Abstract
Background
This study aimed to investigate the underlying mechanisms of matricellular protein periostin (POSTN) on tumour-stroma crosstalk in the liver metastatic microenvironment of colorectal cancer (CRC).
Methods
Postn-knockout mice and hepatic Postn-overexpressing mice were used to investigate the functions of POSTN on the formation of fibrotic microenvironment and the tumour-stroma crosstalk in the liver metastatic microenvironment of CRC. Clinical samples and database were analyzed to show the correlation between POSTN expression and fibrotic features and TGF-β signalling in metastatic livers of CRC.
Results
POSTN deficiency reduced hepatic stellate cell (HSC) activation and liver metastasis, whereas POSTN overexpression in the liver significantly augmented the formation of a fibrotic microenvironment to support the liver metastatic growth of CRC cells in mice. Moreover, HSC-derived POSTN promoted TGF-β1 expression in CRC cells through the integrin/FAK/ERK/STAT3 pathway; conversely, tumour cell-derived TGF-β1 induced POSTN expression in HSCs via the Smad pathway. POSTN levels correlated with fibrotic features and TGF-β signalling in metastatic liver tissues of CRC patients.
Conclusions
POSTN and TGF-β1 cooperatively contribute to the tumour-stroma crosstalk by forming a supporting fibrotic microenvironment to promote liver metastasis of CRC cells via the POSTN/integrin/FAK/ERK/STAT3/TGF-β axis in tumour cells and TGF-β/Smad/POSTN signalling in activated HSCs.
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Data availability
All data are present in the manuscript and the Supplementary Materials. Additional data related to this paper may be requested from the corresponding author.
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Acknowledgements
We are deeply grateful to Prof. Xiaoying Li for providing recombinant adenoviruses and Dr. Fan Liu and Dr. Dan Cui for their valuable support.
Funding
This work was supported by grants from the National Natural Science Foundation of China (81772616, 81470793, 81972748, 82172932, and 82273416) and the Natural Science Foundation of Fujian Province of China (2019J02002).
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BL, TW, BLin, XL and CF acquired experimental data. BL, TW, BLin, GS, CF and GO were involved in manuscript writing. BL, TW, BLin, YL, GS, CF and GO analyzed the data. TW, GS and GO obtained funding. All authors read and approved the final manuscript.
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Human clinical samples were collected with informed consent from the patients. The collection and study of human clinical samples were performed in accordance with the approved guidelines of the Ethics and Scientific Committees of Xiamen Hospital of Traditional Chinese Medicine.
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Liu, B., Wu, T., Lin, B. et al. Periostin–TGF-β feedforward loop contributes to tumour-stroma crosstalk in liver metastatic outgrowth of colorectal cancer. Br J Cancer 130, 358–368 (2024). https://doi.org/10.1038/s41416-023-02516-3
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DOI: https://doi.org/10.1038/s41416-023-02516-3
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