Highlights in Cancer Research: August 2023

Cancer is a systemic disease where primary tumours disrupt host homeostasis through metastasis and the release of soluble factors, such as proteins, metabolites, hormones, and extracellular vesicles and particles (EVPs) into the circulation, affecting both local and distant tissues and organs.

Wang and colleagues discovered that tumour-derived EVPs containing saturated fatty acids, in particular palmitic acid, can be transported to liver resident macrophages, Kupffer cells, triggering the release of TNF via TLR4. TNF-induced immune responses and fatty liver generation occurred in both tumour-bearing mice and cancer patients with extrahepatic metastasis. TNF also suppressed the expression of genes encoding the cytochrome P450 enzymes crucial for drug metabolism, thereby impairing drug metabolism in the livers of tumour-bearing mice. Importantly, the livers of pancreatic cancer patients with extrahepatic metastasis also exhibited downregulated cytochrome P450 enzymes. Treatment of mice with tumour-derived EVPs increased chemotoxicity, providing valuable insights into the diminished effectiveness and reduced tolerance to chemotherapy observed in cancer patients, even in the absence of liver metastasis. Notably, the abundant, non-membranous tumour-derived EVP subpopulation first described by the Lyden group in 2018, the exomeres, had a greater impact on promoting fatty liver disease than exosomes, suggesting that exomeres play a major role in dysregulating liver metabolic function.