Blocking Osteopontin to Prevent Bladder Cancer Metastasis

Investigators at the University of Colorado Cancer Center and Yale University are now reporting in the journal Cancer Cell on a new understanding of the cancer suppressing gene RhoDGI2 and how it may be involved in metastatic bladder cancer. The researchers theorize that by targeting RhoDGI2 it may be possible to improved outcomes.  

The current study demonstrates a promising strategy to block the immune system’s mistaken collaboration with cancer cells, resulting in the inability of circulating cells to seed new sites of metastasis. “What this paper shows is that targeting macrophages and/or CD44 are potential clinical therapeutic options,” said study co-senior author Dan Theodorescu, MD, PhD, who is the Director of the University of Colorado Cancer Center, in a news release. “Working with bladder cancer cells, we were able to show not only how immune system macrophages recognize and aid circulating cancer cells, but also how we might intercede to block this mechanism.”

Several years ago, Dr. Theodorescu and his team discovered RhoDGI2 as a suppressor of tumor growth at metastatic sites. Now, there is another step in this understanding.   

The investigators report that RhoGDI2 specifically suppresses bladder cancer metastasis; however, not primary tumor growth. Activity of the RhoDGI2 gene and the protein it encodes restricts the ability of bladder cancer cells and potentially other circulating cancer cells. Dr. Theodorescu and his colleagues propose that the loss of RhoGDI2 allows a cancer cell to increase production of proteins called endothelin and versican, which signal immune system macrophages to the site of the cancer cells. These macrophages promote the development of new tumors by producing various cancer growth-promoting substances.

The researchers have now demonstrated that one of these substances is the protein osteopontin. They contend that the loss of RhoDGI2 leads to increased endothelin and versican and attracts macrophages. They report that this cascade of events secrete osteopontin, which signals tumor cells to reinitiate stem cell-like programs that promote growth and survival. Osteopontin does this by binding to CD44 receptors on the surface of newly attached bladder cancer cells, jumpstarting their ability to act as seeds of a new tumor site.

When the investigators blocked osteopontin signaling pathway in animal models, bladder cancer cells were not able form metastases in the lungs and lymph nodes. They also found that expression of osteopontin was associated with poor outcomes in human bladder cancer patients. The investigators are hoping that treatment strategies targeting metastasis may be successful if they block osteopontin binding to CD44.