| 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>
|
|
