Sulf-2: an extracellular modulator of cell signaling and a cancer target candidate.

IMPORTANCE OF THE FIELD: Sulf-1 and Sulf-2 are sulfatases that edit the sulfation status of heparan sulfate proteoglycans (HSPGs) on the outside of cells and regulate a number of critical signaling pathways. The Sulfs are dysregulated in many cancers with Sulf-2 in particular implicated as a driver of carcinogenesis in NSCLC, pancreatic cancer and hepatocellular carcinoma. AREAS COVERED IN THIS REVIEW: This review describes the novel activity of the Sulfs in altering the sulfation pattern of HSPG chains on the outside of cells. Thereby, the Sulfs can change the binding of growth factors to these chains and can either promote (e.g., Wnt) or inhibit (e.g., fibroblast growth factor-2) signaling. The review focuses on the widespread upregulation of both Sulfs in cancers and summarizes the evidence that Sulf-2 promotes the transformed behavior of several types of cancer cells in vitro as well as their tumorigenicity in vivo. WHAT THE READER WILL GAIN: Sulf-2 is a bonafide candidate as a cancer-causing agent in NSCLC and other cancers in which it is upregulated. TAKE HOME MESSAGE: Sulf-2 is an extracellular enzyme and as such would be an attractive therapeutic target for the treatment of NSCLC and other cancers.