On page 819 Hosui et al. show how a cancer-fighting molecular pathway turns traitor and becomes a cancer promoter. The work clarifies how chronic liver damage can lead to tumors.
Alcoholism and infection by hepatitis viruses can spur liver fibrosis, which often progresses to cancer. In the liver, key functions that go awry in cancer—such as cell survival and proliferation—are under control of growth hormone. In turn, growth hormone acts through STAT5a and STAT5b. These transcription factors are two-faced, encouraging tumors in some tissues but blocking them in others. Whether the two varieties of STAT5 incite fibrosis and cancer in the liver was uncertain.
To find out, Hosui et al. deleted both STAT5 genes from hepatocytes in mice. The researchers discovered that exposure to carbon tetrachloride—which simulates long-term liver damage—triggered fibrosis and tumors in the STAT5-lacking mice but not in controls.
Loss of STAT5 also boosted levels of the fibrosis-stimulating cytokine TGF-β and hiked the amount of activated STAT3, a cousin of STAT5 that fosters an assortment of solid tumors. TGF-β and STAT5 are adversaries, the researchers found. STAT5 cut the amount of TGF-β by reducing its stability. And TGF-β stopped growth hormone from turning on STAT5. As a result, growth hormone is free to switch on STAT3.
The study shows that STAT5 is protective in the liver. The results also suggest an explanation for the link between fibrosis and liver cancer. As fibrosis worsens, the liver pumps out more and more TGF-β, which prevents growth hormone from activating STAT5. Instead, growth hormone flips on STAT3, and cancer results.
