The Hallmarks of Cancer
Figure 1.2 illustrates 10 functions of a tissue essential for it to behave as a malignant neoplasm: here some drugs which interfere with these processes, the focus of this Volume, are listed also. How many of these hallmarks are necessary or sufficient for progression of the disease in any particular patient?
Accelerators, Brakes and Maintenance Men
There are a bewilderingly large number of cell signalling pathways: cell surface receptors binding messenger molecules which transmit signals via a large number of extremely complex pathways to the nucleus, where gene functions are either up- or down-regulated. These are understood to variable degrees, but sufficiently in many cases for their dynamics to be used in diagnosis, prognosis and treatment with drugs and antibody inhibitors. Reproduced here with permission from “Cell” (Fig. 1.3), simply as indicator of the complexity, and raising the question “How many, and which, specifically, of these many genes need to be mutated for malignant transformation of a cell”?
Fig. 1.3 The circulatory of cancer genomics. Reproduced with permission from Hanahan and Weinberg, published in Cell (2000)
An attractive scenario was prevalent in conversations a decade or so ago and is still found on public websites. http://www.cancer.org/cancer/cancercauses/geneticsand cancer/genesandcancer/genes-and-cancer-oncogenes-tumor-suppressor-genes. This had it that as few as 6 mutations were critical, and sufficient if one or more of these disturbed the process of cell division (by analogy the accelerator of a vehicle); one or more the brakes (control of apoptosis or other processes of cell death); and one or more the ability for DNA repair (maintenance of the vehicle): the vehicle would crash of the accelerator was stuck on; the brakes failed, or the wheels fell off.
Recently, merging the expertise of mathematical modelling with that of cell and molecular biology, it has been proposed that in most epithelial neoplasms, three mutations may be sufficient (Tomasetti et al. 2015). Neoplastic progression (vide infra) will introduce many more, so that it remains a major challenge to determine which type of aberration in which gene might be altering a pathway the correction of which can improve the outcome for a given patient.