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No / Chloroethylaminoanthraquinones are described with intercalating and alkylating capacity that potentially covalently cross-link topoisomerase II (topo II) to DNA. These compounds have potent cytotoxic activity (IC(50) = 0.9-7.6 nM) against the A2780 human ovarian carcinoma cell line. Hydroxyethylaminoanthraquinones also reported in this paper have similar IC(50) values (0.7-1.7 nM) in the same cell line. Alchemix (ZP281M, 1-(2-[N,N-bis(2-chloroethyl)amino]ethylamino)-4-(2-[N,N-(dimethyl)amino]ethylamino)-5,8-dihydroxy-9,10-anthracenedione), an alkylating anthraquinone, retains excellent antitumor activity in Adriamycin-resistant (2780AD) and cisplatin-resistant (2780/cp70) cell lines in vitro and in vivo. This indicates that Alchemix can evade both P-glycoprotein efflux pump and DNA mismatch repair-mediated resistance. In treated cells, Alchemix was shown to preferentially induce drug-stabilized covalent bound topo IIalpha-DNA complexes over topo IIbeta-DNA complexes.

Ovarian cancer is considered to be one of the deadliest gynecological diseases. Over 21,000 women are expected to be diagnosed with this fatal disease in 2020 alone. Obesity, but more specifically a high waist-to-hip ratio, is indicative of abdominal obesity and has been correlated with increased risk of ovarian cancer. How abdominal obesity contributes to this increased risk has not been clearly delineated but much of the current research has been focused on the role of adipocytes. However, in addition to the adipocytes, abdominal white adipose tissue contains the stromal vascular fraction (SVF) which includes stem and progenitor cell populations, immune cells, and fibroblasts. Since the SVF can also be recruited by the cancer cells, we investigated how obesity affects the survival and metastatic potential of cancer cells by investigating changes in the expression of genes that contribute to survival, proliferation, migration, adherence, and invasion. We used culture conditions that mimic the non-permissive peritoneal environment. Cancer related genes, such as Dkc1, Ccnd2, Lig4, and Snai2, were upregulated when adipose derived stem cells (ADSC) were added into MOSE-LTICv spheroids. It was found that peritoneal serous fluid (PSF) from obese mice significantly increased migration of MOSE-LTICv (Serum vs PSF, 517.8 vs 1158.6). These studies brought new knowledge into the field of obesity and ovarian cancer risk and provided direction for future studies involving potential cellular and molecular targets for ovarian cancer diagnosis and treatment. / Master of Science / Ovarian cancer affects many women in the United States. Obesity or more specifically, carrying more weight around the waist, can affect a woman's risk of developing ovarian cancer. Abdominal fat needs to be researched to see if abdominal obesity can affect ovarian cancer on the cellular level. Researchers have looked into how fat cells, known as adipocytes, can affect the progression of ovarian cancer, but more research needs to be done on the contributions of other cells found within adipose tissue. Other cells in abdominal fat include cells such as immune cells, stem and progenitor cells and fibroblasts. We have explored how adipose stem cells from obese mice affect the DNA or "the blueprints" of the cells, survival, and progression of mouse ovarian cancer cells. We found that when adipose stem cells are combined with ovarian cancer cells the expression of certain genes or particular "blueprints" increased. The genes whose expression increased included Dkc1, Ccnd2, Lig4, and Snai2 and when deregulated can cause ovarian cancer cells to become more aggressive. The abdominal fluid from obese mice was found to increase migration of ovarian cancer cells which simulates an increase in metastatic potential. This information has given new insight into the obesity and ovarian cancer relationship.

Obesity is a major global health concern due to its steadily increasing rates and significant contribution to numerous diseases, including cancer. Ovarian cancer specifically, is associated with a 30% increased risk with obesity, although the mechanisms for this are unknown. Waist-to-hip ratio has been especially associated with ovarian cancer, suggesting that visceral fat may be the greatest contributor. Here, we investigated individual visceral fat depots as independent contributors to cancer progression, specifically focusing on adipose tissue-derived stem and progenitor cells, which have previously been shown to be recruited by cancer cells and participate in cancer progression. We confirmed that ovarian cancer tumor burden was indeed significantly increased in mice on a high fat as compared to low fat diet. To further investigate mechanisms, we examined changes in progenitor populations that occurred in intra-abdominal parametrial (pmWAT), retroperitoneal (rpWAT), and omental (omWAT) white adipose tissue (WAT) depots with cancer presence. The greatest tumor burden was evident in omWAT, which also displayed an increase in CD45- cells but a decrease in adipose progenitor cells (APC) and endothelial progenitor cells, suggesting that there was an increase in stromal cells, but that the stem cells were pushed towards differentiation. PmWAT and rpWAT showed remarkably stable progenitor populations. However, a tumor from pmWAT had a significant presence of CD45- cells, actually matching that of its surrounding tissue and differing from the omWAT tumors, indicating that microenvironment has a major influence on tumor stromal cells. We also found that with high fat diet, many cancer-associated changes were exacerbated, such as an increased inflammatory response in all tissues and further decreases in APCs in omWAT. In vitro studies further confirmed that ovarian cancer cells and SVF cells were able to directly interact. Additionally, SVF cells were able to increase the proliferation, mobility, and invasiveness of cancer cells. Conversely, co-culturing also enhanced the proliferation and mobility of SVF cells, providing further evidence that SVF cells may be recruited by cancer cells and that their relationship may be bilateral. Thus, this study provides a good foundation for examining the cellular contributions of adipose tissue to cancer. By further characterizing the mechanism for the association between obesity and cancer development, we could find novel targets to decrease the progress of cancer development in at-risk obese individuals. / Ph. D.

