Pro-metastatic functions of lipoproteins and extracellular vesicles in the acidic tumor microenvironment

Although the overall mortality in cancer is steadily decreasing, major groups of patients still respond poorly to available treatments. The key clinical challenge discussed here relates to the inherent capacity of cancer cells to metabolically adapt to hypoxic and acidic stress, resulting in treatment resistance and a pro-metastatic behavior. Hence, a detailed understanding of stress adaptive responses is critical for the design of more rational therapeutic strategies for cancer. We will focus on the emerging role of extracellular vesicles (EVs) and lipoprotein particles in cancer cell metabolic stress adaptation and how these pathways may constitute potential Achilles' heels of the cancer cell machinery and alternative treatment targets of metastasis. In this context, common extracellular lipid uptake mechanisms, involving specific cell-surface receptors and endocytic pathways, may operate during remodeling of acidic atherosclerotic plaques as well as the tumor microenvironment. The role of endocytosis in regulating the cellular response to hypoxic and acidic stress through spatial coordination of receptor proteins may be exploited for therapeutic purposes. As a consequence, molecular mechanisms of endocytosis have attracted increasing attention as potential targets for tumor specific delivery of therapeutic substances, such as antibody-drug conjugates. The identification of internalizing surface proteins specific to the acidic tumor niche remains an unmet need of high clinical relevance. Among the currently explored, acidosis-related, internalizing target proteins, we will focus on the cell-surface proteoglycan carbonic anhydrase 9.