Treatment Target For Liver Cancer Recurrence And Survival Identified

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Treatment Target For Liver Cancer Recurrence And Survival Identified

ScienceDaily (Apr. 13, 2008) — 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 , 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: Moser;

Bonilla Guerrero, M.D.; Ileana Aderca, Garrity-Park; Hongzhi Zou, M.D.,

Ph.D.; Abdirashid Shire, Ph.D.; Nagorney, M.D.; and Schuyler on,

M.D.; also former fellows: Dalbir Sandhu, M.D.; Tao Han, M.D., Ph.D.; Kenard

; and Hajime Isomoto, M.D.; and former staff member 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 M.

Schulze Family Foundation, and both Mayo Clinic's Miles and Shirley Fiterman

Center for Digestive Diseases and the Cancer Center.

Adapted from materials provided by Mayo Clinic.

http://www.sciencedaily.com/releases/2008/04/080410160839.htm

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