CANCER AND CELL KILLING
There are two major ways in which individual cells can be killed: necrosis or apoptosis. In necrosis (from the Greek for dead: νεκρόσ) some parts of the cell are broken down but in essence, it simply bursts and releases its contents to the surrounding tissues. The chemicals released by the cell may then cause inflammation at the site. Necrosis can be caused by infection or injury and it occurs, for example, in myocardial infarction (a heart attack) when the blood supply to the heart is interrupted. For the same underlying reason it can also be important in cancer: that is, the central regions of solid tumours may have a poor blood supply, as we shall discuss in detail later, and when this happens tumour cells can be killed through lack of blood-borne nutrients. When necrosis blocks the blood supply to the limbs it can lead to gangrene – the body tissues themselves start to decay: the affected region turns black because of the iron released from haemoglobin after blood cells have lysed.
Apoptosis was first observed by John Kerr, Andrew Wyllie and Alastair Currie who, in 1972, showed that it is involved in cell turnover in many healthy adult tissues and also in the elimination of cells during normal embryonic development. Cells undergoing apoptosis break up into fragments that are either shed and carried away by the circulation or taken up by other cells and rapidly degraded. In other words, the evidence is rapidly removed, in contrast to necrosis. One benefit of this is that cells that are no longer required are removed without causing inflammation, a potential cancer-promoting event that we’ll come back to later. The idea that there is a suicidal component built into the normal development of animals might seem counter-intuitive so we should remind ourselves that many animal structures attain their final form by selective degradation of specific parts. Nowadays many parents-to-be will know this if they have ultrasound scans of their unborn baby, which reveal how our fingers develop from what is really a web until the destruction of cells removes the tissue between the digits.
Kerr and colleagues found that apoptosis could always be detected in untreated malignant neoplasms. A number of earlier studies had noted that a component of cell loss/disappearance occurred in growing tumours, the rate of which could approach 50% of the proliferation rate of cells in a tumour. It might come as an even bigger surprise to discover that tumours eliminate some of themselves than to find this going on during normal development. This may, therefore, be a useful point to remind normal tissues to reflect a balance between proliferation and cell loss and that tumours merely represent a slight perturbation of the normal state (Fig. 1).
1. Tissue homeostasis: the balance between cell proliferation and cell death.
There are two major apoptosis pathways: the intrinsic (mitochondria-associated) and extrinsic pathways. The intrinsic pathway represents a response to internal stress signals (e.g. DNA damage or oncogene expression); whereas the extrinsic pathway is externally activated by hormones or cytokines. However, although arising from diverse signals, these pathways converge to activate proteases that are normally latent (caspases 8 and 9) leading to mitochondrial membrane permeabilisation and the progressive proteolytic destruction of the cell (Fig. 2). The caspases are a family of proteases that degrade proteins – mainly each other – at aspartic acid (Asp) residues.
2. Apoptosis: intrinsic and extrinsic pathways.