Prostate cancer is the second-leading cause of cancer-related death in American men, and even deadlier among African American men, who are diagnosed younger and at increased risk for the disease compared to white or Hispanic men. Risk also increases with age and in those with a family history of prostate or other heritable cancers, including breast, ovarian, pancreatic, and colon cancer.
About three-fourths of prostate cancer patients are diagnosed before the disease spreads beyond the prostate. In this stage, most tumors are treatable and curable, though in 20 to 30 percent of patients, prostate cancer can come back after initial treatment. In a minority of patients, prostate cancer is diagnosed in an advanced stage, when it has already spread to other parts of the body. For those patients, a cure is unlikely and oncology providers focus on treatment to better control the cancer.
New research out of VCU Massey Comprehensive Cancer Center and the VCU Institute of Molecular Medicine (VIMM) — led by myself, Swadesh K. Das, PhD, and our team of collaborators — determined that a particular gene is the ringleader behind a molecular domino effect driving prostate cancer growth and metastasis. This gene is called MDA-9/Syntenin-1/SDCBP. Our findings could hold significant clinical implications for the treatment of prostate cancer and other forms of disease.
The study — published in the journal Proceedings of the National Academy of Sciences — aimed to understand the role of the MDA-9 gene in prostate cancer and how this gene communicates with surrounding cells and tissue in the tumor microenvironment to cause the disease to migrate into the bones. Bone metastasis is common in all types of advanced cancer, but particularly among patients with prostate and breast tumors. Once the cancer is in the bones, it drastically deteriorates bone health, often leading to fractures, breaks, and other life-threatening complications.
The final stages of cancer resulting in metastases are invariably fatal; there are virtually no options once a patient’s cancer has metastasized to the bone.
VCU Research Could Lead to Effective Therapies for Prostate Cancer
Extensive research previously conducted by us and our collaborators identified that the MDA-9 gene — a gene that is not specific to tumor cells and is found in all forms of tissue — is a major contributor to the spread of cancer; however, the biological why remained unknown.
Through this new study, we demonstrated for the first time that MDA-9 is largely responsible for initiating a cellular chain reaction that sparks prostate cancer metastasis and empowers the tumor cells to take over control in the bone itself. We identified that MDA-9 activates a protein in tumor cells which regulates cell growth and division and releases it into bones. Then, the protein binds with receptors on the surface of a type of bone marrow cell. These interact with MDA-9 to activate the signaling pathway, which is responsible for cell regeneration. This releases a small migration-stimulating protein which attracts cancer cells into the bone tissue, which in turn interact to produce more protein and continue to draw more cancer cells into the environment, causing a cyclical chain of events that bolsters the growth of disease in bone. Additionally, as the protein is luring more tumor cells into the tissue, it is also causing the deterioration and fracture of the bones by enhancing the reproduction of osteoclasts, a subset of bone cells that destroy the bone.
This study offers a definitive demonstration of communication between prostate cancer cells and normal cells within the tumor tissue, and how this biological conversation between them allows for cancer cells to spread to and multiply in bone.
By eliminating MDA-9 in prostate cancer cells, we interrupted this genetic game of telephone that leads to tumor growth, preventing the spread of disease. We also observed that removing MDA-9 from bone cells did not negatively affect bone tissue.
In this study, the interaction was observed in animal, human, and patient-derived prostate cancer cells, but we believe these findings will hold implications for a variety of solid tumor types in which MDA-9 is also present, including brain, breast, melanoma, lung and pancreatic cancers, among others.
We’re close to something that may go into the clinic, and we have already developed a novel inhibitor drug that has previously shown promise through separate studies.
Research is ongoing to define safety of specific MDA-9 inhibitors in appropriate preclinical models in preparation for translation into the clinic for patients with prostate and other lethal cancers. Our ultimate aim is to define combination therapies that will help us treat patients with aggressive and currently therapy-resistant cancers.
