S100A4, also known as Mts1, is a member of the S100 family of calcium-binding proteins. It is involved in a wide range of biological functions such as angiogenesis, cell differentiation, apoptosis, motility, and invasion. S100A4 is also a potent trigger of inflammatory processes, inducing the release of cytokines and growth factors. It participates in various signaling pathways, and its abnormal expression is associated with multiple diseases, making it an important target for research, and genetic models like knockout mice are valuable tools to study its functions [3].

In murine tumor models, TAMs (tumor-associated macrophages) were isolated from whole-body S100A4-knockout (KO), macrophage-specific S100A4-KO and transgenic S100A4WT-EGFP mice. The results showed that S100A4+ TAM subsets display protumor phenotypes. Mechanistically, S100A4 controls the up-regulation of PPAR-γ, which is required for fatty acid oxidation (FAO) induction during TAM protumor polarization. S100A4-deficient TAMs exhibited decreased protumor activity due to failure in PPAR-γ up-regulation-dependent FAO induction [1]. Also, in breast cancer lung metastasis models, knockdown of S100A4 diminished STC1-induced lung metastasis, as STC1 upregulates S100A4 expression by facilitating EGFR and ERK signaling phosphorylation [2]. In another study, loss of S100A4 in whole-body (S100A4-/-) or specifically in lymphatic endothelial cells (S100A4ΔLYVE1) mice led to impaired tumor lymphangiogenesis and disrupted metastasis of tumor cells to sentinel lymph nodes [4].

In conclusion, S100A4 plays crucial roles in tumor-related biological processes such as macrophage polarization, tumor metastasis, and lymphangiogenesis. Gene knockout mouse models have been instrumental in revealing these functions, providing insights into the mechanisms of diseases like cancer, and suggesting that targeting S100A4 could be a potential therapeutic strategy.

References:

1. Liu, Shuangqing, Zhang, Huilei, Li, Yanan, Wang, Zhaoqing, Qin, Zhihai. . S100A4 enhances protumor macrophage polarization by control of PPAR-γ-dependent induction of fatty acid oxidation. In Journal for immunotherapy of cancer, 9, . doi:10.1136/jitc-2021-002548. https://pubmed.ncbi.nlm.nih.gov/34145030/

2. Liu, Anfei, Li, Yunting, Lu, Sitong, Zou, Fei, Meng, Xiaojing. 2023. Stanniocalcin 1 promotes lung metastasis of breast cancer by enhancing EGFR-ERK-S100A4 signaling. In Cell death & disease, 14, 395. doi:10.1038/s41419-023-05911-z. https://pubmed.ncbi.nlm.nih.gov/37400459/

3. Ambartsumian, Noona, Klingelhöfer, Jörg, Grigorian, Mariam. . The Multifaceted S100A4 Protein in Cancer and Inflammation. In Methods in molecular biology (Clifton, N.J.), 1929, 339-365. doi:10.1007/978-1-4939-9030-6_22. https://pubmed.ncbi.nlm.nih.gov/30710284/

4. Li, Anqi, Zhu, Linyu, Lei, Ningjing, Ni, Chen, Qin, Zhihai. 2022. S100A4-dependent glycolysis promotes lymphatic vessel sprouting in tumor. In Angiogenesis, 26, 19-36. doi:10.1007/s10456-022-09845-6. https://pubmed.ncbi.nlm.nih.gov/35829860/