Abstract
Invasion and metastasis are the main reasons for the high mortality of liver cancer, which involve the interaction of tumor stromal cells and malignant cells. Cancer-associated fibroblasts (CAFs) are one of the major constituents of tumor stromal cells affecting tumor growth, invasion, and metastasis. The heterogeneous properties and sources of CAFs make both tumor-supporting and tumor-suppression effects possible. The mechanisms for CAFs in supporting hepatocellular carcinoma (HCC) progression can be categorized into upregulated aggressiveness and stemness, transformed metabolism toward glycolysis and glutamine reductive carboxylation, polarized tumor immunity toward immune escape of HCC cells, and increased angiogenesis. The tumor-suppressive effect of fibroblasts highlights the functional heterogenicity of CAF populations and provides new insights into tumor–stromal interplay mechanisms. In this review, we introduced several key inflammatory signaling pathways in the transformation of CAFs from normal stromal cells and the heterogeneous biofunctions of activated CAFs. In view of the pleiotropic regulation properties of traditional Chinese medicine (TCM) and heterogeneous effects of CAFs, we also introduced the application and values of TCM in the treatment of HCC through targeting CAFs.
Highlights
Hepatocellular carcinoma (HCC), one of the deadliest malignant diseases, claims more than 2,814,000 lives a year in China [1]
We introduced several key inflammatory signaling pathways in the transformation of cancer-associated fibroblasts (CAFs) from normal stromal cells, the metabolism reprogramming of activated CAFs, and the heterogeneous biofunctions of activated CAFs on HCC progression, metastasis, and recurrence
It has been confirmed that SULF2 expressed by HCC cells can induce hepatic stellate cells (HSCs) into CAFs through the transforming growth factor (TGF)-b/ SMAD3 pathway, which may further inhibit apoptosis and promote epithelial–mesenchymal transformation (EMT) of HCC cells via the SDF-1/CXCR4-related signaling pathway [20]. p300 acetyltransferase promotes TGFb-stimulated HSC activation by both cytoplasm-to-nucleus shuttle for SMAD2/3-tafazzin (TAZ) and histone acetylation mechanisms [26]
Summary
Invasion and metastasis are the main reasons for the high mortality of liver cancer, which involve the interaction of tumor stromal cells and malignant cells. Cancer-associated fibroblasts (CAFs) are one of the major constituents of tumor stromal cells affecting tumor growth, invasion, and metastasis. The heterogeneous properties and sources of CAFs make both tumor-supporting and tumor-suppression effects possible. The tumor-suppressive effect of fibroblasts highlights the functional heterogenicity of CAF populations and provides new insights into tumor–stromal interplay mechanisms. We introduced several key inflammatory signaling pathways in the transformation of CAFs from normal stromal cells and the heterogeneous biofunctions of activated CAFs. In view of the pleiotropic regulation properties of traditional Chinese medicine (TCM) and heterogeneous effects of CAFs, we introduced the application and values of TCM in the treatment of HCC through targeting CAFs
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