Hepatocellular carcinomas have a high mortality rate, which is partly due to an increased tendency towards metastasis. Although the tumour microenvironment is an important determinant of cancer migration and invasion, the mechanistic basis of its contribution to metastasis is not well understood. Now, Xinghai Ning and co-workers (Meng et al., 2021) reveal how an acidic microenvironment, a consequence of aerobic glycolysis and poor blood perfusion, promotes tumour migration. They show that acidic conditions induce epithelial-to-mesenchymal transition (EMT), and enhance migration and invasion in both a low-metastatic and a high-metastatic liver cancer cell line. Furthermore, an acidic microenvironment promotes the expression of the type I membrane protein ROR1, which has known functions in tumour migration and invasion, and its activating ligand Wnt5a. Interestingly, knockdown of ROR1 interferes with the increased migration and invasion capability, as well as the accelerated EMT of hepatocarcinoma cell lines under acidic conditions. Importantly, neutralising the acidic microenvironment with sodium bicarbonate reduces the expression of ROR1 and Wnt5a, delays EMT and lowers the metastatic and invasive potential of tumour cells in vitro and in vivo. Collectively, these results show that acidic microenvironments promote metastasis and invasion by upregulating ROR1 and Wnt5a, and this knowledge could be exploited to devise novel therapeutic strategies to improve cancer treatment.
