Cancer is a deadly disease that destroys human health and well-being. In 2017, there were more than a million new cancers diagnosed and more than 600,000 cancer deaths in the United States.
More than half of these cancer deaths were because of secondary tumors, called metastases that grow in a completely separate part of the body than the primary tumor. Metastases are deadly when they grow in vital organs such as the brain or lung.
The process of tumor metastasis can be compared to how nature sends plant seeds to distant geographic sites, using different methods of transportation.
Tumor seeding and growth in a new location is a complicated process. To begin this process, a single tumor cell must detach from the primary tumor and travel through the surrounding tissue, toward a major circulatory system in the body, such as the blood. Then this cell has to get through a protective wall and enter the bloodstream to travel to a new site in the body. During its ride, this tumor cell must hide from millions of immune cells trained to kill any foreign cells in the blood. If the tumor cell survives this trip, it will then leave the bloodstream at a distant tissue and attempt to grow there. This whole process is very challenging, therefore only about one in ten thousand tumor cells that enter the bloodstream can successfully travel to a new location and start a secondary tumor.
Which cells in the primary tumor decide to take this dangerous trip, and which cells decide not to travel? We are investigating this question by looking closely at specific cellular activities during metastasis. I am part of a research team in Kam Yeung’s lab in the Department of Cancer Biology at the University of Toledo College of Medicine and Life Sciences, formerly the Medical College of Ohio. We are investigating a small cellular protein, called Raf-1 kinase inhibitor protein or RKIP, which suppresses metastasis when it is activated.
We are one of the leading laboratories in the RKIP research field. Several independent studies, including ours, have shown that RKIP suppresses metastasis in different tumor types, such as prostate cancer, melanoma, breast cancer, and colon cancer. This is because RKIP controls several other important proteins in the cell. When the expression of RKIP is turned off in tumor cells, these other proteins behave without control, giving these tumor cells a metastatic travel permit.
Our research team understands that the uninhibited RKIP-binding proteins are just the first step in a cellular signaling pathway to allow a tumor cell to metastasize. We are trying to identify other proteins that are controlled by these RKIP-binding proteins when RKIP is turned off. One potential cellular protein we discovered in a breast cancer cell model is called RhoA.
We know that when RKIP is turned on in breast cancer cells, RhoA is more active. When RhoA is active, it stabilizes another protein that helps keep cells attached to each other. So when there is more RhoA activity in tumor cells, they keep attached to other tumor cells and cannot metastasize. When RKIP is turned off in tumor cells, they have less active RhoA, which decreases cell-cell attachments, giving these cells a metastatic travel permit.
We are investigating the detailed mechanisms of relationships between RKIP, RhoA, and cell attachment proteins in metastatic breast cancer cells. We are also using a breast cancer mouse model to confirm our preliminary findings in the cell culture model. Our ultimate goal is to identify proteins that are regulated by RKIP-binding proteins and target these for therapy to reduce metastasis of breast cancer cells.
Sandun Kalpana is a student earning her PhD in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. She is doing her research in the laboratory of Kam Yeung, PhD, in the Department of Cancer Biology. For more information, contact Gardi[email protected] or go to utoledo.edu/ med/ grad/ biomedical.