Out of all tumors, 74% had identifiable mutations in all three pathways. If one were to trace these three pathways further upstream and include all the components, known and unknown, on which they depend, this percentage would almost certainly be even higher. In other words, in almost every case of glioblastoma, there are mutations that disrupt each of three fundamental controls: the control of cell growth, the control of cell division, and the control of responses to stress and DNA damage.
Strikingly, in any given tumor-cell clone, there is a strong tendency for no more than one gene to be mutated in each pathway. Evidently, what matters for tumor evolution is the disruption of the control mechanism, and not the genetic means by which that is achieved. Thus, for example, in a patient whose tumor cells have no mutation in Rb itself, there is generally a mutation in some other component of the Rb pathway, producing a similar biological effect.
Similar patterns are seen in other types of cancers. A survey of many specimens of the major variety of ovarian cancer, for example, identified 67% of patients as having mutations in the Rb pathway, 45% in the Ras/PI3K pathway (defined more narrowly than in the glioblastoma study), and more than 96% in the p53 pathway. Allowing for additional pathway components not included in the analysis, it seems that most cases of this type of cancer, too, have mutations disrupting the same three controls, leading to misregulated cell growth, misregulated cell proliferation, and abnormal disregard of stress and DNA damage. It seems that these three fundamental controls are subverted in one way or another in virtually every type of cancer.
We have devoted an entire chapter to the cell cycle and growth controls (Chapter 17). Some important details of the other two control pathways are reviewed next.
Mutations in the PI3K/Akt/mTOR Pathway Drive Cancer Cells to Grow
Cell proliferation is not simply a matter of progression through the cell cycle; it also requires cell growth, which involves complex anabolic processes through which the cell synthesizes all the necessary macromolecules from small-molecule precursors. If a cell divides inappropriately without growing first, it will get smaller at each division and will ultimately die or become too small to divide. Cells appear to require two separate signals to grow and divide (Figure 20–26). Cancer depends, therefore, not only on a loss of restraints on cell-cycle progression, but also on disrupted control of cell growth.
The phosphoinositide 3-kinase (PI 3-kinase)/Akt/mTOR intracellular signaling pathway is critical for cell growth control. As described in Chapter 15, various extracellular signal proteins, including insulin and insulin-like growth factors,
Figure 20–26 Cells seem to require two types of signals to proliferate. (A) In order to multiply successfully, most normal cells are suspected to require both extracellular signals that drive cell-cycle progression (shown here as blue mitogen) and extracellular signals that drive cell growth (shown here as red growth factor). how mitogens activate the Rb pathway to drive entry into the cell cycle is described in Figure 17–61. (B) Diagram of the signaling system containing Akt that drives cell growth through greatly stimulating glucose uptake and utilization, including a conversion of the excess citric acid produced from sugar intermediates in mitochondria into the acetyl CoA that is needed in the cytosol for lipid synthesis and new membrane production. As indicated, protein synthesis is also increased. This system becomes abnormally activated early in tumor progression. TCA cycle indicates the tricarboxylic acid cycle (citric acid cycle).