Science & Technology/New Antibody Reduces Cell Proliferation and Induces Cell Death in Human Liver Cancer Cells

Pitt School of Medicine researchers have reported a significant new advance in the search for an effective treatment for human liver cancer.

Using a newly available monoclonal antibody, they have demonstrated significant reductions in tumor cell proliferation and survival in human and mouse hepatocellular cancer (HCC) cell lines.

According to the Pitt research, published in the July issue of Molecular Cancer Therapeutics, this finding has significant implications not only for the treatment of liver cancer but for a number of different types of cancer.

Most cases of HCC are secondary to a viral hepatitis infection or cirrhosis of the liver. Despite recent advances, HCC remains a disease of grim prognosis because of the poorly understood mechanism of how the disease originates and spreads. Most patients live only a short time after diagnosis.

Based on previous studies showing that some pathways that were previously thought to be active only during fetal liver development—particularly the class III receptor tyrosine kinase (RTK) family pathway—became highly active again in the liver of HCC patients, Satdarshan P. Singh Monga and colleagues in Pitt’s medical school obtained rat and human liver cancer cell lines and analyzed them for level of expression of an RTK protein known as platelet-derived growth factor receptor-alpha, or PDGFRα. The investigators also analyzed the cells for their level of activation of the PDGFRα gene.

At an early fetal stage of liver development in the mouse, investigators found that the level of expression of PDGFRα was 37 times higher compared to later stages of development in the adult mouse liver. They also found significantly higher levels of PDGFRα in rat and human liver cancer cell lines as compared to normal cells in culture.

Monga’s group then treated human and mouse liver cancer cell lines with a monoclonal antibody targeted against PDGFRα. It resulted in a significant decrease in tumor cell proliferation and a marked increase in tumor cell death. In fact, all tumor cell lines experienced significant decreases in proliferation in response to the monoclonal antibody, and there was a 4- to 18-fold increase in programmed cell death, or apoptosis, among the cancer cell lines compared to normal control cells.

According to Monga, these results suggest that PDGFRα offers an important new therapeutic target for the treatment of HCC.

“We are very excited, because this is the first targeted therapy for liver cancer,” said Monga, a professor in the medical school’s Division of Cellular and Molecular Pathology. “Other therapies have some modest benefits, but no one knows exactly how they work. We now have identified a pathway that appears to be overly active in more than 70 percent of the cancers we examined and, when targeted, leads to significant reduction in tumor cell proliferation and survival.”

More importantly, targeting the PDGFRα pathway in liver cancer cells does not appear to affect normal liver cells, making the treatment relatively nontoxic. “Normally, regenerating liver cells are not exclusively dependent on this pathway, and it is not overly active in other types of cells. So this monoclonal antibody is a highly targeted treatment for this disease,” Monga added.

Furthermore, because high expression of PDGFRα has been detected in a variety of tumors, such as skin cancer, brain tumors, gastrointestinal tumors, prostate tumors, ovarian cancer, and leukemia, Monga believes these findings could have much broader applications.

The Pitt research was funded by grants from the American Cancer Society and the National Institutes of Health as well as the Cleveland Foundation and the Rango’s Fund for Enhancement of Pathology Research.