Abstract
The tightly orchestrated temporal and spatial control of signal transducer and activator of transcription 3 (STAT3) activity in epithelial, immune and stromal cells is critical for wound healing and tissue repair. Excessive STAT3 activation within cancer cells and cells of the tumour microenvironment can be viewed as a neoplastic mimic of an inflammation-driven repair response that collectively promotes tumour progression. In addition to the canonical transcriptional pathways by which STAT3 promotes stem cell-like characteristics, survival, proliferation, metastatic potential and immune evasion, cytoplasmic STAT3 activity fuels tumour growth by metabolic and other non-transcriptional mechanisms. Here, we review the tumour-modulating activities of STAT3 in light of its role as a signalling node integrating inflammatory responses during wound healing. Accordingly, many of the cytokines that contribute to the para-inflammatory state of most solid malignancies converge on and underpin dysregulated STAT3 activity. Targeting of these cytokines, their cognate receptors and associated signalling cascades in clinical trials is beginning to demonstrate therapeutic efficacy, given that interference with STAT3 activity is likely to simultaneously curb the growth of cancer cells and augment antitumour immunity.
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Acknowledgements
This work was supported by grants from the National Health and Medical Research Council (NHMRC) Australia (GNT1079257 and GNT1125951), United States Department of Defense (CA150132), Grant-in-Aid from the Cancer Council Victoria (GNT1145028 and GNT1143036) and funds from the Operational Infrastructure Support Program provided by the Victorian Government. A.C. is a Career Development Fellow (GTN1062247) and M.E. is a Research Fellow of the NHMRC (GNT1079257).
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Glossary
- Acute phase response
-
An orchestrated response to tissue injury, infection or inflammation that involves the induction of acute phase proteins by the liver.
- Trans-signalling
-
A process relevant to interleukin-6 (IL-6), and possibly IL-11, whereby enzymatic cleaving of the extracellular domain of the corresponding cognate α-receptors enables formation of soluble ligand–receptor complexes, which can bind to and activate any cell expressing GP130 irrespective of the presence of the native α-receptor chains.
- Para-inflammation
-
An adaptive response to tissue stress or malfunction that is characterized by subclinical reversible inflammation that is manifested by excessive signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) activity.
- Electron transport chain
-
(ETC). A series of five protein complexes traversing the mitochondrial inner membrane required for the efficient generation of ATP through oxidative phosphorylation.
- Autophagy
-
A process that is essential to the recycling of unneeded or damaged cellular components during conditions of nutrient stress elicited by many perturbations including cellular transformation and wound healing.
- Autolysosomes
-
Structures that are formed by the fusion of the autophagosome with the lysosome to facilitate digestion of the contents.
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Huynh, J., Chand, A., Gough, D. et al. Therapeutically exploiting STAT3 activity in cancer — using tissue repair as a road map. Nat Rev Cancer 19, 82–96 (2019). https://doi.org/10.1038/s41568-018-0090-8
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DOI: https://doi.org/10.1038/s41568-018-0090-8
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