Moveable feasts: How cancer takes the party on the road

A few years ago I wrote a brief blog about the importance of metastasis to cancer's lethality.  About 90% of cancers deaths are due to metastasis. Metastasis is the process that leads to secondary cancers that arise in areas of the body that are remote to the primary tumor.  Cancer is at its most vicious once it's on the road and looking for new sites to settle, so research into the mechanisms of metastasis are crucial to finding potential new treatments.

In this week's Nature magazine there are a couple of very interesting articles that describe how complex this metastasis process appears to be.  One is about how breast cancer cells escape from the primary tumor in the first place, and the other is about the 'seeding' process that allows the roving cancer cells to set up shop in remote tissue in lethal metastatic prostate cancer. A third article by Hong et al, in Nature Communications also demonstrates the complexity of metastasis in prostate cancer using a similar analysis. What follows is my take-away from the articles. This particular Nature issue has other interesting cancer articles so I recommend looking at the whole thing (may require a subscription for the main papers though).

The view of cancer as just cells gone wild is changing to one of cells behaving badly in a somewhat organized way. The party contains cells that are just like the first cancer cells in the tumor (clonal cells), but also other cells that represent 'sub-clones',  derived from the primary cancer cells but with subtly different, and often competing, personalities.  The distribution of these personalities at the primary cancer site may well determine its fate. Some of these characters appear to be particularly good at evading chemotherapy. Others are good at creating the environment that allows them to escape from the primary tumor, and set out for new pastures through the bloodstream or the lymphatic system.  The Nature article by Wagenblast et al, shows that these Houdini cells (my term), are aided and abetted in their escape by two proteins called Serpine2 and Slpi that they express on their surface.  In breast cancer cells at least, these proteins cause the cells to acquire characteristics of endothelial cells (the cells that line the blood vessels) which means they can form connections between the tumor and blood vessels, thus providing the escape route. As such, they are potential target for new cancer treatments.  The proteins are also anticoagulants which may help keep the blood flowing and the escape hatch open. These so-called vascular mimics are very aggressive cells with what appears to be a focussed mission to get the team on the move. As Mary Hendrix points out in her review of the paper, their presence is a clear advantage for the tumor, but not so much for the patient- those people who show vascular mimicry in their cancers tend to have a poorer clinical outcome.  While the study used breast cancer cells in mice, the same proteins have been found on metastatic lung cells in humans.  Whether the current findings will apply to metastasis more broadly across other tumor types is not known, but it's a good hypothesis that deserves more attention in my view.

The second study of interest in this issue is by Gundem et al and this looks at the evolution of the remote metastatic sites in patients with lethal metastatic prostate cancer.  While prostate cancer is common, associated metastasis is much less common. Using whole-genome sequencing, the studies showed both clonal and subclonal cells to be present in the primary tumor. Hypothetically, the subclones may compete for dominance and in the presence of chemotherapy, those who have the resistance personalities may be able to prevail, changing the composition and fate of the overall tumor.  The studies also showed that at least two subclones were able to seed one metastatic site meaning that is is not only the primary tumor clones that seed the distant sites, but rather clusters of diverse cells. The diversity of these cluster may determine whether the seeding is successful or not. There are many circulating tumor cells but successful metastatic is relatively rare which suggests that the subclasses may cooperate during seeding process by leveraging distinct properties that at the moment are not understood. Michael Shen in his review of the current studies, suggested that disseminated single cells could settle in a remote site and remain dormant until cooperative metastatic cells arrive to help them take hold.  It was also interesting that some of the secondary tumor cells may have come from other secondary tumors as well as the primary tumor meaning that metastases could be reseeded several times from the both the primary and metastatic sites.  

A separate study by Hong et al, found similar results to Gundem et al, and also showed metastatic seeding occurs in temporal waves.  They also found that cells from the primary prostate tumor, can persist in the circulation in the long term, even after the primary tumor has been surgically removed.  This is wildly interesting to me and I am going to research this further for a future blog.  I've always felt understanding temporality is a major key to understanding disease.  This is all groundbreaking stuff and opens up new areas of research that could result in new treatments.   I am left wondering if the temporal waves, or the subclonal signatures could be influenced by epigenetic changes from environmental impacts?  I am off to explore!

 Nature. 16th April 2015. 

