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Isolation and Characterization of Colon Cancer-initiating CellsO'Brien, Catherine Adell 19 January 2012 (has links)
Colorectal cancer is the second leading cause of death from cancer (men and women combined) in the U.S. and Canada. The mainstay of treatment remains surgical resection and although new agents are constantly emerging to treat colorectal cancer, to date none of the agents have been successful at curing patients with advanced disease. In recent years there has been an increasing interest in the notion that cancers are organized as a hierarchy with the cancer-initiating cell (C-IC or cancer stem cell) existing at the apex. The C-ICs only represent a subset of the total tumour cells; however, research indicates that they are responsible for both the initiation and maintenance of tumour growth. In the studies presented here, we determined that human colon cancers are organized in a hierarchical manner. Furthermore, we prospectively isolated a subset of colon cancer-initiating cells (CC-ICs) based on the expression of the cell surface marker, CD133. The identification of CC-ICs has led to a number of questions concerning the molecular mechanisms driving these cells. Functionally all C-ICs are characterized by their ability to: i) generate a xenograft that histologically resembles the parent tumour from which it was derived, (ii) be serially transplanted in a xenograft assay thereby demonstrating the ability to self-renew and, (iii) generate daughter cells that possess some proliferative capacity but are unable to maintain the cancer because they lack intrinsic regenerative potential. It is becoming evident that cancer cells evolve as a result of their ability to hijack normal self-renewal pathways, a process that can drive malignant transformation. Studying self-renewal in the context of cancer and C-IC maintenance will lead to a better understanding of the mechanisms driving tumour growth. In this work we demonstrate that the inhibitors of differentiation genes (Id1 and Id3) play a central role in driving self-renewal in the CC-IC subset. Furthermore, we demonstrate that this effect is partially mediated through the cdk-inhibitor, p21cip1/waf1.
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Isolation and Characterization of Colon Cancer-initiating CellsO'Brien, Catherine Adell 19 January 2012 (has links)
Colorectal cancer is the second leading cause of death from cancer (men and women combined) in the U.S. and Canada. The mainstay of treatment remains surgical resection and although new agents are constantly emerging to treat colorectal cancer, to date none of the agents have been successful at curing patients with advanced disease. In recent years there has been an increasing interest in the notion that cancers are organized as a hierarchy with the cancer-initiating cell (C-IC or cancer stem cell) existing at the apex. The C-ICs only represent a subset of the total tumour cells; however, research indicates that they are responsible for both the initiation and maintenance of tumour growth. In the studies presented here, we determined that human colon cancers are organized in a hierarchical manner. Furthermore, we prospectively isolated a subset of colon cancer-initiating cells (CC-ICs) based on the expression of the cell surface marker, CD133. The identification of CC-ICs has led to a number of questions concerning the molecular mechanisms driving these cells. Functionally all C-ICs are characterized by their ability to: i) generate a xenograft that histologically resembles the parent tumour from which it was derived, (ii) be serially transplanted in a xenograft assay thereby demonstrating the ability to self-renew and, (iii) generate daughter cells that possess some proliferative capacity but are unable to maintain the cancer because they lack intrinsic regenerative potential. It is becoming evident that cancer cells evolve as a result of their ability to hijack normal self-renewal pathways, a process that can drive malignant transformation. Studying self-renewal in the context of cancer and C-IC maintenance will lead to a better understanding of the mechanisms driving tumour growth. In this work we demonstrate that the inhibitors of differentiation genes (Id1 and Id3) play a central role in driving self-renewal in the CC-IC subset. Furthermore, we demonstrate that this effect is partially mediated through the cdk-inhibitor, p21cip1/waf1.
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USING GENE EXPRESSION ANALYSIS TO GUIDE AND IDENTIFY TREATMENTS FOR BREAST CANCER PATIENTSHallett, Robin M. 10 1900 (has links)
<p>Based on breast cancer clinical trial data accumulated over the last several decades it is obvious that standard breast cancer therapeutics extend survival in breast cancer patients. However, only a minority of patients within these trials derive benefit from treatment. In a population of breast cancer patients treated with adjuvant therapy after surgery, many patients are over-treated, as they would never experience relapse even without receiving adjuvant therapies. Among the remaining patients, some achieve durable remission from therapy, whereas others relapse despite therapy. Hence, there is an obvious need to develop biomarkers that can serve to identify these three populations of patients, such that only patients who are likely to benefit from available therapies are treated with these therapies, as well as to develop new therapies for the treatment of patients who aren’t afforded durable remission by approved treatments. Here, we present the identification of biomarkers to identify low risk breast cancer patients who experience excellent long-term survival even without adjuvant therapy. Conversely, high risk patients represent those patients most likely to benefit from intervention with aggressive treatment regimens. We also report on the identification of biomarkers which can predict the likelihood of response to approved chemotherapy regimens, which could be used to further stratify high risk patients into responders and non-responders. Finally, for high risk patients unlikely to be afforded durable remission from available therapies, we report on the identification of agents that target breast tumor-initiating cells, and may be effective for the treatment of these patients.</p> / Doctor of Philosophy (PhD)
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