How cancer shapes evolution, and how evolution shapes cancer

Abstract

Evolutionary theories are critical for understanding cancer development at the level of species as well as at the level of cells and tissues, and for developing effective therapies. Animals have evolved potent tumor suppressive mechanisms to prevent cancer development. These mechanisms were initially necessary for the evolution of multi-cellular organisms, and became even more important as animals evolved large bodies and long lives. Indeed, the development and architecture of our tissues were evolutionarily constrained by the need to limit cancer. Cancer development within an individual is also an evolutionary process, which in many respects mirrors species evolution. Species evolve by mutation and selection acting on individuals in a population; tumors evolve by mutation and selection acting on cells in a tissue. The processes of mutation and selection are integral to the evolution of cancer at every step of multistage carcinogenesis, from tumor genesis to metastasis. Factors associated with cancer development, such as aging and carcinogens, have been shown to promote cancer evolution by impacting both mutation and selection processes. While there are therapies that can decimate a cancer cell population, unfortunately, cancers can also evolve resistance to these therapies, leading to the resurgence of treatment-refractory disease. Understanding cancer from an evolutionary perspective can allow us to appreciate better why cancers predominantly occur in the elderly, and why other conditions, from radiation exposure to smoking, are associated with increased cancers. Importantly, the application of evolutionary theory to cancer should engender new treatment strategies that could better control this dreaded disease.

Figure 1

Oncogenic mutations will rarely be advantageous within a population of healthy, well-adapted stem cells residing in a healthy niche, leading to loss of the oncogenic clone over time (top). But following aging or damage-induced reductions in stem pool fitness, together with damage or degradation of the niche, oncogenic events that improve fitness should provide selective advantages, leading to expansion of the oncogenic clone over time (bottom). Cellular competition is denoted with arrows, with darker arrows indicating greater competition.

Figure 2

Top panel Current chemotherapy regimens initially cause a major reduction of the tumor size, which mostly kills chemo-sensitive cells. This creates a powerful selective pressure that will inevitably benefit clones (shown in dark grey) that have intrinsic resistance to the treatment. Thus chemo-resistant clones, now unhindered by competition from chemo-sensitive clones, can repopulate the landscape and eventually emigrate to other tissues. Bottom Panel. Proposed adaptive cancer therapy, in which the tumor is partially debulked with a mild chemotherapy regimen, but where a portion of the chemo-sensitive population is allowed to survive and oppose the growth of chemo-resistant clones (dark grey cells). Thus this type of treatment would cause the tumor size to follow a sinusoid growth curve, with periods of growth and shrinkage. This approach should control tumor burden, but without the goal of complete eradication of the disease.