Bidirectional interaction between Schwann cells and cancer cells of hepatocellular carcinoma: implications for tumor progression.

In cancer research, the role of peripheral nerves has been extensively studied over the past few decades, with increasing attention recently focusing on Schwann cells(SCs), the primary glial cells of the peripheral nervous system. Tumor-activated SCs have been shown to significantly contribute to cancer progression by modulating the tumor microenvironment (TME) and directly interacting with cancer cells through both paracrine signaling and physical contact. Hepatocellular carcinoma (HCC), the most common primary liver tumor, remains one of the leading causes of cancer-related deaths worldwide. While several studies have highlighted the potential role of autonomic innervation in HCC development and progression, the specific role of SCs in this context remains largely unexplored. To address this gap, we aimed to investigate the biological effects and molecular mechanisms underlying the communication between SCs and cancer cells in the HCC. We decided to focus on the paracrine crosstalk between SCs and HCC cells, employing an in vitro approach based on conditioned media (CM), to explore the potential impact of this dialogue on both HCC cells aggressiveness and SCs reprogramming. We used the human hepatoma Hep3B cell line and human SCs, treating each cell type with either control CM (derived from the same cell type) or with CM from the other cell type. The effects of these treatments were assessed through functional assays and analysis of molecular and morphological profiles. Our results show that Hep3B cells treated with SCs-CM,compared to those treated with control CM, exhibit more aggressive features associated with tumor spread, including enhanced migration, a doubled capacity for matrigel invasion, changes in the protein levels of epithelial-to-mesenchymal transition markers (N-cadherin, E-cadherin, Vimentin) and structural and topographical alterations evaluated by atomic force microscopy. Concurrently, paracrine signals from Hep3Bcells induce a chemotactic response in SCs, promoting processes such as proliferation, migration, matrigel invasion, and the upregulation of repair-related markers (GFAP, N-cadherin), thereby driving their activation. Overall, our findings demonstrate a bidirectional interaction between SCs and HCC cells, emphasizing the importance of a deeper understanding of the glial component in the TME of HCC, as it could significantly influence tumor progression.