The purpose of this thesis was to characterize cancer metabolism in vitro using epithelial ovarian cancer as a model on an untargeted, systems-level, basis with particular attention paid to the difference between cancer stem cell metabolism and cancer cell metabolism. Two-dimensional gas chromatography coupled to mass spectrometry was used to measure the metabolite profiles of the ovarian cancer and cancer stem cell lines under normal baseline conditions and also under chemotherapeutic and environmental perturbations. These two cell lines exhibited significant metabolic differences under normal baseline conditions and results demonstrated that metabolism in the ovarian cancer stem cell line was distinct from that of more differentiated isogenic cancer cells, showing similarities to stem cell metabolism that suggest the potential importance of metabolism for the cancer stem cell phenotype. Glucose deprivation, hypoxia, and ischemia all perturbed ovarian cancer and cancer stem cell metabolism, but not in the same ways between the cell types. Chemotherapeutic treatment with docetaxel caused metabolic changes mostly in amino acid and carbohydrate metabolism in ovarian cancer cells, while ovarian cancer stem cell metabolism was not affected by docetaxel. Overall, these metabolic differences between the two cell types will deepen our understanding of the metabolic changes occurring within the in vivo tumor and will help drive development of cancer stem cell targeted therapeutics.

Recent morphologic and molecular genetic studies have led to a paradigm shift in our conceptualization of the carcinogenesis and histogenesis of pelvic (non-uterine) serous carcinomas. It appears that both low-grade and high-grade pelvic serous carcinomas that have traditionally been classified as ovarian in origin, actually originate, at least in a significant subset, from the distal fallopian tube. Clonal expansions of the tubal secretory cell probably give rise to serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation. In this article, the authors review the evidentiary basis for aforementioned paradigm shift, as well as its potential clinical implications.

BACKGROUND:Neoadjuvant chemotherapy followed by cytoreduction surgery has been used where an accurate cytologic or pathologic diagnosis is usually required before the initiation of neoadjuvant chemotherapy. However, it is difficult to make definitive diagnosis of presence of cancer cells, particularly gynecologic versus non-gynecologic origin, from those ascites specimens due to the absence of specific biomarkers of gynecologic cancers. In the present study, we evaluated if, in addition to the routine morphologic diagnosis, the biomarker PAX8 could be useful in recognition of ovarian epithelial cancer cells prior to the neoadjuvant chemotherapy.METHODS:Two hundred and two cytology specimens including 120 pretreatment ovarian cancer samples, 60 benign controls, and 22 malignant non-gynecologic cases were studied. All cytology slides were morphologically reviewed in a blinded fashion without knowing corresponding pathology diagnosis, if present. A total of 168 cytology specimens with a cell block were stained with PAX8 and Calretinin. These included patients with potential for ovarian cancer neoadjuvant chemotherapy (n=96), metastatic cancers (n=22), and benign controls (n=50).RESULTS:Among the 96 ascitic samples prior to neoadjuvant chemotherapy, 76 (79%) showing morphologic features consistent with cancers of ovarian primary were all PAX+/Calretinin-. The remaining 20 (21%) cases were positive for adenocarcinoma, but morphologically unable to be further classified. Among the 22 metastatic cancers into the pelvis, one case with PAX8+/Calretinin- represented a renal cell carcinoma and the remaining 21 PAX8-/Calretinin- metastatic cancers were either breast metastasis (n=4) and the metastasis from gastrointestinal tract (n=17). Among the 50 benign control pelvic washing cases, 5 PAX8+/Calretinin-cases represented endosalpingiosis (n=4) and endometriosis (n=1), 25 PAX8-/Calretinin+cases showed reactive mesothelial cells, and the remaining 20 specimens with PAX8-/Calretinin- phenotype typically contained inflammatory or blood cells without noticeable diagnostic epithelia.CONCLUSIONS:PAX8 identifies all Mullerian derived benign or malignant epithelia. When combining with Calretinin, PAX8 is a sensitive marker to diagnose the carcinomas of ovarian origin, which will be ideal to be used for those patients with a possible advanced ovarian cancer prior to receiving neoadjuvant chemotherapy.

Peptide recognition domains (PRD) bind to short linear motifs on their biological partners and are found in several cellular pathways including those found to be critical in tumorigenesis. In this study, I aimed to generate peptide probes against PRDs present on proteins involved in ovarian cancer. Using bioinformatics, I identified 66 potential PRDs present on these proteins. I then used peptide phage display to successfully generate peptides against 27 of the 66 domains. To validate my results, I performed an extensive literature review and structural analysis. For several cases, the phage-display derived binding preferences are similar to previously reported studies. However, for a subset of domains, I identified non-canonical binding preferences that have not been reported previously in literature. The binding preferences obtained in this study can be used to design intracellular probes for studying the role of these PRDs in biological pathways important in ovarian cancer.