<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> / Dissertation
| Identifer | oai:union.ndltd.org:DUKE/oai:dukespace.lib.duke.edu:10161/666 |
| Date | 22 April 2008 |
| Creators | Ancrile, Brooke |
| Contributors | Counter, Christopher |
| Source Sets | Duke University |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
| Format | 74441606 bytes, application/pdf |
Page generated in 0.0132 seconds