Osteopontin an Indicator of Metastatic Potential of Hepatocellular Carcinoma



By Will Boggs, MD

NEW YORK (Reuters Health) Mar 21 - Osteopontin is overexpressed in
hepatocellular carcinoma that metastasizes, and its inhibition blocks
hepatocellular carcinoma cell invasiveness, according to a report in the
March 17th advance online issue of Nature Medicine.

The high mortality from hepatocellular carcinoma (HCC) results mainly from
intrahepatic metastases, the authors explain, underscoring the need for
improved means of identifying patients at risk for such metastases.

Dr. Xin Wei Wang from the National Cancer Institute, along with associates
in Bethesda, Maryland, and in Shanghai, used cDNA microarray-based gene
expression profiling and a supervised machine-learning algorithm to generate
a molecular signature for classifying metastatic HCC patients.

"Unexpectedly," the authors report, "the gene expression profiles of primary
and matched metastatic HCC tumors were not significantly different."
However, the report indicates, gene expression profiles differed markedly
between primary metastasis-free HCC and primary HCC with metastatic lesions.
These findings "indicate that changes favoring intrahepatic metastasis are
initiated in the primary HCC."

A gene expression profile derived from the machine-learning algorithm
accurately separated the patients into metastatic and non-metastatic groups,
the researchers report, and patients predicted to have metastatic disease
had substantially shorter survival than did patients predicted to be
metastasis-free.

The osteopontin gene (SPP1) was overexpressed an average of threefold in
metastatic disease, but not in nonmetastatic disease, the results indicate,
and only metastatic tumors stained positive for cytoplasmic osteopontin.

In HCC cell lines, a neutralizing antibody to SPP1 significantly blocked the
invasiveness of the cells, the investigators report. Also, in a model of
HCC, mice treated with SPP1-neutralizing antibody had significantly fewer
lung metastases than did untreated mice in the fifth week after subcutaneous
injection of HCC cells.

"SPP1 is an ideal diagnostic marker because it can be found in all bodily
fluids and because elevated plasma SPP1 can be found in patients with
malignant tumors," the authors point out. "In addition, our data indicate
that SPP1 is a potential target for therapy of HCC patients with metastatic
potential."

"We are doing a large cohort study to validate this and other markers
identified in the signature," Dr. Wang told Reuters Health.

"We do not have any evidence that viral hepatitis will induce osteopontin,"
Dr. Wang added. "We have examined liver tissues from HBV or HCV positive
patients. The results are negative."

Nat Med 2003. www.nature.com/naturemedicine.