The Role of Wnt/Beta-Catenin in the Progression of Castration Resistance of Prostate Cancer in Bone
Abstract
Prostate cancer is the second leading cause of cancer-related deaths among American men. When prostate cancer advances to the metastatic stage, meaning the cancer has spread from the original site, the bone is typically the first site of distant metastasis. These bone metastases are the main cause of poor quality of life and death for patients with prostate cancer. Prostate cancer cells rely on several pathways or signals that allow them to continue to grow. One of the primary pathways is the androgen receptor (AR), which receives signals from androgens like testosterone or dihydrotestosterone (also known as DHT) that tell prostate cancer cells to grow. Doctors can block this signal by giving a treatment known as androgen deprivation therapy (ADT) to stop these signals from communicating with the prostate cancer cells so that they stop growing. Unfortunately, within a relatively short period of time, the prostate cancer begins growing again, and there are currently no therapies that will prevent the disease from resulting in death. Since bone is the primary site of metastasis, doctors and scientists have worked to understand why prostate cancer prefers to grow in bone and how growing in bone results in resistance to therapy. Currently, it is thought that prostate cancer cells and bone cells communicate with each other to support increased growth of prostate cancer and bone cells in bone metastases. Discovering which genes or proteins help prostate cancer cells and bone cells communicate and grow is the focus of ongoing research. There are several ways for prostate cancer cells to overcome ADT; one way is to activate other genes in the cell that allow cells to keep growing. Beta-catenin is a protein that is usually kept “turned off” unless it receives specific instructions from another group of proteins that allows it to be “turned on” or activated, which then allows it to tell cells to grow. In prostate cancer cells, it was discovered that, in about 18% of prostate cancer patients, there are mutations or changes in the normal proteins that control beta-catenin or in beta-catenin itself, that allow it to ignore the signal to “turn off”; therefore, it is always on and telling the cells to grow. Besides helping prostate cancer cells grow, it is possible that beta-catenin also helps prostate cancer cells grow in places outside of the prostate, like bone. Our laboratory has studied beta-catenin to try to understand how it allows prostate cancer cells to communicate with bone cells so that it can grow in bone. We found that beta-catenin activates a protein called HAS2 that constructs a protein called hyaluronan. We believe hyaluronan produced by prostate cancer cells communicates with bone-forming cells, called osteoblasts, through a signal-receiving protein called CD44 that helps prostate cancer cells grow more efficiently in bone. By blocking these cells from making hyaluronan using a chemical treatment or disrupting the signal-receiving protein, CD44, on osteoblasts, it may be possible to reduce the growth of prostate cancer cells in bone. In addition, we are interested in studying the changes or mutations in beta-catenin that were discovered in patients with advanced prostate cancer that allow beta-catenin to be “always on” and to determine whether these mutations help prostate cancer cells grow in bone. These studies will help patients with prostate cancer that has metastasized to bone and will potentially provide a solution for patients that have no alternative care for advanced prostate cancer. These studies will help us understand how prostate cancer and bone cells communicate, as well as determine whether there is a way to limit this communication and therefore limit growth of prostate cancer bone metastasis. I will pursue a career in prostate cancer research as a Principal Investigator (PI); by developing this research plan, I am working toward building the path to independence. This award give
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810171
Entities
People
- Justin Roberts
Organizations
- United States Army
- University of Texas at Austin