Genetic diversity: Driving cancer evolution

Genetic diversity: Driving cancer evolution

There are two related and interesting articles on cancer evolution in a recent edition of eLife. The first is a commentary by Devon M Fitzgerald and Susan M Rosenberg, of the Baylor College of Medicine, on a paper in the same issue  titled “TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24− cancer cells.” As Fitzgerald and Rosenberg explain, mutations don’t always arise randomly at uniform rates. Many cells and organisms have been shown to increase mutagenesis in response to stress. In the case of cancer this could come about through the insult to cancer cells of anti-cancer medication. The paper by Raffaella Sordella, and her colleagues, of Cold Spring Harbor Laboratory documents a good example of this by showing that TGF-beta signaling can temporarily reduce the fidelity of DNA repair leading to genetic diversity in progeny cells. This can result in the evolution of resistance to chemotherapy.

The CSHL team concentrated on CD44+/CD24− cells which arise in cancer cell lines and behave like stem cells in reaction to the TGF-beta signaling pathway so that they become continuously active. These cells are linked to drug-resistance, metastasis and other poor outcomes for patients, they say. The faulty DNA repair causes copy number changes to genes – a well recognised hall-mark of cancer evolution. They also showed that the gene PMS1 – which is important for so-called mismatch-repair of DNA was also less active in CD44+/CD24− cells. Mismatch repair corrects small errors in DNA replication, and so errors here can allow thousands of small point mutations to pile up in cancer cells.

All this, say Fitzgerald and Rosenberg, points to the importance of looking for “anti-evolvability” drugs rather than drugs which try to deal with the outcomes of cancer evolution. By inhibiting evolution you could, theoretically, decrease the chances of the evolution of resistance.

How cancer escapes chemotherapy

How cancer escapes chemotherapy

Prof. Mel Greaves

This is a heads up for a very useful essay, written by Mel Greaves, for The Darwin Cancer Blog – a blog dedicated to commenting on evolutionary approaches to cancer. In this essay, titled “Ways of Escape”, Greaves draws a number of comparisons between chemo-resistance in cancer and antibiotic resistance in bacteria. Both, he points out, frequently come about because the therapy we throw at either bugs or cancer cells selects for pre-existing mutations, rather than inducing de novo mutations (which of course does also occur). Bacteria, he says, that have been discovered in 30,000 year-old permafrost, have mutations that render them resistant to modern antibiotics, for instance. The cancers for which chemotherapy is a success story are very few in number: testicular cancer, acute lymphoblastic leukaemia, and choriocarcinoma – they are the only ones, to date, which retain sensitivity to cancer drugs. In most other cases chemotherapy will have short-lived positive effects but, thanks to selection among cancer clones within the tumor mass, the cancer likely re-occurs with a vengeance.

Cancers are only playing the same evolutionary tricks common throughout the plant and animal kingdom. Escaping from potentially lethal challenge has been a major driving force in evolution, he says, and the majority of species on Earth are parasites and their success depends on immune evasion or disguise. The evolutionary principle could not be simpler – it’s survival of the fittest and the luckiest.

“Given that cells and micro-organisms both divide and mutate, the likelihood of the existence of a mutation endowing resistance is going to be determined by the clone size (number of cells) and the mutation rate. This is why small or ‘early’ tumours are less likely to appear to be resistant. When bacteria are subjected to high levels of stress, they adopt a mutator phenotype which greatly increases the probability of mutations favouring survival. By increasing background mutation rate, the instigation of genetic instability in cancer increases the chance of drug-resistant mutations. The prediction that escape mutations pre-date exposure to cancer drugs and that drug treatment would, essentially, positively select emergent clones with these mutations has now been validated with high depth sequencing of diagnostic samples from patients who later relapsed on targeted drug therapy. It is perhaps one of the ironies of cancer chemotherapy that intensive drug treatment provides strong selective pressure for the emergence of more robust clones.”

