STAT signaling in the pathogenesis and treatment of cancer

Abstract

The malignant behavior of a cancer cell is driven largely by the pattern of gene expression within that cell. Cancer cells are often characterized by the inappropriate activation of transcription factors that regulate genes controlling key cellular processes such as cell cycle progression, survival, and self-renewal. One family of transcription factors that play a central role in regulating these processes under physiological conditions is STATs. The seven STAT family members are physiologically activated by tyrosine phosphorylation, which is induced by a range of cytokines and growth factors. The phosphorylation of STATs is normally rapid and transient to ensure that their target genes are expressed in a controlled manner. In a wide range of human cancers, STATs, particularly STAT3 and STAT5, are activated constitutively. This leads to increased expression of target genes, which drives the malignant behavior of these cells. Understanding how STATs become activated provides insights into key aspects of tumor pathogenesis. In addition, given the central role that STATs play in tumor biology, STATs have emerged as attractive targets for cancer therapy. Several approaches, including rational design and cell-based chemical library screens, have yielded a number of potentially important STAT inhibitors that are now being introduced into clinical trials. Translational research in the area of STAT signaling is likely to continue to provide insight into both the molecular pathogenesis of cancer as well as novel therapeutic strategies for treating this disease.