Researchers at Case Western Reserve University School of Medicine, the National Cancer Institute, and Cleveland Clinic, as well as four other institutions, conducted an innovative study that inhibits cancer metastases through the use of epigenetics.
Epigenetics is the key
Epigenetics is the “study of biological mechanisms that will switch genes on and off.” That is an extremely simplified explanation, but that is the method used by these researchers. In the study, bone cancer (osteosarcoma) cells were halted in their spread to the lungs of mice. This is a major triumph as there is presently no widespread, approved and targeted anti-metastatic therapy for the disease. If metastases is prevented, fatalities from cancers can be reduced significantly.
Peter Scacheri, professor of genetics and genome sciences at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center stated, “More than 90 percent of all cancer deaths are the result of tumor metastasis, not primary-site tumors. While many of the genes responsible for metastasis have been identified, the mechanisms that control these genes are not well defined. Our findings demonstrate that altered gene-enhancer activity is fundamental to a cancer cell’s ability to metastasize.”
These gene-enhancers, actually short segments of DNA, act like switches to activate genes. This is a necessary process for normal development. There are tens of thousands of these in a single cell! Sometimes, however, the process goes awry and contributes to the formation and spreading of tumor cells. This study showed that the on-off switches of metastasized cancer cells are in different positions than those in the primary tumor.
The experiment to inhibit cancer metastases
The researchers consistently noticed certain bunched groups of enhancers (metastatic variant enhancer loci – Met-VELs) were close to cancer genes in the lung metastases of patients with osteosarcoma. This indicated that were crucial to the metastatic process. They then saw that osteosarcoma cell growth in the lung can be diminished with BET inhibitors (current anti-cancer drugs in clinical trials). These interrupt the Met-VELs function in influencing gene expression. They also found that a certain Met-VEL-linked gene, Tissue Factor (F3), must be present for metastatic colonization. This interruption of signaling and the blood clotting factors of F3 prevented metastasis.
“Our experiments show that removing a single enhancer of the F3 gene in tumor cells virtually eliminates their ability to metastasize in mice,” said Scacheri. “Collectively, our findings establish that enhancer elements endow tumor cells with metastatic capacity and that targeted inhibition of genes associated with enhancer alterations, or deleting altered enhancers themselves is sufficient to block metastatic colonization and proliferation. While our work focused on lung metastasis in osteosarcoma, the findings have implications for other types of metastatic cancer as well.”
The benefits
This experiment changes the way researchers look at stopping cancer metastasis. Most research focused on gene mutation, not how – or even if – specific genes could be turned off or on. Studies in how tumors are formed and the differences in cancer cells versus normal cells has also been a primary area of study – usually in the early stages of a disease. At that point, treatment generally targets primary tumors, not those cancer cells that have traveled elsewhere in the body.
With this study, an entirely new treatment possibility may exist. This may not only affect osteosarcoma metastasizing to the lungs, but may mean the primary tumors of other cancers will be stopped before invading secondary areas of the body. This could be a new way to tackle the spread of mesothelioma and give hope to those diagnosed with this fatal disease.
The knowledge and creativity of scientists and researchers worldwide must be applauded as they continue to develop new and more effective treatments for cancers and other devastating diseases.
