1. FSTL1 Secreted by Activated Fibroblasts Promotes Hepatocellular Carcinoma Metastasis and Stemness.
- Author
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Loh JJ, Li TW, Zhou L, Wong TL, Liu X, Ma VWS, Lo CM, Man K, Lee TK, Ning W, Tong M, and Ma S
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Animals, Apoptosis, Biomarkers, Tumor genetics, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Proliferation, Fibroblasts metabolism, Follistatin-Related Proteins genetics, Humans, Liver Neoplasms genetics, Liver Neoplasms metabolism, Male, Mice, Mice, Inbred C57BL, Neoplastic Stem Cells metabolism, Prognosis, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Carcinoma, Hepatocellular secondary, Fibroblasts pathology, Follistatin-Related Proteins metabolism, Gene Expression Regulation, Neoplastic, Liver Neoplasms pathology, Neoplastic Stem Cells pathology
- Abstract
The tumor microenvironment plays a critical role in maintaining the immature phenotype of tumor-initiating cells (TIC) to promote cancer. Hepatocellular carcinoma (HCC) is a unique disease in that it develops in the setting of fibrosis and cirrhosis. This pathologic state commonly shows an enrichment of stromal myofibroblasts, which constitute the bulk of the tumor microenvironment and contribute to disease progression. Follistatin-like 1 (FSTL1) has been widely reported as a proinflammatory mediator in different fibrosis-related and inflammatory diseases. Here we show FSTL1 expression to be closely correlated with activated fibroblasts and to be elevated in regenerative, fibrotic, and disease liver states in various mouse models. Consistently, FSTL1 lineage cells gave rise to myofibroblasts in a CCL
4 -induced hepatic fibrosis mouse model. Clinically, high FSTL1 in fibroblast activation protein-positive (FAP+ ) fibroblasts were significantly correlated with more advanced tumors in patients with HCC. Although FSTL1 was expressed in primary fibroblasts derived from patients with HCC, it was barely detectable in HCC cell lines. Functional investigations revealed that treatment of HCC cells and patient-derived 3D organoids with recombinant FSTL1 or with conditioned medium collected from hepatic stellate cells or from cells overexpressing FSTL1 could promote HCC growth and metastasis. FSTL1 bound to TLR4 receptor, resulting in activation of AKT/mTOR/4EBP1 signaling. In a preclinical mouse model, blockade of FSTL1 mitigated HCC malignancy and metastasis, sensitized HCC tumors to sorafenib, prolonged survival, and eradicated the TIC subset. Collectively, these data suggest that FSTL1 may serve as an important novel diagnostic/prognostic biomarker and therapeutic target in HCC. SIGNIFICANCE: This study shows that FSTL1 secreted by activated fibroblasts in the liver microenvironment augments hepatocellular carcinoma malignancy, providing a potential new strategy to improve treatment of this aggressive disease., (©2021 American Association for Cancer Research.)- Published
- 2021
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