WSU/KCI scientists explore role of tumor suppressor gene in inhibiting prostate cancer cell metastasis
ORLANDO, Fla. – Scientists at Wayne State University and the Barbara Ann Karmanos Cancer Institute in Detroit presented scientific findings at the American Association for Cancer Research’s 102nd Annual Meeting 2011 that detail the role of a human tumor suppressor gene and its role in inhibiting prostate cancer metastasis to the bone.
The poster, “Maspin Induces MET in Prostate Cancer Cell Cultured in 3D-Collagen I,” was presented by Ivory Dean, a graduate student in the Cancer Biology Program at Karmanos and Wayne State University's School of Medicine (WSU SOM). Dean is also an AACR Minority Scholar in Cancer Research Award recipient and contributor to research analysis.
Fellow researchers are M. Margarida Bernardo, Ph.D., senior scientist in the Department of Pathology at Karmanos and WSU SOM; Gregory Dyson, Ph.D., assistant professor in the Department of Oncology at Karmanos and WSU SOM; Xiaohua Li, Ph.D., member of the Department of Pathology at Karmanos and WSU SOM; Sijana Dzinic, Ph.D., associate professor in the Department of Pathology at Karmanos and WSU SOM: Shuping Yin, research associate in the Department of Pathology at Karmanos and WSU SOM; Yonghong Meng, research associate at the University of California at Los Angeles; Alan Dombrowski, former director of the Microarray Core at the Institute of Environmental Health Sciences at WSU SOM and currently assistant professor in the Department of Pediatrics, Division of Clinical Pharmacology and Toxicology at WSU SOM; Kamir Moin, Ph.D., associate professor of Pharmacology at Karmanos and WSU SOM; Wael A. Sakr, M.D., professor and chair of the Department of Pathology at Karmanos and WSU SOM; and Shijie Sheng, Ph.D., professor in the Department of Pathology at Karmanos and WSU SOM.
Research indicates that maspin, a tumor suppressor gene discovered by Dr. Sheng and her scientific colleagues in 1994, inhibits tumor cell motility and invasion, among other cellular activities, and blocks the interaction between prostate tumor cells with bone, a common site of metastasis. Their research goal was to test whether maspin is sufficient to drive mesenchymal-to-epithelial transition, a process found in some cancer cells that have undergone micro-metastasis but have since reverted back to a dormant state. Maspin not only brings about dormancy, but allows cancer cells to remain sensitive to chemotherapeutic drugs.
The study was conducted on a cell line derived from the brain metastasis of prostate cancer in a patient. Cells were cultured in three-dimensional collagen type 1. It is the most abundant protein type found in vertebrates and simulates the bone microenvironment. This phenotype resembles the phenotype that is observed in xenograft tumors that express maspin.
“This system allows us to delineate important molecular pathways and interactions in the reversal of mesenchymal to epithelial phenotype by using three-dimension collagen I,” said Dr. Bernardo, the study’s lead author.
Most carcinomas derive from epithelial cells (functional cells found on the surface of organs) that when damaged become less differentiated and begin to resemble mesenchymal cells, which are normally-functioning cells but are more ‘plastic’ and have the ability to transform into different kinds of cells, which can then turn into cancer cells.
“What we are trying to understand is how epithelial cells transform into mesenchymal cells,” Dr. Sheng said. “In my personal opinion, it is genetics. No matter how tumor cells resemble mesenchymal cells, they are never identical and they are not normal.”
The epithelial to mesenchymal transition (also known as EMT) does not play a role in carcinogenesis but is required in cancer metastasis, Dr. Sheng said.
“Doctors want to target and block this process as early as possible,” she said. “After the cells become metastasized in the distant organs, some cells become reversed and that is a phenomenon called dormancy. They get reverted back to the epithelial phenotype. This process has been found in a significant fraction of metastatic lesions in human patients.”
Because chemotherapeutic drugs used to treat cancer metastasis are toxic to normal tissue and have varied degrees of success in tumor shrinkage, Dr. Sheng and her colleagues are studying ways in which maspin can reverse those cells back to epithelial cells. That would provide a more natural and effective means of slowing down cells and prolonging a cancer patient’s life.
“With maspin, one may actually keep the metastatic tumor cells in a dormant stage,” she said. “That is a significant aspect of cell behavior that researchers really are starting to look at. It’s very exciting that while maspin is helping the cells reverse this EMT process, it does not relinquish the cell sensitivity to drugs. That is very important. You’re killing two birds with one stone.”
Researchers have studied the role of maspin in breast, lung and prostate cancer and acknowledge that maspin protein is present in the thyroid, pancreas, ovaries and colon. Karmanos doctors are also currently involved in Phase II clinical trials targeting maspin as a marker for prostate cancer patients’ drug response.
Sheng said that Dean, 26, has contributed significantly to data analysis and says the research aligns with her study focus. This is Dean’s first time presenting at the AACR conference and she says she is personally intrigued by maspin and how it affects cancer progression.
“From the beginning, learning about maspin and what maspin contributes to suppressing tumors, that’s what piqued my interest first,” she said. “The fact that maspin expression decreases as the tumor becomes more and more invasive, I think that’s very interesting. It’s almost like maspin is one of the big deciding factors whether a tumor metastasizes.”