Last month I read my son's copy of the Summer 2015 edition of VT Magazine. My son has a BA and MA from Virginia Tech. The cover had a photo of ovarian cancer cells and the inside held articles on the cancer research being done at Virginia Tech including a piece on Professor Eva Schmelz's research.
I was fascinated by the cover and so interested in her line of research that I looked on the Tech website and found her e-mail. I wrote to her as an ovarian cancer survivor, blogger and Hokie Mom. I asked her if she would answer questions about her research for my blog. Professor Schmelz was gracious enough to agree to answer some of my questions. While the answers are lengthy, the details are so important that I did not want to edit them. I will be presenting the questions and answers in multiple posts. In this first post you will hear about Prof Schmelz's background, what got her interested in ovarian cancer research and the research she is doing with Dr. Chris Roberts.
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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.
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synthetic
sphingolipid metabolites, the role they play in ovarian cancer and what avenues of research she finds most exciting.
Dee
Every Day is a Blessing!
