Groundbreaking breast cancer research by Ohio State Department of Molecular and Cellular Biochemisty Chair Michael Ostrowski and colleagues is leading to more targeted therapies for cancer patients. It has also revealed remarkably similar processes in the development and progression of heart disease, lung fibrosis, arthritis and other chronic diseases. Most would agree that these far-reaching and internationally significant studies answer the hopes of a
young scientist who 30 years ago decided he wanted to “discover something that would make a difference.”
Michael Ostrowski, PhD, was 19 and a chemistry major at Illinois Benedictine University in suburban Chicago when his grandmother died from breast
cancer. “Treatments then weren’t what they are now; it was pretty
bad for her,” he explains. It was his grandmother’s losing battle with breast cancer that set the direction he would take in his research. “I decided then I wanted to work in cancer research and discover something that would make a difference.”
Ostrowski went to graduate school at the University of South Carolina, where he performed early work on androgen-regulated genes in accessory sex organs, like the prostate and seminal vesicles. After completing his PhD in chemistry in 1980, Ostrowski accepted a fellowship at the National Cancer Institute. “Scientists were just beginning to clone oncogenes [the genes responsible for a normal cell’s transformation into a cancer cell], specifically the Ras gene, which I worked with.” Ras genes communicate
signals from outside the cell to the nucleus. Mutations in Ras genes generate faulty transmissions within cells, leading to prolific cell growth and division and, later, to cancer.
In 1985, Ostrowski moved to the Duke University Comprehensive Cancer Center, where he delved deeper into the Ras gene’s pathway within a cell, and how Ras affects other genes in the development of cancer. Although this work was foundational, “cell line models, either mouse tumor cells or human tumor cells, are actually a pretty poor model for studying cancer, because the change has already occurred,” Ostrowski acknowledges. “You can’t see the steps that got those cells to that point.”
Homing in on Breast Cancer Biomarkers
Ostrowski joined Ohio State’s Department of Molecular Genetics in 1995, a move that gave him the opportunity to expand his research to mouse cell microenvironment models. These microenvironments present more naturally occurring circumstances, allowing researchers to observe the effect tumor cells have on surrounding cells, and vice versa. “It’s caused a significant shift in my lab over the last six or seven years. It’s an idea that has been rediscovered. People knew the microenvironment was important, but it was pushed to the side with all the emphasis on genes.”
Ostrowski explains: “Microenvironment models allow us to experiment with different genetics in different cells. For example, we can have an epithelial cell [the cells that form the tissues that line the body’s organs, where most human cancers form] that’s being driven by an oncogene to become a breast cancer cell. In another cell, such as a fibroblast [the cells that form connective tissues in mammals], we can knock out the tumor suppressor gene PTEN which, by itself, doesn’t promote cancer, but when combined with the cancerous epithelial cells in the tumor microenvironment, results in cancer developing much earlier, with tumors growing much faster and metastasizing much more readily.”
After a discovery such as this in a mouse model, Ostrowski and his lab are correlating their findings with observations in human cancer microenvironments, using technology such as DNA microarrays to compare the expressions of genes in both models. “This correlation may help us pare a list of 300 suspected genes down to 50,” says Ostrowski. “Then we’re into systems biology, doing network analysis. We know about these 50 genes in the fibroblasts, but what about the other cell types: the tumor cells themselves, immune cells like macrophages, blood cells, endothelial cells? Now we’re trying to see how the changes in the fibroblasts affect these other cells.”
Ostrowski says the goal is to identify biomarkers, genetic indicators that tell clinicians what kind of breast cancer a patient has, whether it’s going to metastasize and whether it’s going to be aggressive or nonaggressive. “Over the next five years, that’s where we hope to be,” says Ostrowski. “These are the first steps.” Discovery of these biomarkers could eventually help clinicians provide patients with more-targeted therapies.
It’s work that has taken plenty of time and patience, but Ostrowski and his colleagues are beginning to produce papers on their findings. A paper on the lab’s work with fibroblasts has been accepted for publication in Nature, one of the most prestigious journals in science.
The Root of Other Diseases, Too?
The study of microenvironments necessitates collaboration, which Ostrowski says plays to Ohio State’s strengths. “We’re working on tumor microenvironment projects that involve five colleges and eight different departments. We share leadership and work together to move things ahead. Even the training of fellows and graduate students ends up being very collaborative. It’s really been fun. The eagerness to collaborate is one of the traits, in my opinion, that distinguishes Ohio State from other research institutions. People here are really interested in talking about science, interacting and doing things together.”
Although Ostrowski’s focus is in cancer, work with researchers in other areas is revealing that heart disease, various pulmonary diseases, rheumatoid arthritis and a number of chronic diseases are actually microenvironment diseases. “There may be one cell type that’s the culprit,” explains Ostrowski. “But it’s really the interactions among several types of cells that are going awry. We’re hoping to be able to move some of our basic findings into those areas as well.”
Collaboration does not come without challenges, though. “When you do multidisciplinary research, you’ve got bioinformatics people at the table, biostatistics, imaging, oncologists, surgeons, basic scientists, and mouse modelers. We all speak slightly different languages, we all have different training and different perspectives. It takes work, but that’s what makes it fun.”
If his grandmother could see him today, on the cusp of discoveries that may fundamentally change the future of health care, would his grandmother be proud? “I hope so,” smiles Ostrowski. “Yeah, I think so.”