Tumor-Derived Exosome-Educated Hepatic Stellate Cells Regulate Lactate Metabolism of Hypoxic Colorectal Tumor Cells via the IL-6/STAT3 Pathway to Confer Drug Resistance

PURPOSE: Colorectal cancer cells spread to the liver and crosstalk with the microenvironment, and hepatic stellate cells (HSCs) are the major stromal components in the liver. However, the role of the interaction between colorectal tumor cells and HSCs in chemotherapeutic resistance remains unclear. The present study aimed to determine the mechanism of colorectal tumor cells educating the HSCs to reprogram the metabolism of adjacent tumor cells and fuel themselves in the metastatic microenvironment of the liver. PATIENTS AND METHODS: Immunohistochemistry (IHC) examined the expression of the monocarboxylate transporters 1 (MCT1) and lactate dehydrogenase B (LDHB) in colorectal liver metastases (CRLM). The Mann–Whitney U-tests analyzed the association between IL-6 levels and clinical parameters. The mechanisms of normoxic tumor-derived exosomes in the education of HSCs were investigated using IHC and ELISA. The conditioned medium of activated HSCs in the regulation of hypoxic tumor cells was analyzed by CCK-8 and cell apoptosis assays. RESULTS: The expression of MCT1 and LDHB was high in the liver metastases of irinotecan-resistant patients, and the high level of IL-6 in the plasma of patients with CRLM was associated with poor response to irinotecan-based chemotherapy. The colorectal tumor-derived exosomes activated HSCs to secrete excessive IL-6. Furthermore, the conditioned medium of activated HSCs enhanced the lactate metabolism of hypoxic tumor cells by activating the IL-6/STAT3 pathway and upregulating the downstream MCT1 and LDHB, in order to confer the resistance of SN38, which is the active metabolite of irinotecan. CONCLUSION: Taken together, the cultured supernatant of normoxic exosome-educated HSCs enhances the lactate metabolism of hypoxic tumor cells via the IL-6/STAT3 pathway, in order to confer the SN38 resistance in a mimic liver metastatic microenvironment.