Personalized medicine starts to hit its stride

The flexible genome [pic from nature.com]

I recently attended a conference at Harvard Medical School on big data and translational medicine.  Translational medicine is the discipline that links scientific discovery (bench insights) to patient care (at the bedside, hence the term that is sometimes used..."bench to bedside").  The general idea is that we never have a truly clean slate of health.  We are conceived, born, live our lives and eventually die.  During this time, we are in a constant state of change. While we have  a solid set of genes in our personal genetic code, they are under considerable pressure from other elements such as regulatory genes and epigenetic signals that are influenced by an individual's internal and external environment.  Some of the changes wrought by these elements are permanent and others are transient but either way, they affect the expression of the our genes in real time throughout our lives and constantly nudge us towards disease.  Add to the mix DNA repair mechanisms that also become less effective as we age, and the scene is set for our gradual demise from before we are even born. At any given time, we have a number of mutations and damaged physiological systems that do not constitute enough for overt disease.  Over time, these effects multiple and at some point we will experience a symptom or two and eventually, a diagnosis.  By the time the symptoms appear, the disease has become quite complex and pervasive, and because of this it is much more difficult to treat. If it could be caught in the earlier stages where there are fewer factors involved, and fewer compensatory systems triggered, it could potentially be nipped in the bud. This is one major goal of translational medicine- to identify the unique signals that show disease or disease risk at a stage where treatment is likely to be more targeted and more successful.

Everything above is old news, but the conference revealed exciting new directions for translational medicine.  For the first time, I have hope that personalized medicine is really starting to become a reality.  Large data sets are being collected, not by physicians or pharmaceutical companies, but by patients.  Over 95% of these patients are allowing their data to be used for massive projects that will attempt to connect early signs and symptoms with the risk of various chronic diseases.  Linking seemingly insignificant phenotypic changes to chronic disease development will eventually allow serious diseases to be detected before they become fully fledged and more entrenched.  For instance, already we know that slow blink rate is related to Parkinson's Disease and this can be used as a flag to look for additional symptoms in patients who are at risk of  Parkinson's.  Whether medicines can be developed and given to patients at these very early stages remains to be seen, but a critical step is incorporating some of these phenotypic or 'patient-reported-outcomes' (PROs) into clinical trials so that the more subtle signs associated with disease can be used to monitor effectiveness of treatments in early stages.  Big data is crucial here, and that patients are willing to share their data at such an unprecedented rate is remarkable.  I have had ideas about epigenetic disease triggers, PROs as trial endpoints, and very early disease intervention for many years, and to see it start to come together as translational medicine is absolutely thrilling to me.
I believe we are on the edge of a precipice and that this science will now begin to accelerate on a logarithmic scale.  Astra Zeneca just signed a nice deal with PatientsLikeMe, which is a strong indication that personalized medicine is about to go mainstream.  I can't image a more exciting time to be in healthcare.  Now, if we can also figure out the economics of the system and make that work in favor of the patient versus the insurers, we would be firmly on the path to better health for all.

News on personalized medicine

http://www.technologyreview.com/biomedicine/23620/ Craig Venter underscores the caution needed when interpreting genetic tests. While variance is almost non-existant for the number and constituency of the base pairs detected, differences in the patterns of gene expression that are used for analysis give rise to significant differences in intepretation of data. Venter finds the data encouraging for the future of personalized medicine but cautions about inappropriate conclusions to be drawn from data in these early stages of personal genome analysis.
http://www.technologyreview.com/business/23997/page1/A new company, Generation Health attempts to decipher genetic test results to put risk and benefit into perspective for the patient, the doctor, and the pharmacist. This comes hot on the heels of CVS announcement that they will partner with this company to define the most useful tests that may then become available through CVS pharmacies. However, the main target for Generation Health's research is the health insurance industry. The company hopes to create the compelling evidence that will encourage insurers to get behind genetic testing as a way to target medications, for better health outcomes and to reduce costs. A trick to making sense of genomic/genetic/phenotypic information is going to be the application of a robust data analysis system. News on this seems to have been a bit quiet lately so I'm off on a search to see what's going on...

