An electron micrograph showing an apoptotic haematopoietic cell (Bar = 2 
m) © Nicola McCarthy.
By the late 1960s, it was recognized that the spontaneous loss of tumour cells was an important component in the growth of tumours and, although cell death was the most likely cause, little was known about the mechanisms involved. John Kerr had already shown that cells died with a morphology that was distinct from necrotic cells, but it was not until the description of apoptosis in a 1972 review by John Kerr, Andrew Wyllie and Alastair Currie that specific roles for cell death in cancer development were proposed.
Kerr, Wyllie and Currie suggested that, unlike necrosis, apoptosis might represent a genetically regulated cell-suicide programme, and, importantly, they stated: "We should now like to speculate that hyperplasia might sometimes result from decreased apoptosis rather than increased mitosis, although we emphasize that we know of no definitive studies to support such a hypothesis."
Importantly, in 1988, David Vaux, Suzanne Cory and Jerry Adams showed that expression of the B-cell lymphoma 2 (BCL2) gene, which had been identified by others as being translocated in follicular lymphoma (see Milestone 10), could promote the survival of haematopoietic cells after the removal of growth factors (Gwyn Williams and co-workers were later to show that these growth factors suppressed apoptosis). Vaux and colleagues also showed that the oncogene Myc cooperated with Bcl2 to produce tumours in immunocompromised mice. They suggested that BCL2 provided a distinct survival signal that might contribute to neoplasia by allowing a clone to persist until other oncogenes, such as Myc, became activated. This and subsequent work provided evidence that cell survival was regulated independently of cell proliferation, and that impaired cell death, similar to enhanced proliferation, was indeed a key step in tumour development. In the same year, John Reed and colleagues found that overexpression of BCL2 in an immortalized mouse cell line did not induce proliferation or transformation in vitro. Although these cells did produce tumours in mice, further mutational events were required. In 1989, Tim McDonnell, Stanley Korsmeyer and colleagues reported that the expression of a BCL2–immunoglobulin fusion protein in B cells prolonged their survival — an event that this group also showed was tumorigenic.
Soon after, other oncogenes, such as the breakpoint cluster region (BCR)–Abelson leukaemia viral oncogene (ABL; also known as ABL1), were shown to suppress apoptosis. Conversely, several groups, including those of John Cleveland and Gerard Evan, reported that overexpression of MYC induced apoptosis. Initially, this seemed counterintuitive — why would the upregulation of an oncogene associated with increased proliferation induce cell death? It was proposed that MYC-induced apoptosis was part of a tumour suppression mechanism. Apoptosis as a mechanism to limit tumorigenesis was further supported by the finding that the tumour suppressor p53 induced apoptosis (see Milestone 20).
These discoveries and many others have shown that failure to induce apoptosis produces hyperplasia, whereas further mutations are required to produce overt neoplasia. Overall, the concept that the inability of a cell to die was potentially tumorigenic revolutionized the way in which tumorigenesis was viewed and greatly influenced treatment strategies.
