CANCER AND ANIMAL CELL BEHAVIOUR
Animal cells are continuously responding to the question of whether they should embark on the process of division or remain quiescent. As we’ve seen, the positive signals for proliferation come in the form of growth factors, the pathways that they activate ultimately communicating with the machinery of the cell cycle. In a counterbalancing act, some cytokines deliver anti-growth signals, the most notable of these being the transforming growth factor beta (TGFβ) family that inhibit the growth of most normal types of cell. The TGFβs signal in essentially the same way as other protein hormones but in normal cells, their effect is to inhibit cell division, the most critical target in this context being transcriptional repression of MYC. The anti-proliferative effect of TGFβ can thus combine with the restrictive effects of members of the tumour suppressor family in limiting cell cycle progression. Prominent among the latter are RB1 and p53 and these, as we have seen, are frequently inactivated in cancers. The inhibitory effects of TGFβ are ablated in tumour cells in much the same way that growth factor signalling can become constitutively activated: by the acquisition of mutations in pathway components. For TGFβ the outcome is that either its signals are no longer transmitted to the cell or intracellular signalling is inhibited or subverted. However, the role of TGFβ is more complex than merely being a negative regulator of cell proliferation. While this cytokine certainly inhibits cell cycle progression and indeed can promote suicide in many types of normal cell, in a variety of tumours these responses are lost but the signalling function of TGFβ is switched to promote an invasive and metastatic phenotype. TGFβ can contribute to a malignant phenotype by activating the synthesis of metalloproteinases and it also can induce an angiogenic response in the endothelium. Thus, signalling pathway mutations appear to convert TGFβ from tumour suppressor to tumour promoter.
We have seen that normal cells carry on a balancing act with regard to proliferation and that the resulting homeostasis is a feature of all multicellular organisms. There’s nothing particularly startling about this concept, although the scale and range of the associated activity are breathtaking. Just to stay as we are, human beings make one million new cells every second. After development is completed we make almost no new neurons, skeletal muscle cells or heart muscle cells (cardiac myocytes) and red blood cells, once released from the bone marrow, cannot divide and they survive in the circulation only for about 120 days. The inability of myocytes to proliferate is one reason why heart attacks are so serious – any resultant loss of heart cells cannot be replaced. On the other hand, epithelial cells that line organs such as the skin, lung and intestine, proliferate rapidly throughout life. The lining of our blood vessels is the endothelium: it’s made up of a specialised sort of epithelial cell and, although endothelial cells don’t usually proliferate, they switch on rapidly if we injure ourselves, as part of the process that repairs our blood vessels. This turns out to be very important in the development of solid tumours and we shall return to it shortly.
So some cells are dividing very rapidly while others have completely lost the capacity to divide at all and some, like circulating B lymphocytes, are just waiting for the right cue to switch on division. But mammalian cells have an inbuilt capacity for committing suicide, for example as a reaction to DNA damage, by apoptosis (Fig. 1) and it has emerged that this suicide programme is inhibited in most, perhaps all, cancer cells.
1. Apoptosis or programmed cell death.