Every now and again I enjoy a nice lump of cancer with my evolution coffee in the morning, and today happened to be one of those mornings. A paper published in PNAS appeared in my aggregator that I just couldn’t keep from devouring. Entitled Toward a genetics of cancer resistance, George Klein of the Karolinska Institute takes us on a brief tour of what we currently know about our susceptibility to cancer, and what it is evolution is telling us.

Klein introduces the topic of cancer resistance with a very relevant “glass half full” perspective:

The devastating effects of cancer are highly visible in the human population. Approximately one in three persons is struck by neoplastic disease at one time or another. It is less often emphasized that two of three persons remain unaffected. Even the majority of heavy smokers, who bombard their lungs with carcinogens and tumor promotors over many years, remain cancer free.

Yet, despite there being this large 800lb gorilla staring us all in the face, very little has been done to explore cancer resistance. Citing a plausible “evolutionary” paradox that may in fact be the reason so little is being invested in resistance research, Klein demonstrates the idea of natural selection not favoring protective mechanisms due to its overwhelming occurrence in older individuals to be simply untrue. Males of a variety of species, including many that have been studied in the order Primates, lack an upper limit to their reproductive age. In fact, in certain species the older males tend to father most of the offspring.

There are very good reasons to believe mechanisms are in place that have accumulated over evolutionary time to counteract the development of cancer cells. Such resistance has been demonstrated already in lab mice through the breeding of low cancer strains, implying the ability to gain genetic resistance to cancer over time. But, what about in humans? Well, it just so happens that it has been demonstrated in us as well: research by Pharoah et al. (2002) found that an equal proportion of the human population is very resistant to cancer as is very susceptible. Also, researchers in Iceland are currently planning a study on the families of 200 cancer-free women of old age who are self reported long-term smokers, and members of the families with a low risk of cancer with then be selected for further study. From studies such as these it is hoped we will be able to understand a bit better the mechanisms of cancer reistance Klein is so excited about, and to use this understanding to treat.

According to Klein, there are currently five mechanisms with “proven anticancer surveillance function” with a possible sixth on the way: (1) immunological, (2) genetic, (3) epigenetic, (4) intracellular, (5) intercellular, and the possible sixth is (6) HAMLET, “a protein-lipid complex formed by the interaction between a component of human milk and a lipid cofactor at the acid pH in the stomach of the breast-fed child.” Of these, genetic and intracellular mechanisms of resistance are the most powerful (DNA repair and apoptosis, respectively) at least according to current evidence. Microenvironmental control (intercellular surveillance), however, is by far and away the most interesting, in my opinion.

According to a study done all the way back in 1975, the microenvironment of cancer is extremely important. Mintz & Ilmensee (1975) showed that highly malignant diploid teratoma cells could be “normalized” if implanted into mouse embryos. In other experiments more recent, researchers have correlated suppression of cancer development to the distance between cancerous and non-cancerous cells, known as contactual inhibition. This is a very exciting finding, as it may be where the answer lies as to why the majority of most disseminated tumor cells never become metastases, and current research is being done on mice to determine the evolutionary genetics behind this phenomenon.

Merely observing our ability to resist cancer in such large proportions has planted a seed in the minds of many researchers, and now it appears that we are beginning to learn something from the study of evolution and cancer as a result. While the genetics of tumor resistance may be “the great terra incognita of cancer genetics” as Klein states in his conclusion, it is certainly a land worth discovering, and one that may hold the secret to cancer prevention.

(References)

Klein, G, 2009, ‘Toward a genetics of cancer resistance’, Proceedings of the National Academy of Sciences. 10.1073/pnas.0811616106

Mintz, B, 1975, ‘Normal Genetically Mosaic Mice Produced from Malignant Teratocarcinoma Cells’, Proceedings of the National Academy of Sciences, vol. 72, no. 9, pp. 3585-3589. 10.1073/pnas.72.9.3585

Pharoah, P, Antoniou, A, Bobrow, M, Zimmern, R, Easton, D & Ponder, B, 2002, ‘Polygenic susceptibility to breast cancer and implications for prevention’, Nature Genetics, vol. 31, no. 1, pp. 33-36. 10.1038/ng853