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Ras Signaling in Tumor Initiation and Maintenance

dc.contributor.advisor Counter, Christopher Ancrile, Brooke 2008-08-01T12:53:20Z 2011-07-26T04:30:03Z 2008-04-22
dc.description.abstract <p>The Ras proteins, composed of H, N, and KRas, are a family of small GTPases that normally transmit extracellular cues to the cell in a regulated manner. However, Ras is commonly mutated to be inappropriately activated in human cancers, promoting a vast array of tumor phenotypes. Activation of the Raf, PI3K, and RalGEF Ras effector pathways is required to promote Ras-mediated tumorigenesis, leading not only to cell autonomous tumor phenotypes, but also the establishment of a tumor microenvironment. However, following tumor initiation, the requirement upon oncogenic Ras signaling is reduced to activation of PI3K, most likely due to a contribution of the tumor microenvironment. In order to further delineate the requirements for oncogenic Ras signaling pathways during tumorigenesis, I sought to 1) identify PI3K-independent factors necessary for tumor initiation, and 2) determine how PI3K activation maintains tumor growth in the absence of oncogenic Ras. Using cell-based assays and tumorigenesis assays in mice, I have shown that interleukin-6 (IL-6) is secreted upon induction of Ras expression, is required for Ras-mediated tumor initiation, and promotes tumorigenesis in a paracrine manner by fostering angiogenesis. Additionally, I have shown that eNOS, a downstream target of the PI3K pathway, is required for Ras-induced tumor initiation and maintenance, and, moreover, that eNOS-mediated S-nitrosylation and activation of wildtype Ras proteins is required throughout tumorigenesis. Pancreatic cancer is the cancer most highly associated with oncogenic Ras mutations, and I have shown that both IL-6 and eNOS are required for the tumorigenic growth of pancreatic cancer cell lines in mice. I therefore suggest that these proteins, perhaps in combination with other Ras inhibitors, may provide potential anti-cancer targets for oncogenic-Ras driven cancers in the clinic.</p>
dc.format.extent 74441606 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Biology, Genetics
dc.title Ras Signaling in Tumor Initiation and Maintenance
dc.type Dissertation
dc.department Genetics and Genomics
duke.embargo.months 24

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