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Cover for Drivers of cancer cell invasion and metastasis
dc.contributor.advisorWellstein, Antonen
dc.creatoren
dc.date.accessioned2013-06-11T18:09:49Zen
dc.date.available2013-06-11T18:09:49Zen
dc.date.created2012en
dc.date.issueden
dc.date.submitted01/01/2012en
dc.identifier.otherAPT-BAG: georgetown.edu.10822_558683.tar;APT-ETAG: 14c7dc5b8d1e0b569e16bbd695732e74; APT-DATE: 2017-01-30_12:13:53en
dc.identifier.urien
dc.descriptionPh.D.en
dc.description.abstractMetastatic spread of cancer cells from their primary site requires invasion into the vasculature, extravasation at the distant organ site and colonization of the distant organ. Here we studied mechanisms of attachment and invasion into endothelial monolayers by cancer cells to identify driver molecules and signaling pathways that are crucial for the invasive phenotype.en
dc.description.abstractWe found that human cancer cell invasion of an endothelial monolayer is altered by the density at which the cancer cells are grown in tissue culture. Gene expression analysis showed that immune response cytokines such as IL6, IL8, CXCL1, 2 & 3 are upregulated and serve as drivers of transendothelial invasion of subconfluent MDA-MB-231 cells. Blocking the receptors of these cytokines inhibited cancer cell migration and endothelial invasion in vitro. Conditioned media (CM) from invasive MDA-MB-231 cells restored the invasive phenotype to non-invasive MDA-MB-231 cell subpopulations, and CM from non-invasive cells inhibited the invasive phenotype suggesting that the invasive phenotype is dependent on factors released from the cells.en
dc.description.abstractMDA-MB-231 cell subpopulations with different invasive phenotypes was also studied in live zebrafish embryos. These in vivo studies corroborated the distinctly invasive phenotype of the cancer cell subpopulations in vitro. CXCR2 blocking antibodies inhibited MDA-MB-231 invasion and changed their homing pattern in the zebrafish model. Additionally, the non-invasive MDA-MB-231 showed reduced lung colonization when injected in the tail vein of nude mice. We conclude that autocrine and paracrine acting cytokine networks contribute to cancer cell invasion.en
dc.description.abstractIn an independent functional genomics approach to dissect driver pathways of malignant progression different human and mouse cancer cell lines were transduced with lentiviral-based genome or kinome-targeted shRNA libraries. Cancer cell subpopulations were then selected for their loss-of-function in an endothelial invasion assay in vitro. After several rounds of selection, the respective shRNA targeted genes were identified from the selected cancer cell populations. Two to four distinct shRNAs targeted each identified gene.en
dc.description.abstractWe conclude that cancer cell invasion of endothelial monolayers can model one of the hallmarks of invasive cancer and can be used to identify driver pathways of malignant progression that may translate into targets for therapy.en
dc.formatPDFen
dc.format.extent95 leavesen
dc.languageenen
dc.publisherGeorgetown Universityen
dc.sourceGeorgetown University-Graduate School of Arts & Sciencesen
dc.sourceTumor Biologyen
dc.subjectbreast canceren
dc.subjectcell Densityen
dc.subjectcytokinesen
dc.subjectinvasionen
dc.subjectmetastasisen
dc.subject.lcshCytologyen
dc.subject.lcshMolecular biologyen
dc.subject.lcshOncologyen
dc.subject.otherCellular biologyen
dc.subject.otherMolecular biologyen
dc.subject.otherOncologyen
dc.titleDrivers of cancer cell invasion and metastasisen
dc.typethesisen


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