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  • Cancer as a Disease of the Cell Cycle

    The word “cancer” is terrifying to most of us because it carries with it images of doom. However, there is no one disease called “cancer” but rather a number of diseases that share a common feature: the growth of cells that have lost the ability to control the cell cycle. Some of these diseases are quite treatable, while others are much more difficult and are, in fact, life threatening and often terminal.

    The commonality of the diseases has to do with the cell cycle itself, shown below with several of the key control points indicated:

    figure1

    As you recall from you earlier coursework, cells progress through the stages of the cycle, beginning in G1 (gap 1), into S (synthesis) during which DNA is replicated, on to G2 (gap 2) and finally into M (mitosis or meiosis). The stage G0 is a resting stage that is outside of the cycle proper. G1 and G2 were so-named because they were originally observed as “gaps” between the S and M stages, when gross changes were apparent by microscopic observation. We now know that these two “gaps” are actually very critical. In fact it is during G1 that the important signals are transmitted that tell the cell whether or not to divide. These signals involve a number of gene products, some of which are shown in the figure above.

    Two very important proteins are Rb and p53, both of which act to stop the cell from dividing when it is not required. Rb (so named because it is the defect in the autosomal recessive disorder retinoblastoma) acts to hold in check a protein called E2F. When Rb is inactivated by cdk4.6/cyclin D kinase phosphorylatio, E2F can act. E2F is a transcription factor that activates the synthesis of mRNAs for genes needed during the S stage of the cell cycle. In addition, the combination of Rb and E2F act as a transcriptional repressor of certain genes. When Rb is inactivated by phosphorylation, these genes can now be transcribed and the cell enters S. p53 (so named because of its size) is also a negative regulator of the cycle. In this case, p53 acts to activate the transcription of the mRNAs for two proteins, p21 and p27. p21 and p27 are inhibitors of the cdk/cyclin kinases and therefore work to block the transition of the cell from G1 to S.

    The events of the cell cycle are in turn regulated by a number of other signaling systems in the cell. Some of these are shown in the next figure:

    fig2

    These include growth factors, growth factor, transmembrane receptors intracellular receptors, intracellular signal transducers and transcription factors in the nucleus. As we will see, cancers may involve changes in any of these control points, be it of the cell cycle itself or of one of these parts to the signaling pathway.

    A particular cancer is rarely the outcome of a single change in one of these systems. Rather, most cancers have been shown to be the result of a progressive breakdown of control, stemming from multiple mutational events. In the end, the cells that have lost growth control are able to compete with other cells, eventually overwhelming a particular organ system.

    Oncologists speak of a multi-step model for carcinogenesis. These steps include:

    • dysplasia
    • carcinoma in situ
    • malignant carcinoma
    • metastasis
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