| | |  | | NEWSLETTER ::: NO. 13 ::: NOV 2016 | | PEACING THE PARTS TOGETHER | | Clear cell renal cell carcinoma is the most frequent form of kidney cancer. One out of 65 people will develop this disease. To determine which gene mutations are responsible, an NCCR Kidney.CH research group has been testing numerous gene combinations in mice. After years of research they have managed to successfully recrea or developing new therapies. |  | | Micro-computed tomography image of clear cell renal cell carcinomas in the kidneys of a mouse. | | Cancers result from the perturbation of normal physiological processes. The study of cancer is therefore inseparable from the study of physiology. The major focus of the research carried out in my laboraCancers result from the perturbation of normal physiological processes. The study of cancer is therefore inseparable from the study of physiology. The major focus of the research carried out in my laboratory over the last seven years, during the period of Cancers result from the perturbation of normal physiological processes. The study of cancer is therefore inseparable from the study of physiology. The major focus of the research carried out in my laboratory over the last seven years, during the period of my Assistant Professorship in the Zurich Integrative Human Physiology network, has been to develop an understanding of the molecular and cellular causes of the most frequent form of human kidney cancer, clear cell renal cell carcinoma (ccRCC). One person in about 65 will develop this disease within their lifetime and many of these patients will die from the disease because currently available therapies are effective in only some cases. | | DECLINING OXYGEN LEVELS INCREASE RISK | | It is an unusual epithelial cancer because ccRCC is uniquely characterised in the vast majority of cases by the mutation of the von Hippel–Lindau (VHL) tumour suppressor gene. The protein that is produced by this gene, pVHL, functions in every cell in our bodies as the gatekeeper of cells’ responses to changing oxygen levels. Oxygen controls the activity of pVHL with regard to two other key proteins, the hypoxia-inducible factors HIF-1α and HIF-2α. Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreasing oxygen in the cells, so-called hypoxia. HIF-1α and HIF-2α control the expression of hundreds or even thousands of genes that help the cell to adapt in many different ways to the changing oxygen environment. Because VHL is mutated, the cells that initially form ccRCC tumours ‘think’ that they are permanently in a low-oxygen environment. For reasons that are still not clear, it seems that kidney tubular epithelial cells, in comparison to most other cell types in the body, are particularly sensitive to this condition, which dramatically increases the chances that they will develop into cancer cells. | | IN SEARCH OF THE RIGHT GENES | | However, cancers of epithelial tissues are never caused by the mutation of just one gene, but rather by the cooperative effects of mutations in many different genes. The challenge is firstly to find out which genes are the important ones and secondly to understand how their mutation contributes to the development and spread of a tumour. This is where our research comes in: we try to recreate ccRCC by introducing different mutations into normal renal epithelial cells to see if this turns them into tumour cells. | | A COMPLEX RESEARCH TASK | | A nice analogy via which to understand the challenge that we face is to imagine being asked to build a television. You are given one functioning television that contains all of the necessary parts and circuits, but the television in fact contains another 50 random parts that do absolutely nothing. This is similar to the case in tumours; we think that there are some parts (mutations) that are essential for the tumour, and other parts that have just ‘come along for the ride’ and don’t contribute at all. You can start by cataloguing and naming all of the parts of your television but this doesn’t help you much—all of them could be important. What you need in order to narrow down the search are hundreds of similar but slightly different televisions so that you can see what parts are similar or identical between them and what parts are unique to each different unit. The common ones are the ones that are probably necessary—you can then start putting them together and trying to recreate a new television. Fortunately, we can now compare the full ‘parts list’ or genetic makeup of hundreds of human ccRCCs. We now know which mutations are likely to be the most important in most cases of ccRCC. This gives us our list of candidate genes, which we have been altering in different combinations using genetically modified mice. | | SUCCESSFULLY NARROWING DOWN THE SEARCH | | Over the last 13 years, including my research as a postdoc, we have tested 23 different combinations of mutations and have learnt a lot about what does and doesn’t cause ccRCC. We successfully recreated some of the early stages of ccRCC and could show that defects in primary cilia, antenna-like structures that project from the surface of epithelial cells, which are pathogenically altered in diverse renal cystic diseases, are also important contributors to the initiation of ccRCCs. We genetically proved that both HIF-1α and HIF-2α are strictly necessary for the initiation of the earliest stages of tumour formation, an important observation now that inhibitors of the activities of HIF-1α and HIF-2α are becoming clinically available. In our work in the context of Kidney.CH we identified that HIF-1α is specifically responsible for the regulation of the metabolism of tubular epithelial cells as it changes the pathways by which these cells generate energy, and also showed that HIF-1α activity in epithelial cells sends signals to neighbouring cells, recruiting new blood vessels to places where they normally should not be. This ‘artificial’ genetic situation has dramatic effects on the normal functioning of the kidney, but also provides a model that mimics the pathological situation in which a newly forming tumour has to establish a lifeline to the blood supply of the kidney to allow it to be nourished and grow. |  | | Low magnification (left) and high magnification (right) views of a ccRCC tumour in a mouse kidney | | EFFORTS PAY OFF: GOAL ACHIEVED | | Our biggest success however is our most recent one. To return to the television analogy, we’ve always argued that until you can build something from scratch, you don’t really know how it works. For more than two decades, the research community has tried to ‘build’ accurate mouse models of ccRCC, without success. By combining three different mutations in mice, we have finally achieved this goal and could show that the tumours that arise in these mice share many molecular and cellular similarities with human ccRCC, and also respond to current ccRCC therapies in similar ways. While, on one hand, this represents the achievement of a 20-year-goal, we are also very excited about it being the beginning of a new 20-year project to make more and better models of this disease, enabling us to accelerate the search for optimal therapies that can be offered to patients in the future. I am also convincedthat we will learn a lot more about the normal physiology of kidney cells along the way. | | | Jan James Frew has been Professor at the Zurich Centre for Integrative Human Physiology (ZIHP) of the University of Zurich, and participant within the NCCR Kidney.CH. From January 2017, he will continue his research at the University Hospital of Freiburg (Germany). His new lab will be based at the Centre for Translational Cell Research (ZTZ) and he will be affiliated with the BIOSS Centre for Biological Signalling Studies and the Comprehensive Cancer Centre Freiburg (CCCF). |
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| | | | Kidney - Control of Homeostasis | | is a Swiss research initiative, headquartered at University of Zurich, which brings together leading specialists in experimental and clinical nephrology and physiology from the universities of Bern, Fribourg, Geneva, Lausanne, and Zurich, and corresponding university hospitals. |
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