Nita J. Maihle, PhD
Researchers have identified the molecular basis behind two concepts in ovarian cancer that allow tumor stem cells to survive and proliferate even after treatment, suggesting that targeting certain proteins with tailored therapies could be an effective treatment strategy for this difficult-to-treat disease.
The researchers utilized high-throughput deep sequencing to determine whether there is a molecular basis to the concepts of a “cancer stem cell” as well as the “seed and soil” that make up a tumor microenvironment. Even when a treatment kills off tumor cells, a small portion of difficult-to-identify cells manage to survive and keep the tumor growing. These cancerous cells are able to thrive in a microenvironment that allows for the growth and spread of these cells.
“Both concepts have particular relevance for the treatment of adult solid tumors such as ovarian cancer, which has been notoriously difficult to diagnose and treat,” said Nita J. Maihle, PhD, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences and a member of Yale Cancer Center, and one of the co-authors of the study. “Ovarian cancer patients are plagued by recurrences of tumor cells that are resistant to chemotherapy, ultimately leading to uncontrolled cancer growth and death.”
The researchers focused on Lin28, a stem cell factor that is expressed in undifferentiated human embryonic stem cells but not in most normal adult tissue cells. Lin28 has been found to be activated and detected in certain malignancies. Researchers have also looked into the role of the bone morphogenetic protein (BMP) family in relation to cancer, since these proteins are implicated in cellular processes such as proliferation and migration associated with cancer.
The researchers found that in epithelial ovarian carcinoma cells, Lin28 binds to one of these proteins, BMP4, a protein that is implicated in the proliferation of ovarian cancer stem cells. When this happens, the expression of the protein is promoted at a post-transcriptional level. Additionally, the researchers determined that higher expression of Oct4—a transcription factor associated with the regulation of stem cell pluripotency that has been implicated in ovarian cancer—is associated with poorer prognosis if it is co-expressed with Lin28. Together, they are capable of producing high levels of the aforementioned BMP4.
“These results are supported by the latest molecular ovarian cancer prognosis data, which also suggest an active role for the tumor microenvironment in ovarian carcinogenesis,” said Maihle and Yingqun Huang, MD, associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences, and lead investigator. “Together these studies reveal new targets for the development of cancer therapies.”
The findings were published online by the journal Cell Cycle
Ma W, Ma J, Xu J, et al. Lin28 regulates BMP4 and functions with Oct4 to affect ovarian tumor microenvironment [published online ahead of print January 7, 2013]. Cell Cycle. doi: 10.4161/cc.23028.