If a cancer is caused by the over-activation of proteins that enhance growth, then blocking these enzymes should stunt the tumor. Yet, in liver cancer, drugs that inhibit growth enzymes do not seem to slow the cancer growth. And the most recent research suggests that cancer biology is more complex than previously thought.
"When it comes to liver cancer, I think we've been making strategic mistakes," said Gen-Sheng Feng, professor at the University of California, San Diego, and the study’s senior author. "In cancer development, we always thought about two distinct families of enzymes -- one promotes cancer, one inhibits it.”
Indeed, this line of thinking has led to the creation of drugs that, for the most part, do one or the other. That is, they either block the over-active pro-cancer enzymes or stimulate the activity of anti-cancer proteins. “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,” said Feng. This explains why the intended consequences for anticancer drugs don't always work.
To better understand the mechanism behind why cancer drugs fail in liver cancer, the team honed in on the balance of tumor-suppressor genes versus those that promote tumor growth in a mouse model. They found that mice that lacked both types of proteins are, paradoxically, most susceptible to liver disease and cancer.
In particular, the two opposing cancer proteins were identified as Shp2 and Pten. Shp2 is well-characterized as a tumor-promoting protein, while Pten is a known tumor-suppressing protein. Yet, mice with a loss of both of these proteins had the largest and most prominent tumor formation in the shortest amount of time.
"So the roles of tumor-promoting and tumor-suppressing enzymes are not as simple as we thought," Feng said. "This also explains many unwanted side effects with drugs that target these enzymes. Their consequences can differ depending on cell type."
Feng’s team theorized that loss of the two enzymes triggered uncontrolled inflammation and fibrosis in the liver, which helped promote tumor formation. Interestingly, when they analyzed human liver cancer samples, the team found a similar pattern – those with low or deficient levels of SHP2 and PTEN typically had the poorer prognoses.
"Liver cancer is more complicated than we thought. These pathways, when over-activated, stimulate tumor development, but so does inhibiting them," Feng said. "That's why we can't rush to conclusions like we have in the past. But 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."
Additional sources: UC San Diego Health