Protein Mechanism That Spurs Tumor Growth In Prostate, Other Cancers, Unveiled

Date: Oct-17-2012US researchers have discovered how a protein called Trop2 controls the growth and proliferation of cancer cells in prostate and probably other epithelial cancer
tumors, It involves a mechanism where the protein "cleaves" into two parts: one inside the cell and the other outside. They hope their discovery will lead to new therapies that
stop cancer growing.

Study leaders Tanya Stoyanova and Owen Witte, of the University of California at Los Angeles (UCLA), and colleagues, write about their findings in the 15 October
issue of Genes and Development.

Witte, a professor in the department of microbiology, immunology, and molecular genetics at UCLA, says in a press statement:

"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."

Scientists already knew that Trop2 is expressed on the surface of many types of epithelial cancer cells, the types that lead to tumors in the skin and the inner and
outer linings of organs, but not much was known about how the protein helps cancer cells grow and multiply.

The UCLA team found Trop2 has a mechanism where it splits into two parts: one part inside the cell and the other outside. This "cleaving" mechanism is how it
spurs cancer cells to self-renew and grow into tumors.

The part that lies inside the cell comes away from the membrane and accumulates in the nucleus.

They tested the effect of increasing expression of this part of the protein:

"Heightened expression of the Trop2 intracellular domain promotes stem/progenitor self-renewal through signaling via β-catenin and is sufficient to initiate
precursor lesions to prostate cancer in vivo," they write.

Also, by mutating those sites on the protein where the cleavage occurs, they showed it was possible to remove its ability to facilitate cancer cell self-renewal and
hyperplasia in the prostate.

"These findings suggest that heightened expression of Trop2 is selected for in epithelial cancers to enhance the stem-like properties of self-renewal and
proliferation," they add.

The team believes the discovery may help drug developers find a way to stop Trop2 from cleaving and sending out molecular signals that spur cancer growth.

"Defining the mechanism of Trop2 function in self-renewal and transformation is essential to identify new therapeutic strategies to block Trop2 activation in
cancer," they conclude.

They suggest it may be possible in this way to prevent tumor growth in all kinds of epithelial malignancies, including cancer of the prostate, colon, mouth,
pancreas, ovaries, and others.

The study was supported by grants and funds from the California Institute for Regenerative Medicine, the US Department of Defense Prostate Cancer Research
Program, and the Howard Hughes Medical Institute.

Written by Catharine Paddock PhD

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