Natural selection may be the answer to the cancer riddle, but can we beat evolution?

Essential organs tasked with keeping us alive and reproducing – such as the heart, brain or uterus – may have evolved better protection against cancer than larger and paired organs, we have proposed.

In an article published today in the journal Trends in Cancer, we hypothesise humans can more easily tolerate tumours in large or paired organs than in small, critical organs. Therefore the larger organs may have evolved fewer cancer defence mechanisms.

Malignant tumours are more commonly found in larger, paired organs that are potentially less essential to survival and reproduction. Previous studies have attributed such organ-specific cancer difference to either external factors, such as smoking, or internal factors, such as the frequency of cell division in the organ.

We propose that natural selection theory could supplement these understandings. We also hypothesise that small, important organs could easily be compromised even when they carry only a few tumours, while larger organs can carry the burden of malignant transformations.

We are not saying this is the explanation for the different susceptibility of organs to cancer, but believe it could be a contributing factor.

An evolutionary approach to cancer research can offer new perspectives to therapeutic solutions.

Elephants and humans

Despite significant discoveries and treatment advances, human interventions can claim only a 5% reduction in cancer deaths since the 1950s. And this result is almost entirely attributable to increased awareness of risk factors and early detection.

A key contributor to the failure to find a magic bullet to cure cancer is that its progression is an evolutionary process. Cancer appeared more than half a billion years ago and has been observed in nearly the entire animal kingdom, from bivalves to whales.

Its appearance has been linked to the evolutionary transition from unicellularity to multicellularity. The latter requires a high level of co-operation among cells and the suppression of uncontrolled reproduction, known as proliferation, of individual cells.

With organisms increasingly being made of more complex cells, having a longer lifespan and larger bodies comes the likelihood of proliferation that can lead to malignant tumours.

Yet despite their larger size, elephants do not have a significantly higher rate of cancer than humans. This makes for the argument that their complex makeup has concurrently led to greater need to evolve tumour suppressor mechanisms. A recent study demonstrated, for instance, that the genetic makeup of Asian and African elephants contained 15 to 20 times as many copies of one of the major tumour suppressor genes (P53) as are found in humans.

The study’s author proposed the higher number of these genes may have evolved as a mechanism to counteract the increased chance of cancer in these long-living, large animals.

An evolutionary process

A cancer cell’s ability to proliferate governs its survival. Cells that maximise proliferation inside local tissues will have a higher chance of passing on their genes to the next generation within the lifetime of their host.

A general problem with current cancer therapies is that they aim to eradicate tumours as quickly as possible to prevent the evolution of the cancer’s resistance to treatment, as well as its spread to other organs, called metastasis.

Maximally aggressive therapy, where the same drugs and doses are applied through multiple cycles, may work well with small tumours made up of highly similar cells. But most tumours are complex, changing ecosystems with myriad cells that have diverse levels of susceptibility to treatment.

If human intervention fails to eliminate all the malignant cells, some will be able to escape and survive. These can acquire higher potential to proliferate, become more aggressive and malignant and eventually metastasise, causing the death of the host.

It is becoming clear that applying evolutionary theory to cancer treatment – by exploiting the mechanisms of tumour suppression of multicellular organisms – allows researchers to improve techniques to control malignant progression and prevent therapeutic failures.

Evolution-based therapy

Some of the most exciting evolutionary approaches to cancer therapy originate from knowledge obtained from pest control and bacterial antibiotics resistance. The latter have shown that although we cannot outrun bacteria or pests evolving resistance to antibiotics or pesticides, we can control the speed and extent of the process.

A similar theory in cancer research, adaptive therapy, is based on the simplistic assumption that tumours consist of treatment-sensitive and treatment-resistant cells. Aggressive, high-dose treatment will eliminate the sensitive cells but leave the highly resistant ones. These will then proliferate, leading to a more aggressive cancer.

The goal of adaptive therapy is to avoid this by administering the minimum necessary (but not maximum possible) dose to sufficiently control tumour growth and improve symptoms, without complete elimination. Such an approach allows for the survival of both types of cells, which compete for the same resources and space. The presence of treatment-sensitive cells will concomitantly control the growth and proliferation of aggressive, treatment-resistant cells.

In 2009, adaptive therapy was tested in ovarian cancer mouse models. Researchers measured the growth of the tumour: if the tumour volume increased between two consecutive measurements, they would simultaneously increase the dose of the chemotherapy drug carboplatin. If the tumour volume decreased between measurements, they reduced the drug dose.

When results were compared to those of a high-dose chemotherapy trial, adaptive therapy was shown to be better at controlling tumour growth and prolonged the lifespan of the mice. Similar results have been seen in mice with breast cancer. These tests are promising but further experiments are needed to validate whether adaptive therapy will become the ultimate solution to control cancer progression in humans.

Natural selection has had millions of years to find ways to avoid and cope with cancer in different organisms, so it seems timely to harness this knowledge.

Beata Ujvari receives funding from ARC, Ian Potter Foundation, CNRS France, Australian Academy of Science.