Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance.
While tumors become addicted to oncogenes like Ras, the microenvironment in which tumor cells reside changes during tumorigenesis; the cells are surrounded initially by normal tissue and later by tumor tissue. Hence, we asked if Ras exerts its oncogenic effects through the same set of effectors during different stages of tumorigenesis. We now show in human cells that the Ras effector pathways MAPK, RalGEF, and PI3K are required to initiate tumor growth. Conversely, activation of the PI3K/AKT pathway replaced Ras once tumors formed, although other effectors were still activated independently of Ras, presumably by factors provided upon the establishment of a tumor microenvironment. Thus, as tumorigenesis progresses the addiction of cancers to their initiating oncogene is reduced to, at least in the case of Ras, the PI3K/AKT pathway.
Lim
Kian-Huat
KH
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Counter
Christopher M
CM
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction
D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D016283:Proto-Oncogene Proteins p21(ras)