Mfge8, also known as milk fat globule-epidermal growth factor 8, is a secreted protein that plays diverse roles in multiple biological processes. It binds to integrin families like αVβ3/αVβ5, α8β1, and integrin β3, and is involved in pathways such as PI3K/AKT, ERK/AKT, and integrin-mediated signaling, impacting angiogenesis, cell proliferation, fibrosis, and insulin signaling, which are crucial for normal physiological functions and disease-related processes [1,2,4].

In esophageal squamous cell carcinoma (ESCC), the MFGE8 secreted by cancer-associated fibroblasts (CAFs) promotes tumor progression, angiogenesis, and metastasis by activating PI3K/AKT and ERK/AKT pathways upon binding to Integrin αVβ3/αVβ5 receptors. Targeting CAFs-secreting MFGE8 or its receptor significantly inhibits ESCC growth and metastasis in vivo [1]. In colorectal cancer, CRC-derived extracellular vesicles containing MFGE8 enhance macrophage efferocytosis of cisplatin-induced apoptotic CRC cells, promoting drug resistance. MFGE8-knockout CRC cells' EVs fail to upregulate macrophage efferocytosis in vitro and in vivo [3]. In gastric cancer, MFGE8 promotes cell proliferation, EMT progress, and tumor growth by activating the IL-6/JAK/STAT3 signaling pathway. Silencing MFGE8 suppresses gastric cancer cell viability, proliferation, migration, and invasion, and accelerates apoptosis [5].

In conclusion, Mfge8 is a multifunctional protein involved in various biological processes and disease conditions. Gene knockout models in these studies have revealed its significant role in cancer progression, intestinal fibrosis, and drug resistance, providing potential therapeutic targets for diseases like ESCC, intestinal fibrosis, and colorectal and gastric cancers.

References:

1. Liu, Beilei, Zhang, Baifeng, Qi, Jiali, Wang, Xin, Guan, Xin-Yuan. 2023. Targeting MFGE8 secreted by cancer-associated fibroblasts blocks angiogenesis and metastasis in esophageal squamous cell carcinoma. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2307914120. doi:10.1073/pnas.2307914120. https://pubmed.ncbi.nlm.nih.gov/37816055/

2. Lin, Sinan, Wang, Jie, Mukherjee, Pranab K, Fiocchi, Claudio, Rieder, Florian. 2024. Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis. In Gut, 73, 1110-1123. doi:10.1136/gutjnl-2022-328608. https://pubmed.ncbi.nlm.nih.gov/38378253/

3. Ma, Zhixin, Sun, Yu, Yu, Yang, Xiang, Xi, Li, Zhigang. 2024. Extracellular vesicles containing MFGE8 from colorectal cancer facilitate macrophage efferocytosis. In Cell communication and signaling : CCS, 22, 295. doi:10.1186/s12964-024-01669-9. https://pubmed.ncbi.nlm.nih.gov/38802814/

4. Datta, Ritwik, Podolsky, Michael J, Yang, Christopher D, Lizama, Carlos O, Atabai, Kamran. 2023. MFGE8 inhibits insulin signaling through PTP1B. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.05.30.542928. https://pubmed.ncbi.nlm.nih.gov/37398282/

5. Ding, Long-Long, Zhang, Meng, Zhang, Tao, Liu, Hui, Liu, Peng-Fei. 2024. MFGE8 promotes gastric cancer progression by activating the IL-6/JAK/STAT3 signaling. In Cellular signalling, 125, 111486. doi:10.1016/j.cellsig.2024.111486. https://pubmed.ncbi.nlm.nih.gov/39490801/