Periostin–TGF-β feedforward loop contributes to tumour-stroma crosstalk in liver metastatic outgrowth of colorectal cancer

• Published in: British journal of cancer 2024-02, Vol.130 (3), p.358-368
• Main Authors: Liu, Bin, Wu, Tiantian, Lin, Biyu, Liu, Xingxing, Liu, Yingfu, Song, Gang, Fan, Chuannan, Ouyang, Gaoliang
• Format: Article
• Language: English
• Subjects: 631/67/322; 631/67/327; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell activation; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Drug Resistance; Epidemiology; Hepatocytes; Humans; Integrins - metabolism; Liver; Liver - metabolism; Liver cancer; Liver Neoplasms - pathology; Metastases; Metastasis; Mice; Microenvironments; Molecular Medicine; Oncology; Periostin; Signal transduction; Smad protein; Stat3 protein; Stroma; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b; Transforming growth factor-b1; Tumor Microenvironment; Tumors
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-023-02516-3

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.