Tumour cells acquire the ability to proliferate uncontrollably, resist apoptosis, sustain angiogenesis and evade immune surveillance. STAT proteins — especially STAT3 and STAT5 — regulate all of these processes and are persistently activated in a surprisingly large number of human cancers. Consequently, STAT proteins are emerging — unexpectedly — as ideal targets for cancer therapy.
Signal transducer and activator of transcription (STAT)-family proteins are latent cytoplasmic transcription factors that convey signals from cytokine and growth-factor receptors to the nucleus.
STAT proteins, particularly STAT3 and the STAT5 proteins, are frequently overactivated in a variety of human solid tumours and blood malignancies.
Continuous deregulation of nuclear gene expression by persistent STAT3 and STAT5 signalling promotes the growth and survival of tumour cells, thereby contributing to malignancy.
Persistent STAT3 signalling in tumour cells induces tumour angiogenesis and suppresses anti-tumour immune responses, further enhancing tumour progression.
Tumour cells that become dependent on persistent STAT3 signalling are more sensitive to STAT3 inhibitors than normal cells, providing a therapeutic window based on transient or partial inhibition of STAT3.
Proof-of-concept studies in cell-culture and animal models have validated STAT3 and STAT5 proteins as promising molecular targets for novel cancer therapies, including small-molecule inhibitors of STAT signalling.
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We thank members of our laboratories for stimulating discussions, A. Levitzki for inspiring the title of this review, R. Buettner for assistance with references, J. Brugger for first drafts of the figures, and A. Bruce for secretarial assistance. Work in the authors' laboratories was supported by grants from the NIH, the Dr. Tsai-Fan Yu Endowment for Cancer Research and the Angela Musette Russo Foundation.
The authors declare no competing financial interests.
- DANGER SIGNALS
Inflammatory mediators produced during viral or bacterial infection that alert the immune system to danger. These signals include cytokines, chemokines and other physiological mediators, such as nitric oxide.
- T-CELL TOLERANCE
The inability of T cells to respond to danger signals. It is induced when T cells are initially exposed to antigens in the absence of danger signals. Tolerance results in the suppression of immune responses to tumours.
- BYSTANDER EFFECT
The indirect inhibition or killing of tumour cells that are adjacent to those directly affected by gene therapy or pharmacological inhibitors. This could involve soluble factors that are released by apoptotic cancer cells or immune responses.
- DECOY OLIGONUCLEOTIDE
A short stretch of synthetic DNA that contains the cognate DNA-binding site of a transcription factor and thereby serves to sequester and functionally inactivate that factor.
Small, organic molecules that mimic short stretches of amino acids and can be engineered to bind competitively to native proteins, and can therefore be used as drugs that disrupt protein function.
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