Greaves goes on to explain a number of Houdini acts common among cancers before asking what we can do about it. We need to be smarter, he says, which is why we are seeing some success with combinatorial therapy, employing a number of cancer toxins to cut off several escape routes at once. Alternatively, he says, we can make use of appropriate scheduling and dosage of drugs to push cells into a more benign evolutionary trajectory or lower fitness cul-de-sac. This is the “live with cancer, rather than try to eradicate it” approach taken by Bob Gatenby and his colleagues at the Moffitt Cancer Center in Florida.

Inflammaging – the role of inflammation in the aging process

Inflammaging – the role of inflammation in the aging process

Aging is associated with a number of chronic diseases – cardiovascular disease, diabetes, Alzheimer’s disease and other dementias, and cancer. They are all part of the process of immunosenescence. The chronic inflammation that is a feature of the declining efficiency of geriatric immune systems has a deleterious effect on normal metabolic and hormonal signaling, is increased by the accumulation of cell debris as we age (for instance in the eye), and is typified by chronically elevated levels of circulating pro-inflammatory cytokines.These processes are well reviewed in a recent paper in the journal Aging Mechanisms and Disease, titled “Macrophages in age-related chronic inflammatory diseases”, by Yumiko Oishi and Ichiro Manabe. These chronic inflammatory processes, say the authors, tend not to be dramatic but are long-term, low-grade smouldering responses to things like tissue repair and insult by pathogens. And changes in the behavior of macrophages in particular, as we age, are central to driving inflammation. Macrophages, they say, not only promote inflammation and tissue dysfunction but also are essential for resolution and healing of inflammation, as well as maintenance of tissue homeostasis. But, as we age, while macrophages turn on the inflammation that underlies healing processes and resistance to infection, they become less good at turning inflammation off when it has done its job. Thus macrophages appear to contribute crucially to the paradoxical activation of basal chronic inflammatory states in the elderly and to the progression of age-associated diseases.

 

 

 

Great resource for human microbiome research – Microbiome Digest

Great resource for human microbiome research – Microbiome Digest

Many of you microbiome aficionados out there may already be aware of a very useful online resource for papers and articles about the role of the microbiome in health and disease – it’s called Microbiome Digest – Bik’s Picks. It used to be run exclusively by Elisabeth Bik, now the Science Editor at uBiome.com, but she now helped out by a number of volunteer colleagues. Although the posts are grouped under sections it tends to be quite a rag-bag of potentially interesting publications, not specifically chosen for relevance to evolutionary medicine, and not all of them are open access or they are published in fairly obscure journals. That said, if you pick and choose, there will always be something of interest.

 

R.I.P. Hygiene Hypothesis

R.I.P. Hygiene Hypothesis

I’ve just come across this excellent article in the current issue of PNAS – by science writer Megan Scudellari. The article is liberally sprinkled with quotes from the doyen of the so-called “old friends” hypothesis, Graham Rook of University College, London, and his colleague from the London School of Hygiene and Tropical Medicine, Sally Bloomfield. Both argue that the term “hygiene hypothesis” is an historical anachronism and a misnomer because it is widely taken to mean that the key to later immune health requires a slackening in standards of hygiene, and that an obsession with hygiene and antimicrobial cleaning products is to blame for the current epidemics of allergic and autoimmune diseases. Although none of this will come as much of a surprise to members of the evmed community this is a very readable and well researched piece which seeks to replace the literal interpretation of the hygiene hypothesis with the understanding that it is the dysbiosis of the gut microbiome that is to blame for the poor regulation of our immune systems. Rook is quoted and saying: “We know an awful lot now about why our immune system’s regulation is not in terribly good shape, and it’s got absolutely nothing to do with hygiene,” while Bloomfield weighs in with: “I’ve even seen things in the media saying we shouldn’t wash our hands. What the hell are they talking about?” Well worth a read.