Calculus bovis hijacks the tumor microenvironment in liver cancer cells in a multifaceted approach: A falling row of dominoes.

Calculus bovis (C. bovis) is widely used in traditional Chinese medicine due to its anti-tumor effects. C. bovis shifts liver cancer tumor microenvironment towards regression by hindering tumor-associated macrophages polarization. Huang et al have demonstrated in their study that C. bovis inhibits M2-tumour-associated macrophages (TAM) polarization by halting the Wnt/β-catenin pathway. The mechanism of action by which C. bovis exerts its anti-tumor effects is multifaceted and includes network pharmacology, transcriptomics and molecular docking. In vitro assays demonstrated that C. bovis-containing serum inhibited M2-TAMs polarization in human hepatocellular carcinomas cells. C. bovis was found to have 22 active components of which 11 were detected in the bloodstream. The anti-neoplastic activity of C. bovis lies in suppressing M2-TAM polarization by modulation of the Wnt/B-catenin pathway. In vitro and in vivo experiments have shown that C. bovis suppresses M2-TAM polarization and halts the Wnt signaling pathway. The inhibitory effect of C. bovis on M2-TAM was reversed by SKL2001, a Wnt agonist, which highlights C. bovis's selectivity and specificity. C. bovis inhibits M2-TAM polarization by modulating the Wnt/ β-catenin pathway, thus impeding liver cancer growth. Owing to the "cross-talk" between transforming growth factor-β (TGF-β) signaling pathways, this paper highlights the potential significance of C. bovis in controlling the tumor microenvironment not only through hindering the polarization of M2-TAMs via the Wnt signaling pathway, but also by downregulating TGF-β. Therefore, C. bovis serves as an igniter to fuel a cascade of signaling events that culminates in the regression of the tumor microenvironment by compromising oncogenesis and angiogenesis. TGF-β is also known for its pro-fibrotic properties. Therefore, C. bovis may play a pivotal role in treating liver fibrosis by downregulating TGF-β, thus hindering oncogenesis, angiogenesis and liver fibrosis. Hence, the "domino effect".