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Stromal fibroblast-derived MFAP5 promotes the invasion and migration of breast cancer cells via Notch1/slug signaling

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Abstract

Background

The tumor microenvironment (TME) regulates tumor progression, and cancer-associated fibroblasts (CAFs) are the primary stromal components of the TME, with the potential to drive tumor metastasis via the secretion of paracrine factors, but the specific mechanisms driving this process have not been defined.

Methods

Proteins secreted from CAFs and normal fibroblasts (NFs) were analyzed via proteomic analysis (fold change > 2, p < 0.05) to identify tumor-promoting proteins secreted by CAFs.

Results

Proteomic analysis revealed that microfibrillar-associated protein 5 (MFAP5) is preferentially expressed and secreted by CAFs relative to NFs, which was confirmed by Western blotting and RT-qPCR. Transwell and wound healing assays confirmed that MFAP5 is secreted by CAFs, and drives the invasion and migration of MCF7 breast cancer cells. We further found that in MCF7 cells MFAP5 promoted epithelial–mesenchymal transition, activating Notch1 signaling and consequently upregulating NICD1 and slug. When Notch1 was knocked down in MCF7 cells, the ability of MFAP5 to promote invasion and migration decreased.

Conclusion

CAFs promote cancer cells invasion and migration via MFAP5 secretion and activation of the Notch1/slug signaling. These data highlight this pathway as a therapeutic target to disrupt tumor progression through the interference of CAF–tumor crosstalk.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81172517) and Beijing Breast Prevention Institute of Breast Cancer Prevention and Treatment Research Fund and the Beijing Municipal Health System Academic Leaders of High-Level Health Personnel Program (No. 2011-2-28).

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Authors and Affiliations

  1. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China

    Z. Chen, K. Li, Y. Ling & H. Kang

  2. School of Basic Medical Sciences, Capital Medical University, Beijing, China

    X. Yan

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Correspondence to H. Kang.

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Ethics approval has been obtained from the Institutional Review Board and the Human Ethics Committee of Xuanwu Hospital. Capital Medical University.

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Chen, Z., Yan, X., Li, K. et al. Stromal fibroblast-derived MFAP5 promotes the invasion and migration of breast cancer cells via Notch1/slug signaling. Clin Transl Oncol 22, 522–531 (2020). https://doi.org/10.1007/s12094-019-02156-1

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