This study reveals the critical role of FSTL3 in colorectal cancer-associated fibroblasts (CCAFs) through the TfR1/AKT/mTOR signaling pathway in promoting vasculogenic mimicry (VM), while demonstrating the synergistic effect of FSTL3-targeting antibodies combined with bevacizumab in suppressing VM formation and metastasis.
Literature Overview
The article "Cancer-associated fibroblasts expressing FSTL3 promote vasculogenic mimicry formation and drive colon cancer malignancy", published in "Cell Death & Disease", reviews the mechanisms by which FSTL3 promotes vasculogenic mimicry through tumor microenvironment regulation in colorectal cancer-associated fibroblasts, and its association with poor patient prognosis. The study further explores the synergistic anti-tumor effects of FSTL3-targeting antibodies combined with bevacizumab, offering novel solutions for overcoming drug resistance in anti-angiogenic therapies for colorectal cancer.
Background Knowledge
Colorectal cancer (CRC) is a highly heterogeneous, vascular-rich malignancy where traditional anti-angiogenic therapies (e.g., VEGF-targeted therapies) often face limitations due to drug resistance. Vasculogenic mimicry (VM) refers to endothelial cell-independent vascular-like structures formed autonomously by tumor cells, which correlate with tumor invasiveness and poor prognosis. While cancer-associated fibroblasts (CAFs) in the tumor microenvironment are known to contribute to VM formation, their specific mechanisms remain unclear. FSTL3 (Follistatin-like 3), a secreted glycoprotein, promotes epithelial-mesenchymal transition (EMT) in gastric cancer via the BMP/SMAD pathway and participates in tumor progression by antagonizing factors like activin and TGF-β. This study first identifies FSTL3 as highly expressed in colorectal cancer fibroblasts under hypoxic induction, where it binds TfR1 (transferrin receptor 1) to activate the AKT/mTOR pathway, enhancing endothelial-like transformation and VM formation in tumor cells, providing a new therapeutic target for colorectal cancer.
Research Methods and Experiments
The study integrated multiple public colorectal cancer datasets (TCGA-COAD, GSE39582, GSE17536) and applied WGCNA analysis to identify core genes associated with CAF infiltration and VM formation. Using single-cell sequencing data, the research team validated the specific expression of FSTL3 in CAFs and its significant correlation with poor prognosis. Immunohistochemistry and immunofluorescence staining in 157 patient samples confirmed FSTL3 co-localization with VM structures. In vitro and in vivo models demonstrated that FSTL3 silencing or antibody blockade significantly inhibits VM formation, with combination therapy with bevacizumab further enhancing efficacy.
Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically elucidates the pivotal role of FSTL3+ CCAFs in VM formation during colorectal cancer progression, revealing a non-VEGF-dependent angiogenic mechanism between CAFs and tumor cells under hypoxic microenvironment. This provides mechanistic insights into anti-angiogenic drug resistance and supports dual intervention strategies targeting both FSTL3 and VEGF. Future research directions include further investigation of FSTL3/TfR1 pathway regulatory mechanisms and its conservation across other tumor types. Additionally, FSTL3 serves as a potential plasma biomarker for early diagnosis or treatment monitoring in colorectal cancer.
Conclusion
This study systematically reveals the mechanism by which FSTL3 in colorectal cancer-associated fibroblasts promotes VM formation through TfR1/AKT/mTOR signaling pathway regulation. FSTL3 functions not only as a hypoxia-induced tumor-promoting factor but also shows significant correlation with poor patient prognosis. FSTL3-targeting antibodies effectively inhibit VM formation with notable synergy when combined with bevacizumab, offering a novel intervention strategy for overcoming anti-angiogenic therapy resistance in colorectal cancer. The research expands our understanding of fibroblast heterogeneity and VM-promoting mechanisms in tumor microenvironment, establishing a foundation for developing FSTL3- or TfR1-based combination therapies.
