Cancer's Place in Nature
Why does cancer exist and why do we get it? Is it inevitable?
By Francesco Pezzella
Cells are the smallest unit containing all the features necessary and sufficient to life. In 1863 the German pathologist Rudolf Virchow introduced the concept of cellular pathology by stating that diseases are due to the occurrence of alterations at cellular level. This is very much the case with cancer, a disease of multicellular organisms in which, following the occurrence of genetic damage, one “renegade” cell develops into a tumour mass which grows escaping all the normal rules of cell co-existence which regulates multicellular organisms. We define a malignant tumour as one which spreads throughout the body forming new lesions, i.e. metastases, and a benign tumour as one which is localised and does not causes metastases.
As a disease of multicellular organisms, cancer is found mostly throughout the Metazoa but it is also present in some plants. It is not inevitable, as evolution has protected some forms of life from cancer. A simpler neoplastic behaviour, called “cheating”, is present instead even among the simplest multicellular bacterial organisms, where cells can start to grow excessively escaping normal social rules. From the cheating, observed in bacterial colonies though to the carcinomas afflicting humanity, we can detect that a complex spectrum of different situations is present.
Three main categories have so far been defined in an attempt to classify these phenomenona but it should be noted that the boundaries between them are blurred: Cheating is defined as “the breaking of shared rules, including genetically encoded phenotypes or behavior, that leads to as fitness advantage for the cheater”. This definition is applied to unicellular and multicellular organisms alike. Cancer-like growth occurs in early multicellular organisms, and describes fast growing lesions in which necrosis and ulceration occurs. In cancers, alongside the previous features, there is also formation of satellite lesions (the metastases), made up by cells which have abandoned the primary tumour.
Two classic examples which illustrate that cancer is not an inevitable consequence of the formation of multicellular organisms are those of blue whales and elephants. Blue whales are known to only rarely die of cancer compared to other mammals such as wild mice who often develop cancer, yet blue whales are approximately six million times larger than a mouse and have life spans in excess of 100 years. Moreover, in humans by the age of 80, 5% of the population has colorectal cancer while in blue whales cancer altogether is almost absent. How is it that some large, long-lived animals manage to have such a low rate of cancer? According to natural selection, this is because a mechanism protecting from cancer must have been selected in order to allow large animals to develop big bodies and to have a long life span. While no studies are available for blue whales to offer concrete conclusions for this particular species, some have been carried out on other animals.
One of these is the elephant, a notoriously large mammal that can live in the wilderness for up to 60-70 years with a low cancer incidence. In this pachyderm the protective mechanism is suggested to be a redundancy of a tumour suppressor function. Both the African and Asian species have 20 copies of the tumour suppressor TP53 gene. An interesting fact is also that male elephants only start to reproduce when they reach approximately 40 years of age, therefore, through selection, genes with resistance to several diseases, including cancer are passed to the next generation. It can be argued that gene gain and loss involved in DNA repair, cell-cycle regulation, cancer, and ageing could be responsible for the lack of malignancies in the bowhead whale, possibly the longest lived mammal, estimated to have a life span in excess of 200 years.
The high levels of cancer observed currently in humans probably recognise many different causes. One possibility is the recent increase in our life span. For millennia, the human life span has been considerably shorter, with death due mostly to childbirth, infection, starvation, and violent accidents. Hence, the predisposition to tumours has never affected our ability to reproduce and genomic configurations predisposing to cancer have been passed on through reproduction. Only now, with the increase in our average life span, is their effect fully emerging.
Cancer therefore is a highly complex disease that follows, without any interruption of continuity, cancer-like lesions and cheating. As the development of an organism broadly recapitulates its evolutionary history, in the same way, cheating and cancer-like lesions (e.g. benign tumours) occur in humans either on their own or during the development of a cancer. By investigating the biology of this phenomenon in all types of living creatures, we should be able to gain more insight into the biology of this disease and improve our ability to develop new treatments.
Francesco Pezzella is Professor of Tumour Pathology at the University of Oxford, UK, and Consultant Pathologist at the Oxford University Hospitals. He is a co-editor of the Oxford Textbook of Cancer Biology (Oxford University Press, 2019).
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