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 associated with various pathways, for example, it can regulate fatty acid oxidation (FAO) through the peroxisome proliferator-activated receptor γ (PPAR-γ) pathway. It also plays a crucial role in cancer malignancy and is implicated in inflammation-associated diseases [3]. Genetic models, like knockout (KO) mouse models, are valuable for studying its functions.

In murine tumor models, TAMs from whole-body S100A4-knockout, macrophage-specific S100A4-KO and transgenic S100A4WT-EGFP mice were studied. S100A4-deficient TAMs showed decreased protumor activity due to failure in PPAR-γ up-regulation-dependent FAO induction, indicating that macrophagic S100A4 enhances protumor macrophage polarization [1]. In breast cancer, S100A4 knockdown diminished STC1-induced lung metastasis, showing its role in metastasis [2]. In pulmonary fibrosis models, nintedanib alleviated PF by inhibiting the FAK/ERK/S100A4 signalling pathway [4]. Also, loss of S100A4 in whole-body or specifically in lymphatic endothelial cells (LECs) led to impaired tumor lymphangiogenesis and disrupted metastasis of tumor cells to sentinel LNs, suggesting S100A4 in LECs promotes lymphatic vessel sprouting [5].

In conclusion, S100A4 is essential in multiple biological processes, especially in cancer-related events such as tumor macrophage polarization, metastasis, and lymphangiogenesis. The use of S100A4 KO/CKO mouse models has significantly contributed to understanding its role in these disease areas, providing potential therapeutic targets for treating cancer and other related diseases.