CANCER AND DORMANT TUMOURS
Microscopic foci of tumour cells that do not expand were first detected early in the twentieth century. More recently autopsies of road traffic accident victims came up with the rather perturbing finding that many adults have a substantial number of microscopic colonies of cancer cells (also known as in situ tumours). These contained ~105 cells, occurred in a variety of organs and tissues and would have been undetectable had not accidental deaths made these tissues available for pathological analysis. These micro- tumours were clearly dormant: their carriers died in accidents and they had shown no signs of cancer. Furthermore, knowing what we do about the time course of cancer development, we can be sure that most of them would not have gone on to manifest cancer for many more years or even decades. Clearly, the dormant tumours had spontaneously ceased to grow; the presumption is that this was due to inability to switch on angiogenesis. Considerable evidence from mouse models of tumour dormancy now supports this conclusion. Thus, tumour cells that are not angiogenic and remain dormant when injected into mice initiate growth when angiogenic factors are supplied. Furthermore, human tumour cells (breast carcinoma, glioblastoma, osteosarcoma and liposarcoma) that remains dormant for prolonged periods in mice before switching to a rapidly growing phenotype show a similar change in their pattern of gene expression as they do so.
Notably, the switch involves down-regulation of the angiogenesis inhibitor thrombospondin and up-regulation of the PIK3 and EGFR signalling pathways.
Consistent with these observations are the dozen or so cases of organ transplants where the donor had previously been treated for melanoma and same cancer subsequently developed in the recipient. The elapsed time between the donor undergoing surgery for melanoma and organ transplantation ranged from 6 months to 16 years. In each case, the graft had carried with it melanoma cells, despite the donor being free of any evidence of secondary disease and detectable metastases at the time of his death, and these developed into tumours in the recipients.
These observations in humans have a parallel in some long-standing experiments in rats in tumour cells failed to develop into liver metastases unless the rats were subjected to surgery. Following up to three repeats of this trauma, all the animals developed tumours. Although not confirmed, it seems probable that the activation of angiogenesis in response to surgery had the side- effect of switching on the generation of blood vessels to supply dormant tumours. An alternative explanation for dormancy has emerged from recent experiments using transgenic mouse models. These suggested that, rather than inhibition of angiogenesis, it is the action of the immune system that suppresses the growth of disseminated tumour cells. Moreover, these studies provide further evidence that tumour cells can dissociate from a primary tumour during the earliest stages of its development, long before a primary tumour can be detected. The mice (in which the human RET oncogene is expressed in melanocytes) develop spontaneous melanomas (in the eye) and cells derived from a primary tumour can be detected in distant organs (notably the lung) within three weeks of birth. Genomic sequencing confirmed that the very early metastases were indeed composed of cells from a primary tumour. Nevertheless, the development of these distant metastases into tumours is suppressed for prolonged periods – the median age is about one year for the lung tumours.
The suppression of growth in these early metastases is critically dependent on a subpopulation of lymphocytes (CD8+ T cells, also called cytotoxically or killer T cells): when these are depleted metastatic growth is switched on. In other words, CD8+ T cells that would normally be present in the circulation inhibit proliferation of tumour cells in the metastases.
The concept of a tumour ‘immunosurveillance’, proposed some 40 years ago, holds that malignant cells are generally killed by the action of the immune system, a major reason why so few develop as metastases. These results show, however, that signals generated by lymphocytes (interferon-γ (IFNγ) or tumour necrosis factor-α (TNFα)) can suppress proliferation in disseminated so that they remain in a dormant state for prolonged periods.