Lim Kian-Huat, Counter Christopher M
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Cancer Cell. 2005 Nov;8(5):381-92. doi: 10.1016/j.ccr.2005.10.014.
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.
虽然肿瘤会对Ras等癌基因产生依赖，但肿瘤细胞所处的微环境在肿瘤发生过程中会发生变化；最初细胞被正常组织包围，后来则被肿瘤组织包围。因此，我们询问Ras在肿瘤发生的不同阶段是否通过同一组效应器发挥其致癌作用。我们现在在人类细胞中发现，Ras效应器通路MAPK、RalGEF和PI3K是启动肿瘤生长所必需的。相反，一旦肿瘤形成，PI3K/AKT通路的激活就取代了Ras，尽管其他效应器仍独立于Ras被激活，推测是由肿瘤微环境建立时提供的因子所激活。因此，随着肿瘤发生的进展，癌症对其起始癌基因的依赖至少在Ras的情况下减少到了PI3K/AKT通路。
