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

Abstract

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”.

Keywords: Calculus bovis; Wnt/β-catenin signaling pathway; M2-tumor-associated macrophages; Liver cancer; Transforming growth factor-β; Angiogenesis; Liver fibrosis

Core Tip: Calculus bovis (C. bovis) is an herb used in traditional Chinese medicine known for its various anti-inflammatory and anti-tumorigenic effects. C. bovis influences the tumor microenvironment by targeting immune-related pathways. Transcriptome sequencing revealed that C. bovis plays a crucial role in the regulation of M2-tumor-associated macrophages polarization and halting the Wnt/β-catenin pathway. This study provides a solid and promising evidence concerning potential drug therapy in the treatment of liver cancer. In this paper, we shed light on the inevitable “cross talk” between the Wnt and transforming growth factor-β signaling pathways, thus connecting angiogenesis, oncogenesis and liver fibrosis. C. bovis is deemed a priming molecule that sets the stage for a series of related and inter-connected events, such as angiogenesis, hepatocarcinogenesis and hepatic fibrosis. This process brings about the “domino effect” whereby one event uncovers another related event as a falling row of dominoes.