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Browsing by Subject "Cancer stem cells"

Now showing 1 - 3 of 3
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    Differential biophysical mechanisms driving cancer stem cell migration
    (2022-01) Heussner, Rachel
    Cancer stem cells (CSCs) are known to have a high capacity for tumor initiation and are likely a key player in the formation of metastases. We have previously shown that in aligned collagen constructs similar to in vivo structures indicative of disease progression, breast CSCs demonstrate enhanced directional and total motility compared to the carcinoma population as a whole (WP). Here, we show that increased motility is maintained by CSCs in diverse environments including elastic, nonaligned 2D polyacrylamide gels at various stiffness; 3D randomly oriented collagen matrices; and ectopic cerebral slices representative of common metastatic sites. The consistency of CSCs’ enhanced motility across diverse environments suggests a general shift in cell migration mechanics between well differentiated carcinoma cells and their stem-like counterparts. To further elucidate the source of differences in migration, we demonstrate that CSCs are less contractile than the carcinoma population as a whole and concomitantly produce fewer and smaller focal adhesions. This shift in CSC biophysical behavior can be tuned via contractility. The WP can be shifted to a CSC-like enhanced migratory phenotype using partial myosin II inhibition. Inversely, CSCs can be shifted to a less migratory WP-like phenotype using microtubule destabilizing drugs to increase contractility. This work begins to elucidate the mechanistic differences driving CSC migration and raises important implications regarding the potentially disparate effects of microtubule-targeting agents on the motility of different cell populations.
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    Synthesis and evaluation of parthenolide analogues: chemical probes and therapeutic agents
    (2013-03) Wang, Dan
    Cancer stem cells (CSCs), also known as tumor-propagating cells or tumor-initiating cells, are subpopulations of undifferentiated, highly tumorigenic cells found within bulk tumors. The rapid advances of cancer research and development of relative technologies have provided more and more evidence for the existence of CSCs, as well as the important roles they play in drug resistance and disease relapse of cancer. However, because of their quiescent nature and the similarities to normal stem cells, eradicating CSCs presents a challenging task. Chapter one provides an overview of cell surface markers of CSCs. Those markers are potential diagnostic macromolecules and targets for drug delivery.Parthenolide (PTL) is a sesquiterpene lactone natural product isolated from Mexican Indian medicinal herb Tanacetum parthenum (feverfew plant), a known medical herb utilized for centuries. PTL has been extensively studied as an anticancer agent, showing significant efficacy towards a wide spectrum of human cancer cells. In 2005, the identification of PTL as the first stand-alone and selective cytotoxic agent against the acute myeloid leukemia CSCs further heightened its therapeutic potential. However, the mechanism of action of PTL's CSC inhibitory activity is still an area of debate. Our efforts to elucidate the molecular targets of PTL is described in chapter two. The design and synthesis of two PTL affinity probes with diverse biological activity as well as their utilization in comparative and competitive protein pull-down experiments to enrich the cellular protein targets of PTL is presented. Although exhibiting promising anticancer and anti-CSC activities, the modest biological potency and poor water solubility prevent further development of PTL. Chapter three describes our efforts to synthesize PTL analogues, as well as our strategy to prepare water-soluble PTL prodrugs.
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    Targeted magnetic hyperthermia for lung cancer
    (2013-01) Sadhukha, Tanmoy
    Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need to develop an effective means to treat NSCLC. Magnetic hyperthermia is a novel non-invasive approach for ablation of lung tumors, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance. Additionally, non-targeted delivery of these particles to the healthy tissues can result in toxicity. To overcome these problems, we used aerosol-based, tumor-targeted SPIO nanoparticles to induce highly selective hyperthermia for the treatment of lung cancer.Mechanistic study on the mode of cell kill by magnetic hyperthermia revealed that the extent and mechanism of MH-induced cell kill is dramatically altered with aggregation of SPIO nanoparticles. While well-dispersed SPIO nanoparticles induced apoptosis similar to that observed with conventional hyperthermia, sub-micron size aggregates, induced temperature-dependent autophagy through generation of oxidative stress. Micron size aggregates caused rapid membrane damage and acute cell kill, likely due to physical motion of the aggregates in alternating magnetic field. Overall, this work highlighted the potential for developing highly effective anticancer therapeutics through designed aggregation of SPIO nanoparticles. Cancer stem cells (CSCs) are a sub-population of stem-like cells that are thought to be responsible for tumor drug resistance and relapse. We determined the susceptibility of CSCs to magnetic hyperthermia. Multiple assays for CSCs, including side population phenotype, aldehyde dehydrogenase expression, mammosphere formation and in vivo xenotransplantation, indicated that magnetic hyperthermia reduced or, in some cases, eliminated the CSC sub-population in treated cells. Magnetic hyperthermia demonstrated pleiotropic effects, inducing acute necrosis in some cells while stimulating reactive oxygen species generation and slower cell kill in others. These results suggest the potential for lower rates of tumor recurrence after magnetic hyperthermia compared to conventional cancer therapies. We then studied the effectiveness of inhalation delivery of tumor targeted SPIO nanoparticles for magnetic hyperthermia treatment of lung cancer. We developed EGFR-targeted, inhalable SPIO nanoparticles for magnetic hyperthermia of NSCLC. EGFR targeting resulted in 50% higher concentration of iron oxide in the lungs 1 week post inhalation, when compared to non-targeted SPIO nanoparticles. Magnetic hyperthermia using targeted SPIO nanoparticles resulted in significant inhibition of in vivo tumor growth over a period of one month. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC, using targeted magnetic hyperthermia.