Ras Intrinsic and Extrinsic Pathways in Human Cancer

<p>The Ras family of proteins, composed of H, N, and KRas, function as small GTPases that act as "molecular switches" relaying signals from the cell membrane to the rest of the cell in a highly regulated manner. However, Ras signaling is aberrantly activated in a majority of human cancers either through an activating mutation or by activation or overexpression of upstream or downstream elements in the Ras pathway, endowing cells with many tumorigenic phenotypes. Ras is known to promote tumorigenesis through activation of cell intrinsic signaling including the Raf, PI3K, and RalGEF pathways. In regards to the latter, RalGEFs activate two other small GTPases, RalA and RalB. The role of these two proteins in Ras-mediated cancer was poorly understood. I thus assessed the requirement of RalA and RalB in tumor metastasis discovering that both proteins promote this critical step in cancer.</p><p>Ras does not, however, function solely by intrinsic cell signaling. Indeed, it was recently shown that oncogenic Ras signaling induces secretion of cytokines, a category of small molecules involved in cell to cell communication and inflammatory response. Moreover, the release of these cytokines was shown to promote tumorigenesis in an extrinsic fashion by increasing tumor vasculature, or angiogenesis. I noted that one of these cytokines hCXCL-8 (IL-8) belonged to the ELR+ CXC family of cytokines, suggesting that the entire family of ELR+ CXC cytokines may promote Ras driven tumorigenesis. Indeed, I found that expression of oncogenic Ras led to secretion of all ELR+ CXC chemokines in oncogenic Ras driven tumor cell lines, a mouse tumor, a human tumor, and were sometimes elevated in the serum of pancreatic cancer patients, the cancer most associated with oncogenic Ras mutations. Moreover, knockdown of one of these chemokines, hCXCL-1, in pancreatic cancer cells or genetic ablation of the receptor for these cytokines in mice, reduced Ras driven tumorigenesis. Taken together, these results suggest that oncogenic Ras also promotes tumorigenesis through a cell extrinsic pathway by secretion of ELR+ CXC chemokines.</p>Dissertatio