Metabolic reprograming of cancer cells by tumor microenvironment

Exosomes are a class of extracellular vesicles ranging in size from 40 to 100 nm, which are secreted by both cancer cells and multiple stromal cells in the tumor microenvironment. Following their secretion, exosomes partake in endocrine, paracrine and autocrine signaling. Internalization of exosomes by tumor cells influences several cellular pathways which alter cancer cell physiology. Tumor-derived exosomes secreted by cancer or stromal cells can also confer anticancer drug-resistant traits upon cancer cells. These exosomes transmit their cargo which includes nucleic acids, proteins, and metabolites to cancer cells or act as a decoy for immunotherapeutic targets. Mass spectroscopy analysis revealed that exosomal delivery of micro-RNAs upregulates glucose and pyrimidine metabolism and increased tri-phosphate-nucleotide levels in cancer cells. This induces reprograming of enzymatic pathways in cancer cells and also competed directly with chemotherapy agents for incorporation into the DNA chain. Depletion of exosomes can reverse some of the detrimental effects on tumor metabolism and restore drug sensitivity to chemotherapeutic treatment.

The ability of exosomes to mediate autocrine and paracrine signaling in target cells, along with their natural structure and low immunogenicity also render them an attractive vehicle for the delivery of anticancer drugs to tumors.