The relevance of genomic information

I don't know about you but I am overwhelmed and energized by the recent explosion in interest in the relevance of gene knowledge to human difference. For several years we have been sequencing and profiling genes looking for aberrant genes and SNPs in the hope of identifying critical variants that explain disease risk, behavior, physical looks and so on. Only recently have we reached the point of understanding where can begin to realize the enormity of the task ahead in personalized meedicine. Recent papers in Nature have told us that the one-gene one-product hypothesis is only true for about 6% of our 20,000 or so genes. This is comforting given that our absolute gene number seems to equate with a mere nematode worm. The worm's genes can't seem to multi-task as well as ours do so it seems we are more evolved after all. Phew. This multi-tasking nature of most of our genes arises because a particular gene is separated along the DNA by areas of non-relevant DNA (to that gene at least) which means the gene can be read in a number of ways depending on the physical configuration of the DNA and possibly according to the influence of regulatory genes. This leads to 'alternative splicing' which results in different proteins being produced by a given gene. This finding is fascinating. No wonder SNP research has yielded so little in terms of identifying disease causing genes. The SNP is such a minoscule part of the altnertive splicing universe. Every issue of Science and Nature lately seems to have a plethora of articles and editorials on gene findings and their relevance to humans. I sense we are on the verge of a tipping point that will lead to novel hypotheses about the degree of determinisim we can reasonably expect from our genes. I'm excited about what we will come up with but hesitant because I know how long it can take to shift a paradigm. I hope we do not continue with more of the same and hope for some different conclusions. The alternative splicing effect should give us pause for thought; a reason to step back and question our assumptions about the role of genes and what we can expect from personalized medicine research in the future. What a fortunate time to be a biologist after all those years of sequencing and collecting the data--we can now begin to really look for the story our genes seem ready to tell.

Health advances-not so fast

A section of New York Magazine, June 16th 2008, begins with the words, ‘medicine advances at astonishing speeds’. It’s a profound statement but is it accurate? Of course it depends on what you mean by astonishing speed, but I think medicine progresses quite slowly considering the rate at which we accumulate new insights into disease and it’s potential treatments. We hypothesis and test at an alarming rate, but it can take an interminably long time for a new medicine to reach the pharmacy, or for a medical paradigm to shift. Take the Human Genome Project for example. This was a 13-year old project coordinated by the National Institutes of Health and the US dept of energy. Multiple countries participated as did the Wellcome Trust, a premier UK research foundation. Much was made of the effort which identified most of the 12-25,000 genes estimated to make up the human genome, and determined the sequence of the 3 billion chemical base bases that make up human DNA. (ref: www.ornl.gov/sci/techresources/Human_Genome/home.shtml). As it neared completion, widespread anticipation grew among the general public about the slew of medicines that would surely follow the last gene identified. We are now 5 years on and there is little to show for it in terms of medical breakthroughs. The NIH itself admits that the analyses of the data will continue for many years. The most obvious outcome to date is the availability of a relatively cheap way to get a genetic profile for those that are brave enough. Even this though, is not a definitive depiction of the future for those that take the test. Genes are rarely deterministic, depending on environmental conditions to trigger and support their directives to vulnerable cells and systems. Some companies that administer the tests also supply the putative nutritional safeguards that go along with each potential risk, playing on the fears of the patient and pocketing the rewards as a result. Not that genetic testing is bad; rather that it needs to be kept in perspective. Knowing your genetic risk can be a good thing if the risk is well characterized and there are things you can do to off-set the disease. For most genetic risks, that is not the case. Human physiology in health and disease is fascinating and complicated and inherently unique. Understanding the interactions of genes with each other and the environment in which they operate requires lengthy research and analysis. We should learn to set our expectations. Accumulation of observations is indeed fabulously fast. But translation to, and acceptance of, real benefit will always be, by comparison, painstakingly slow.

Welcome to the Future Health Trends Blog

Our health environment is changing as information becomes more available about diseases, treatments and the effects of our own body's characteristics on the effects of both.  There is so much information out there, in fact, that we can get bogged down answering even the simplest of questions when we turn to the internet, the TV or media.  The problem with the ubiquity of information is that not all information is relevant to each one of us, and the trick is to understand what is meaningful in our own context, and what is not.

Science and technology has been quite reductionist for a while. For several centuries in fact.  Now, however, we are recognizing that the power of science and technology can only be increased by integrating with the arts and the humanities. It is at the intersections of art and science that true discoveries are often made. This blog is intended to explore the future of health and medicine from the perspective that integrative approaches to health and wellness are better than linear, discipline based approaches.  We will also report on key developments that stand to improve access and effectiveness of diagnostics and treatments based on the understanding of individual physiological, psychological and socioeconomic characteristics.