Sunday, April 26, 2015

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. 

Wednesday, April 15, 2015

Personalized medicine starts to hit its stride

Image result for Epigenetics
The flexible genome [pic from]
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.