Medicine and Health Sciences Commons^™

Functional Role Of Dream And Dyrk1a In High-Grade Serous Ovarian Cancer Cell Dormancy, Pirunthan Perampalam

Electronic Thesis and Dissertation Repository

High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The majority of women are disproportionately diagnosed at an advanced stage (stage III-IV) of the disease when tumours have progressed beyond the ovaries or fallopian tubes and into the peritoneal cavity. Survival rates at late-stage are as low as 25% and chemoresistant disease recurrence is common, affecting up to 90% of patients. Multicellular clusters called spheroids contribute to dormancy, chemoresistance, and metastases and are a major challenge to treatment of HGSOC. Spheroid cells undergo reversible quiescence to evade chemotherapy in a process mediated by the mammalian DREAM …

Epithelial-To-Mesenchymal Transition Leads To Disease-Stage Differences In Circulating Tumor Cell Detection And Metastasis In Pre-Clinical Models Of Prostate Cancer, Lori E. Lowes, David Goodale, Ying Xia, Carl Postenka, Matthew M. Piaseczny, Freeman Paczkowski, Alison L. Allan

Anatomy and Cell Biology Publications

Metastasis is the cause of most prostate cancer (PCa) deaths and has been associated with circulating tumor cells (CTCs). The presence of >= 5 CTCs/7.5mL of blood is a poor prognosis indicator in metastatic PCa when assessed by the CellSearch (R) system, the "gold standard" clinical platform. However, similar to 35% of metastatic PCa patients assessed by CellSearch (R) have undetectable CTCs. We hypothesize that this is due to epithelial-to-mesenchymal transition (EMT) and subsequent loss of necessary CTC detection markers, with important implications for PCa metastasis. Two pre-clinical assays were developed to assess human CTCs in xenograft models; one comparable …

Generation Of Organ-Conditioned Media And Applications For Studying Organ-Specific Influences On Breast Cancer Metastatic Behavior, Matthew M. Piaseczny, Graciella M. Pio, Jenny E. Chu, Ying Xia, Kim Nguyen, David Goodale, Alison Allan

Anatomy and Cell Biology Publications

Breast cancer preferentially metastasizes to the lymph node, bone, lung, brain and liver in breast cancer patients. Previous research efforts have focused on identifying factors inherent to breast cancer cells that are responsible for this observed metastatic pattern (termed organ tropism), however much less is known about factors present within specific organs that contribute to this process. This is in part because of a lack of in vitro model systems that accurately recapitulate the organ microenvironment. To address this, an ex vivo model system has been established that allows for the study of soluble factors present within different organ microenvironments. …

Oncolytic Virus Therapy For The Treatment Of Metastatic Ovarian Cancer, Jessica Tong

Electronic Thesis and Dissertation Repository

The management of patients with epithelial ovarian cancer (EOC) faces two major challenges which standard treatments fail to effectively address: 1) Diffuse metastasis as a consequence of late stage diagnosis and 2) intra-tumoral heterogeneity, which fuels tumor evolution and drives the acquisition of chemotherapeutic resistance. In this thesis, we tested new therapeutic strategies using a 3-dimensional in vitro spheroid culture model that mimics key steps of epithelial ovarian cancer metastasis; and another model that mimics both temporal and cellular heterogeneity by establishing multiple cell lines from a single patient over the course of disease progression. Using these models, we investigated …

Recent Advances In The Molecular Characterization Of Circulating Tumor Cells, Lori E. Lowes, Alison L. Allan

Anatomy and Cell Biology Publications

Although circulating tumor cells (CTCs) were first observed over a century ago, lack of sensitive methodology precluded detailed study of these cells until recently. However, technological advances have now facilitated the identification, enumeration, and characterization of CTCs using a variety of methods. The majority of evidence supporting the use of CTCs in clinical decision-making has been related to enumeration using the CellSearch((R)) system and correlation with prognosis. Growing evidence also suggests that CTC monitoring can provide an early indication of patient treatment response based on comparison of CTC levels before and after therapy. However, perhaps the greatest potential that CTCs …

Adaptation Of Semiautomated Circulating Tumor Cell (Ctc) Assays For Clinical And Preclinical Research Applications, Lori E. Lowes, Benjamin D. Hedley, Michael Keeney, Alison L. Allan

Anatomy and Cell Biology Publications

The majority of cancer-related deaths occur subsequent to the development of metastatic disease. This highly lethal disease stage is associated with the presence of circulating tumor cells (CTCs). These rare cells have been demonstrated to be of clinical significance in metastatic breast, prostate, and colorectal cancers. The current gold standard in clinical CTC detection and enumeration is the FDA-cleared CellSearch system (CSS). This manuscript outlines the standard protocol utilized by this platform as well as two additional adapted protocols that describe the detailed process of user-defined marker optimization for protein characterization of patient CTCs and a comparable protocol for CTC …

Imaging Breast Cancer Progression And Lymph Node Metastases In Murine Models Using Mri And Magnetic Nanoparticles, Vasiliki Economopoulos

Electronic Thesis and Dissertation Repository

Most breast cancer related deaths are caused by the spread or metastasis of the primary tumor to distant sites in the body. The lymph nodes are one of the first places where metastases can be detected and are frequently examined for macroscopic metastases to help determine course of treatment for patients. However, little is known about the significance of microscopic metastases and disseminated individual cancer cells within the nodes. The goal of this work was to use MRI to monitor the development of primary tumors and lymphatic metastases in models of breast cancer.

In this thesis, we examined the MRI …

Metastatic Disease: Interactions Between Tumor Cells And Host Environment During Cancer Cell Spread, Jennifer M. Maclean

Electronic Thesis and Dissertation Repository

Tumor and metastasis formation are not cell autonomous phenomena, but rather an evolution of disease within and responding to the host environment. Metastatic spread from a primary tumor occurs as a result of a complex interplay between tumor cells and the host, wherein tumor cells must escape the primary tumor, enter the host vasculature, travel to and arrest in a distant tissue and survive and grow in that new organ. It is known that cells that progress through these stages must both escape and exploit host systems, yet the mechanisms used are not fully understood. Therefore, the goal of this …

High Aldehyde Dehydrogenase And Expression Of Cancer Stem Cell Markers Selects For Breast Cancer Cells With Enhanced Malignant And Metastatic Ability, Alysha K. Croker, David Goodale, Jenny Chu, Carl Postenka, Benjamin D. Hedley, David A. Hess, Alison L. Allan

Anatomy and Cell Biology Publications

Cancer stem cells (CSCs) have recently been identified in leukaemia and solid tumours; however, the role of CSCs in metastasis remains poorly understood. This dearth of knowledge about CSCs and metastasis is due largely to technical challenges associated with the use of primary human cancer cells in pre-clinical models of metastasis. Therefore, the objective of this study was to develop suitable pre-clinical model systems for studying stem-like cells in breast cancer metastasis, and to test the hypothesis that stem-like cells play a key role in metastatic behaviour. We assessed four different human breast cancer cell lines (MDA-MB-435, MDA-MB-231, MDA-MB-468, MCF-7) …