) that promotes tumor cells survival, and the formation of tumor spheres, which have been demonstrated to have a more aggressive phenotype. Moreover, obesity has been proposed to support ovarian cancer development and progression. Therefore, this work investigated the impact of oxygen deprivation, sphere formation, and white adipose tissue-derived stromal cells on ovarian cancer cells progression. The results showed that all these factors contribute to the aggressive potential of ovarian cancer cells by increasing the drug resistance, and modulation of cellular metabolism. The understanding of the interactions between ovarian cancer and other cells within their unique microenvironment may provide critical targets for chemotherapeutic interventions that are aimed to control the aggressiveness of ovarian metastases in their hypoxic tumor microenvironment, and enhance the life of women afflicted with ovarian cancer.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/74235 |
| Date | 10 January 2017 |
| Creators | Liu, Lu |
| Contributors | Human Nutrition, Foods, and Exercise, Schmelz, Eva M., Huckle, William R., Frisard, Madlyn I. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Thesis |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
Page generated in 0.0021 seconds