 | | | (Reprinted with permission from the Spring 2007 issue of CenterPiece, the quarterly magazine of Northwestern University's Office for Research) Vincent L. Cryns, MD, Division of Endocrinology, was one of the inaugural winners of the Senyei Translational Awards in the fall of 2006. The awards were made possible through a $1 million gift to the Feinberg School of Medicine from Drew Senyei, MD, a medical alumnus and member of the Northwestern University Board of Trustees. Coordinated by the NUCATS Institute, the awards support Northwestern’s commitment to enhance programs in translational research throughout the University, Feinberg School, and affiliated hospitals.
Dr Cryns uses the tools of molecular biology to dissect cells to reveal how they die. This process, known as apoptosis, eliminates damaged or “old” cells, much to our benefit normally. But apoptosis has a dark side. As a physician-scientist, Cryns is particularly interested in understanding how abnormalities in cell death lead to cancer and neurodegenerative diseases and hopes to “translate” these insights into better diagnostic tests and treatments. He came to Northwestern in 1997 after completing his medical and postdoctoral training at Harvard Medical School. He sat down recently with CenterPiece, a publication of the NU Office for Research, to discuss the Senyei award and his research. That’s a surprisingly difficult question to answer. Although virtually all funding agencies want to support translational research, no one can quite agree on its precise definition. It’s sometimes referred to as “bench-to-bedside” research because it aims to bring discoveries at the laboratory bench to the patient’s bedside in the form of improved diagnostic and prognostic tools, preventive agents and, of course, treatments. But this is only half of translational research. There is a growing awareness that the path between the bench and the bedside is neither linear nor one way. Patient encounters stimulate questions that can be tested in the laboratory, which in turn, lead to new discoveries that can impact patient care, and so on. In this sense, translational research is “bench-to-bedside-and-back-again” (and again). While this sounds pretty straightforward, the devil is in the details. There have to be strong incentives for investigators who are trained in bench or clinical research to leave the comfort zone of their own research programs to take on the combined challenges of both arenas. There also has to be a commitment to working with a multidisciplinary team of scientists with different agendas. It requires quite a leap of faith and a lot of meetings. Our work focuses on cancer stem cells. The idea that cancer arises in stem cells is more than 100 years old, but new tools and recent landmark studies have revived the “cancer stem-cell hypothesis.” Cancer stem cells are not embryonic stem cells, but rather adult or tissue-specific stem cells that have “gone bad” because they have acquired mutations that change them into cancer stem cells. The distinction between embryonic and adult or tissue-specific stem cells is important for more than political and religious reasons. Unlike embryonic stem cells, adult stem cells give rise only to the cell types in a given tissue or organ. In the case of the breast or mammary gland, there is a small population of self-renewing and long-lived stem cells that can generate all the epithelial cells in the breast. During pregnancy and breast feeding, there is an enormous expansion of breast tissue to make milk, but after breast feeding stops, breast tissue undergoes dramatic apoptosis. New breast tissue is then generated from breast stem cells. The cycle repeats itself with each pregnancy and breast feeding. What is the connection between breast stem cells and breast cancer?
Several laboratories have shown that if you disperse human breast tumors or other solid tumors into individual cancer cells and inject them into mice, only a very small percen-tage of the cells in a given tumor can form new tumors. These so-called “tumor-initiating cells” express many proteins characteristic of breast stem cells, such as the cell surface glycoprotein CD44, suggesting that the tumor-initiating cells are breast-cancer stem cells — normal breast stem cells that acquired cancer-causing genetic and epigenetic changes. Another molecular property of many stem cells is their ability to express a cell-surface transporter that pumps out toxins, chemotherapy drugs, and dyes — a protective mechanism that ensures their long-term survival. We have used this property to identify breast-cancer stem cells from cultured human breast-cancer cells by exposing the cancer cells to a fluorescent dye and looking for cells that don’t fluoresce because they pump out the dye. Strikingly, we have found that these “pale” or non-fluorescent cells are highly efficient at initiating tumors in mice compared with the fluorescent cells, as you would predict from the cancer stem-cell hypothesis. 
