--> 1. You are currently an Associate Professor of human nutrition, foods, and exercise at the College of Agriculture and Life Sciences at Virginia Tech. Tell us more about your academic background and what sparked your interest in ovarian cancer research?
I received a MS degree in Human Nutrition from the Justus-Liebig University in Giessen, Germany, and a Ph.D. in Human Biology/Nutrition from the same University in 1992. This provided me a strong background in biochemistry, physiology and nutrition although at that time, my research projects were not cancer related. I had the opportunity to join Dr. AH Merrill’s lab in the department of Biochemistry at Emory University in 1992 for post-doctoral research, investigating the potential of dietary sphingolipids to suppress chemically-induced colon cancer in mice. This was a very successful project and we found a 50-70% reduction of tumor incidence in mice fed doses of complex sphingolipids that could be achieved in the human diet—not pharmacological doses. There were also no deleterious side effects of the treatment. This encouraged us to investigate if cancer of other organs could also be suppressed. When I moved to the Karmanos Cancer Institute in Detroit, we next focused on breast cancer and found that dietary sphingolipids could suppress the progression of early stage breast cancer but had little effect on fast-growing tumors. Taking a step back from considering only at the cancer cells as target cells for our treatment (toxicity, molecular mechanisms etc.), we wanted to investigate the impact of our treatments on the tumor microenvironment, focusing on female cancers. Ovarian cancer is especially challenging because it is so genetically and histologically heterogeneous, deadly when detected late and early stages cannot be investigated because of the lack of a model. However, there was no mouse cell model available that could be used in mice with an intact immune system- most researchers use human cells in immune-deficient mice so these can grow aggressive human tumors. The immune system is important since inflammatory cells are now directly linked to the generation of a “permissive niche” that allows for the survival and growth of the tumor cells. I therefore collaborated with researchers who had developed a model for progressive ovarian cancer that could be injected into mice and would allow for investigations of multiple stages of the disease. This model is called the Murine Ovarian Surface Epithelial or MOSE model, and consists of benign cells that do not form tumors, cells that are transitioning to the aggressive disease, cells that can form tumors albeit slowly (slow-developing disease) and those that can develop lethal disease in a very short period of time with few cells (fast-developing disease). In collaboration with Dr. Chris Roberts, we have since then characterized the molecular changes in the ovarian cancer cells that are associated with their progression, and identified important functional categories that could be targeted for the suppression of metastatic disease.
Other information: I am also the co-director of the Cancer Biology Focus of the new Translational Biology, Medicine and Health graduate program. This is a new doctoral program that integrates genetics, molecular biology with tumor physiology and novel approaches to treat and detect cancer. This is intended to broaden the view of the new cancer researchers of how to tackle cancer.
2. The cover of VT Magazine was a photo of ovarian cancer cells credited to you. How was the photo taken? How do those cells differ from normal cells?
Researchers usually grow cancer cells on plastic culture dishes for their experiments, taking advantage of the programming of epithelial to attach to a surface in order to grow. However, ovarian cancer cells metastasize throughout the peritoneal cavity as single cells that can cluster together (sometimes named spheroids or tumor spheres). When we grow our cells under conditions that prevent attachment, tumorigenic cells very rapidly form these spheroids also in cell culture. Benign cells that cannot form tumors in mice are not able to form spheroids and they will die off over a short period of time. The images were taken of live spheroids with an inverted microscope with 40-fold magnification, documenting the clustering of aggressive MOSE cells. However, if you put about a million cancer cells into the culture dish, in a few days all of them have aggregated and we are able to see those without magnification. The images in the article itself show the aggressive cells forming spheroids and –in green- macrophages that loosely associate with those cells. When we inject cancer cells into the mouse and after several days flush the peritoneal cavity and take the cells back out, many cells have aggregated similarly to what is shown in the picture and we are currently using this culture technique for our studies to mimic more closely what is happening in the peritoneal cavity.
3. The VT Magazine article “Cancer Under Attack- Virginia Tech community forms a strong front against cancer” noted that you are collaborating with virologist P. Christopher Roberts (Virginia-Maryland College of Veterinary Medicine) to develop an animal ovarian cancer model. Tell us more about that research. Which animals are you using? Are the studies conducted in vitro or in vivo? How will this model help you discover the initial changes that occur when cancer develops?
As mentioned above, Dr. Roberts was instrumental in the generation of the progressive MOSE model. This model can be used in 2D and 3D tissue culture but also can be injected into mice with a functioning immune system (syngeneic model= the cells were derived from C57BL6 mice that are also used for all our in vivo cancer studies). This is a unique model in that we can compare benign, transitional and aggressive cancer cells both in vivo and in vitro (this is limited to tumorigenic cells as the benign cells do not form tumors). Dr. Roberts has also isolated the stem-like cells of these lines and we are beginning to investigate those since these are critical for tumor recurrence. In collaboration, we have shown the genetic changes that are important in ovarian cancer progression, focusing on the differing cellular organization and the metabolism of these cells since most genes that are differentially expressed in the aggressive cells and can be modulated by the sphingolipids are in these functional categories. These studies are critical in order to identify targets for the sphingolipids or other drug treatments to prevent metastasis, and, most importantly, to control the efficacy in future human trials.
We are at this point not trying to prevent primary ovarian cancer but are focusing on the characterization of cellular and molecular factors that are critical for progression and metastasis since most women die of recurrent disease. Dr. Roberts’ expertise in virology and vaccine development has led to the generation of ovarian cancer cells that express various anti-cancer cytokines on their surface. In a just accepted paper in the Journal of Interferon and Cytokine Research we report that the local expression of IL-12 on the cancer cells reduced their tumorigenic potential and impacts the immune cell profile in the main site of ovarian cancer metastasis, the omentum. This is important because while IL-12 has been used before to suppress tumor growth, the systemic administration leads to severe side effects – the local expression in the omentum, however, does not.
Epidemiological studies have demonstrated that obesity - specifically in the increase in abdominal (visceral) fat- is associated with an increase risk of metastatic ovarian cancer and a lower survival rate. We are interested in the changes in the peritoneal cavity that convey or contribute to the increased risk, using the MOSE model to characterize specific changes that could support tumor cell adhesion and outgrowth. Again, any identified molecular mechanism could be used as a drug target to prevent secondary tumor outgrowth after the removal of the primary tumor. Dr. Roberts was also instrumental in the design and analyses of these studies, investigating changes in inflammatory markers associated with obesity and obesity-mediated disease. We have since characterized the immune profile of the omentum in virgin and parity mice and showed differences that could contribute to a lower risk in the parity group; epidemiological studies have also shown that child-bearing lowers the risk of ovarian cancer. Currently, we are investigating if and how obesity alters the conditions in the peritoneal cavity to support metastatic growth.
Tomorrow's post will discuss Dr Schmelz's research on-->synthetic sphingolipid metabolites, the role they play in ovarian cancer and what avenues of research she finds most exciting.
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