Investigators at University of California San Diego (UCSD) School of Medicine have discovered what they believe is a potential reason for why some drugs that have been developed to inhibit the overactive enzymes have failed to work against liver cancer. Some cancers are caused by loss of enzymes that should keep cell growth in check—yet conversely, some are caused by overactivation of enzymes that enhance cell growth. In this new study, UCSD researchers found that, counterintuitively, the lack of both types of these enzymes can lead to liver disease and cancer. Moreover, in human liver tumor samples, the scientists discovered that deficiencies in two enzymes, called Shp2 and Pten, are associated with poor prognosis.
“When it comes to liver cancer, I think we've been making strategic mistakes,” remarked senior study investigator Gen-Sheng Feng, Ph.D., professor of pathology and biological sciences at UC San Diego. “In cancer development, we always thought about two distinct families of enzymes—one promotes cancer, one inhibits it. Many drugs have been developed to block the cancer-promoting pathways, but we and others are now finding that many classical pro-cancer proteins are actually inhibitors.”
Based on Shp2's well-known role in promoting tumor formation, researchers have long assumed that drugs inhibiting the enzyme would stop tumor formation. But Dr. Feng and his colleagues previously found the opposite to be true—loss of the Shp2 enzyme can promote liver cancer. In contrast, the UCSD team discovered that removing both Shp2 and Pten, a tumor-suppressing enzyme, neutralized leukemia development.
“So the roles of tumor-promoting and tumor-suppressing enzymes are not as simple as we thought,” Dr. Feng noted. “This also explains many unwanted side effects with drugs that target these enzymes. Their consequences can differ depending on cell type.”
For the current study, Dr. Feng and his team noticed that Shp2 and Pten cooperate to suppress liver tumor formation in experimental mice. When the researchers deleted both the Shp2 and Pten genes specifically in the mice's liver cells, early-onset liver disease (nonalcoholic steatohepatitis, or NASH) was more severe and liver tumors occurred earlier and more frequently than in control mice with one or both enzymes functioning.
The findings from this study were published recently in Cell Reports in an article entitled “Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells.”
While normal mice did not experience any tumors, in mice lacking either Pten or Shp2, liver tumors began to appear after approximately 7 or 12 months. However, for mice lacking both enzymes, 80% spontaneously developed liver tumors in 5 months—with 100% having tumors at 7 months. The UCSD researchers hypothesized that the increased severity of liver disease and frequency of liver cancer in these models is likely because the lack of Shp2 and Pten enzymes activates molecules involved in lipid metabolism, inflammation, and fibrosis.
Due to their surprising findings in mice, the researchers speculated whether the same phenomenon occurs in human liver cancers. They analyzed 335 human liver tumor samples and found that approximately 52% of the tumors were low in both Shp2 and Pten enzyme levels. Those patients with low Shp2 and Pten enzyme levels in the tumors had a poorer prognosis than those with higher levels of one or both enzymes—at 50 months after surgery, approximately 60% of patients with low Shp2 and Pten were alive, compared to approximately 90% of patients with high Shp2 and Pten levels.
“Liver cancer is more complicated than we thought,” Dr. Feng concluded. “These pathways, when overactivated, stimulate tumor development, but so does inhibiting them. That's why we can't rush to conclusions like we have in the past. Now that we have a good model that mimics the human pathogenic process and we can use that to work out the mechanisms that lead to liver disease and cancer, and search for novel drug targets.”