Protein sulfatase 2 a possible treatment target for liver cancer recurrence and survival

Deadly and difficult to treat, liver cancer has long resisted attempts by researchers to develop ways to prolong life and prevent recurrence.

But Mayo Clinic Cancer Center, in collaboration with the National Cancer Institute, reports in the April issue of Hepatology that the protein sulfatase 2 (SULF2) may provide one of the keys needed to begin the design of new therapies.

Mayo Clinic Cancer Center leads the field in researching the impact and effect of SULF1, a protein whose normal role is to degrade heparin sulfate proteoglycans -- molecules that are part sugar and part protein. Mayo scientists have found that the protein also helps inhibit tumor growth. Now, Mayo researchers are studying a related gene, SULF2. The role of the SULF2 gene and protein has not been fully defined, but in this study, researchers investigated the effect of SULF2 on liver tumor growth in the laboratory. They found that increased expression of SULF2 enhances cancer cell growth and migration, whereas decreased expression reduces both.

“The liver is designed to excrete toxins, and its tumors are no exception,” says Mayo Clinic gastroenterologist Lewis Roberts, M.B.Ch.B., Ph.D., the study's primary investigator. “Our problem is that the tumors tend to excrete chemotherapeutic agents rather than be affected by them. So we are looking for ways to get around that.”

The researchers sought answers by examining a protein related to one they already knew had a role in suppressing liver tumors. SULF1 and SULF2 are similar proteins, but cause opposing results. SULF1 removes sulfate groups that allow growth factors to bind to cells, thus inhibiting growth. The investigators found that SULF2 did the opposite -- it increased binding of a specific growth factor, fibroblast growth factor 2 (FGF2), to tumor cells, and also increased expression of the heparan sulfate proteoglycan glypican 3 (GPC3), which plays an important role in cell division and growth. These findings were confirmed in mouse models.

This discovery indicates if scientists can decrease the levels or activity of SULF2 in a tumor, they might be able to stop its development. Mayo researchers are exploring use of an agent that mimics heparin and inhibits SULF2. They are also examining whether preventing heparin sulfate synthesis would inhibit tumor growth.

“If something has a very broad effect on signaling by growth factors, it may lead to an effective treatment,” says Jinping Lai, M.D., Ph.D., a Mayo oncology researcher and the lead author of the study. “SULF2 has a number of characteristics that make it an attractive target, such as the fact that it is widely present in tumors. We are exploring a number of options with SULF2 as a focal point for treatment not only in liver cancer, but also in head and neck, pancreas, breast and other types of cancer.”

The researchers hope to identify drugs that block SULF2, and seek to thoroughly understand the mechanisms involved, including the determination of what other growth signaling pathways are affected by SULF2. They are also looking further at GPC3 as a potential biomarker for liver cancer or as a possible therapeutic target.

In 2007, Dr. Lai presented information at the annual meeting of the American Association for Cancer Research on the role of SULF2 in survival of patients with head and neck cancer -- the first concrete link to survival of patients with a specific tumor type.

Additional Mayo researchers on this study include: Catherine Moser; Ruben Bonilla Guerrero, M.D.; Ileana Aderca, Megan Garrity-Park; Hongzhi Zou, M.D., Ph.D.; Abdirashid Shire, Ph.D.; David Nagorney, M.D.; and Schuyler Sanderson, M.D.; also former fellows: Dalbir Sandhu, M.D.; Tao Han, M.D., Ph.D.; Kenard Jackson; and Hajime Isomoto, M.D.; and former staff member Alex Adjei, M.D., Ph.D., and Chunrong Yu, Ph.D., both currently of Roswell Park Cancer Institute, Buffalo, N.Y. Other collaborators included Ju-Seog Lee, Ph.D., and Snorri Thorgeirsson, M.D., Ph.D., of the National Cancer Institute, Bethesda, Md.

This research was supported by the National Institutes of Health, The Richard M. Schulze Family Foundation, and both Mayo Clinic's Miles and Shirley Fiterman Center for Digestive Diseases and the Cancer Center.