|
 |
Conference 2008 RoskildeThursday - ResearchSee also Abstracts -- Friday report -- Saturday report
The Eighth Biennial Medical Symposium on von Hippel-Lindau (VHL) convened today, September 4, 2008, in Roskilde, Denmark, west of Copenhagen, at the foot of a fjord.
One hundred twenty-four people from 16 countries on five continents gathered in this ancient capital of the Vikings to learn from one another and build up our knowledge of VHL. There were 82 people from 10 countries of Europe, 17 from the U.S., 2 from Canada, one from Brazil, 4 from Australia, 5 from Japan, 2 from China, and for the first time, one from India.
Thursday was a day for the molecular scientists to share their findings, put forward their hypotheses, and find collaborators to answer some of the open questions. Even to those of us who understood about ten percent of the content of this highly technical day it was clear that the amount we have learned in the past fifteen years has been nothing short of phenomenal.
Peter Staller, Ph.D., of the Biotech Research and Innovation Center in Copenhagen, kicked off the day with a discussion of te rold of ypoxia-inducible factors (HIF) in aggressive cancer behavior in many cancers. While this group is accustomed to talking about HIF in the context of VHL, Dr. Staller made it clear that HIF plays a role in the aggressiveness of all cancers, and VHL plays a role in regulating HIF.
The body normally seeks a state of “oxygen homeostasis” – just the right amount of oxygen. Air has about 21% oxygen. Our lungs usually have about 18% oxygen, and our inner organs about 6%. If those inner organs get down to a level of 3% oxygen or less, this constitutes a state of “hypoxia” – a serious shortage of oxygen, which the body is programmed to respond to with
And if this state of hypoxia persists,
Dr. Patrick Maxwell of Imperial College, London, England, continued the discussion with a description of the role VHL plays in glucose-sensing, again playing a role in helping the body maintain homeostasis, a state of balance, around blood sugar.
Dr. Ian Frew of the Institute of Cell Biology, Zurich, Switzerland, described primary cilium, a microtubule-based cellular antenna important for suppression of uncontrolled kidney epithelial cell proliferation and cyst formation, both in the kidney and in the epididymis, and the role of pVHL, Pten, and P13K signaling.
In all, as we learned from Dr. Maria Czyzyk-Krzceska of the University of Cincinnati, Ohio, USA, VHL upregulates some 900 genes in clear cell renal cancer alone. The major binding sites on the gene can be used for two purposes – responding normally when oxygen levels are normal, and responding as the oxygen regulator when the tissues are low on oxygen. Our goal is to understand which proteins are adjusted up or down in each of these two scenarios, and to learn how to help the find its way back to normal oxygen levels, realize that all is well, and turn off the angiogenesis and erythropoeisis responses when they are no longer needed instead of continuing to build capillaries (creating angiomas) and to promote cell proliferation (cancer).
Dr. Norma Masson of the University of Oxford, UK; Dr. James Gnarra of the University of Pittsburgh, USA; Dr. Eijiro Nakamura of Kyoto University, Japan; Dr. Stephen Lee of te University of Ottawa, Canada; Dr. Xiaoqing Wu of the University Clinic, Frankfurt, Germany; and Dr. Arnim Paul of McGill University, Montreal, Canada, each discussed different aspects of these connection issues, explaining what they had determined about the critical interactions between VHL and a series of other proteins in the cell that have been seen to be important in the development and proliferation of cancer.
Dr. Rachel Giles and Dr. Ellen van Rooijen of the University Medical Center, Utrecht, the Netherlands described their work with animals, seeking the ideal animal model to see the impact of changes in the VHL gene of c. elegans (worms), zebra fish, and drosophila fruit flies, each of which have VHL genes. Zebrafish are particularly interesting since you can see right through their skin and watch the embryonic development as it happens witout sacrificing the animal. Dr. Giles reviewed the other available animal models, including 22 different VHL mice, modified to show some aspects of VHL which then can be tested for potential response to therapy. The problem with all of them is that none as a phenotype, or set of symptoms, that is exactly like the human response.
Instead of kidney cancer, for example, VHL mice get liver cysts. Nonetheless, one of the quickest ways to get a mouse to develop a VHL tumor is to inject some human tumor cells under its skin and watch a tumor develop. This tumor might then be treated with any of a number of potential therapies to see whether the tumor shrinks.
Dr. Tien Hsu of the University of South Carolino described his work with VHL and Drosophila. One major advantage of using fruit flies is that they go through so many generations in days, instead of the weeks required for mice. They are also smaller so you can house many more in the same space it takes for one mouse.
Dr. Ding Xing-hua of Huashan Hospital in Shanghai, China, reported is work analyzing the gene expression of hemangioblastomas of VHL. He feels that it takes more than just VHL to generate a hemangioblastoma. He feels that protein CD52 is also required, and that the stromal cells are the real tumor marker for hemangioblastomas.
Dr. Ashok from India asked whether it was clear that this was another primary factor, or whether CD52 was a secondary feature of a hemangioblastoma (being created after the hemangioblastoma emerged) This needs more research, but it is an interesting finding that might lead to a better diagnostic tool.
Dr. Eric Jonasch of M.D. Anderson Cancer Center in Houston, Texas, USA, reported that in his clinical trial of Sutent for VHL kidney cancer he is seeing renal cancers shrink, but no shrinkage of hemangioblastomas. He wonders too chat additional factors may need to be targeted in order to get hemangioblastomas to shrink. He suggests using an agent that would block endothelial receptors and intracellular pathways central to the maintenance of hemangioblastoma viability.
Michael Wiesener closed the session with a report on LOX and LOXL2 (the lysyl oxidases) which suppress e-cadherin, another protein down-regulated by HIF. He left us with a list of questions: What is the role of Snail, SIP1, ZEB1, Twist, CF3, Notch?
Could these be attractive candidates for drug targeting As Dr. Lennart Friis-Hansen of Denmark said in his summary for the day, while we still have a long list of open questions, the good news is that we have better targeted questions now than ever before.
Dr. Peter Maxwell noted that when he began attending these meetings ten years ago we were only beginning to understand what VHL did. Now we know a number of additional steps in the many pathways where VHL plays a role. We have learned a great deal, which in turn has taught us more about what we don’t know.
See also Abstracts -- Friday report -- Saturday report
|
| Contact Us | Copyright 1993-2009 |