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While much is understood regarding the molecular events that initiate tumour growth, many of the requirements to maintain this growth remain to be elucidated. One protein often activated in cancer cells that is known to be essential to both the initiation and maintenance stages of tumour progression is the oncogene Ras. Activated Ras binds to and activates a number of downstream proteins or effectors, notably i) Rafs, serine/threonine kinases that trigger the MAP-kinase cascade that is well established to promote cell proliferation, ii) PI3-kinase, a lipid kinase that activates the pro-survival AKT pathway, and iii) RalGEFs, GDP exchange factors for Ral A and B that are critical for the tumourigenic conversion of normal human cells. We now show by activating specific effectors of Ras that oncogenic Ras employs different effectors during the initiation and maintenance steps of tumourigenesis. Specifically, initiation of tumour growth requires all three of these effector pathways whereas when Ras signalling is silenced after tumour initiation, tumour growth continues only if PI3-kinase is still stimulated. This latter effect depended upon activation of the downstream target AKT, as an activated version of AKT or a decrease in the tumour suppressor PTEN, a negative regulator of this pathway5, similarly maintained tumour growth upon the loss of Ras signalling. In fact, just the presence of a malignant cells allowed otherwise non-malignant cells with an activated PI3-kinase pathway to populate tumours to the extent they comprised the majority of the tumour bulk. We therefore conclude that firstly, once tumour growth is initiated, activation of the pro-survival PI3-kinase/AKT pathway is sufficient to maintain this growth, and secondly, pre-malignant cells that activate this pathway can contribute significantly to the neoplastic growth of tumours.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]