| Breast cancer: A portrait of cellular chaos
Normal breast cells and breast cancer cells behave very differently in three-dimensional tissue culture. Normal breast cells form highly organized, hollow gland-like structures (inset) that mimic features of the normal breast, while breast cancer cells form grossly enlarged, chaotic solid masses that look and behave like breast tumors in many ways. Confocal image courtesy of José Moyano, postdoctoral fellow in the laboratory of Vincent L. Cryns, endocrinology. |
We have several translational goals. First, we will isolate normal breast stem cells from women undergoing breast-reduction surgery and breast-cancer stem cells from women with breast cancer and compare their gene expression profiles, a method that provides a “gene signature” of RNA levels across the genome. These studies should tell us a great deal about the underlying differences between normal breast stem cells and breast-cancer stem cells and provide us with gene signatures of breast-cancer stem cells. Given the likely role of cancer stem cells in initiating, maintaining and spreading tumors to distant sites, we predict that their gene signatures will provide us a much more accurate assessment of a patient’s prognosis — that is, her risk for relapse, metastases to distant organs, and survival chances.
Unfortunately, existing prognostic factors in breast cancer, such as tumor histology and lymph-node status, are not very reliable at predicting an individual patient’s prognosis. This information is vital for making treatment decisions. Patients are sometimes unnecessarily treated with chemotherapy or inadvertently withheld chemotherapy because we can’t predict their future clinical course. We will also test whether the breast-cancer stem cell signatures predict response to specific chemotherapy drugs, a critical issue that would allow us to tailor treatment to the molecular characteristics of the breast tumor. Another major goal of our work is to translate the gene signature of breast-cancer stem cells into new treatments that specifically target cancer stem cells. Existing chemo-therapy drugs and radiation are often quite effective at debulking breast tumors but fail to kill cancer stem cells because they are slow dividing and resistant to DNA damage and apoptosis. This failure to eradicate cancer stem cells could explain why breast cancer sometimes recurs after many years of apparent remission. We will use the gene signatures of breast-cancer stem cells as a molecular blueprint to find signaling networks that we can target with drugs, some of which may already be available. As an example of this approach, our preliminary results from cultured human breast-cancer cells point to specific survival proteins in the Bcl-2 family that are highly expressed in breast-cancer stem cells but not in non-stem cancer cells. Recently, small molecule inhibitors of these Bcl-2 family proteins have been developed, which we plan to test against breast-cancer stem cells in the near future. Without a doubt. I think the very existence of the Drew Senyei MD Awards and the recent formation of the Northwestern Clinical and Translational Sciences (NUCATS) Institute indicate a genuine commitment to this kind of research. We also have access to a large and diverse patient population at Northwestern Memorial Hospital and a growing number of basic scientists who want to apply emerging technologies like chemical biology, RNA inter-ference, and nanotechnology to human diseases. We are fortunate at Northwestern to have all the required elements already in place. The team of Northwestern collaborators we put together for our translational project illustrates this point nicely. Seema Khan, surgery, and Bill Gradishar, medicine, are clinicians and clinician investigators who treat breast cancer patients and understand the most urgent, unmet needs of their patients. Their unique perspective drives many of the questions that we seek to answer in the laboratory. They also provide us with access to patients and tumors, and they will design and direct all of the clinical interventions that emerge from our studies. Charles Clevenger, pathology, will assist us in translating the gene signatures of breast-cancer stem cells into new biomarkers that we hope will better predict prognosis and treatment response for breast cancer patients. This will require developing methods to detect protein expression of stem-cell markers in breast-cancer tissue. John Kessler, neurology, has been helping us to understand and grow stem cells. Marty Watterson and the Center for Drug Discovery and Chemical Biology will provide invaluable input in the design and testing of breast-cancer stem cell-targeted drugs. And then there’s me. In addition to directing most of the breast-cancer stem cell work in my own laboratory, I have to make sure the clinical and basic science agendas remain in sync as the project moves forward. I guess that makes me both a cheerleader and a coach. I want to thank all the bright, hard-working, and creative people that I’ve been fortunate to recruit to my laboratory. I won’t name them all, but I would like to especially thank Fruma Yehiely, who has spearheaded the breast-cancer stem cell work in my group, and José Moyano who spent many hours working out the details of the 3D tissue-culture system.
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