This discovery is important because it may prove essential for creating new therapies that stop the growth of cancer, the researchers said. The study is featured on the cover of the Oct. 15 issue of the journal Genes and Development.
The Trop2 protein is expressed on the surface of many types of epithelial cancer cells — cells that form tumors that grow in the skin and the inner and outer linings of organs — but little was known about the protein’s role in the growth and proliferation of cancer cells. The UCLA researchers discovered that Trop2 controls those processes through a mechanism that leads to the protein being cleaved into two parts, one inside the cell and one outside. This Trop2 division promotes self-renewal of the cancer cells, resulting in tumor growth.
“Determining the mechanism of this protein is important for planning treatments that stop the growth of prostate cancer, but it is also overexpressed in so many other types of cancer that it might be a treatment target for many more patients beyond that population,” said senior author Witte, director of the Broad Center and a professor in the department of microbiology, immunology, and molecular genetics at UCLA.
The finding may have a critical clinical impact, the researchers said, since preventing the cleavage of Trop2 by mutating those sites on the protein where it splits eliminates the protein’s ability to promote tumor cell growth. Using this knowledge, they said, new therapy strategies can be developed that block Trop2 molecular signaling, thus stopping its ability to enhance tumor growth in a variety of epithelial malignancies, including prostate, colon, oral cavity, pancreatic and ovarian cancers, among others.
“The reason I became interested in Trop2 was that it is highly expressed in many epithelial cancers but no one knew precisely how the protein worked to promote the disease,” said Stoyanova, the study’s first author and a postdoctoral scholar in the department of microbiology, immunology and molecular genetics at UCLA.
Funding for the study was provided by the California Institute for Regenerative Medicine Training Grant (TG2-01169), the U.S. Department of Defense Prostate Cancer Research Program (PC110638) and the Howard Hughes Medical Institute.
The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.