Tumor-derived exosomes (TEX) are important intercellular messengers that contribute to tumorigenesis and metastasis through a variety of mechanisms such as immunosuppression and metabolic reprogramming that generate a pre-metastatic niche favorable to tumor progression. Researchers at the Roswell Park Comprehensive Cancer Center have contributed further to the understanding of the miRNA payloads in TEX by demonstrating that human melanoma-derived exosome (HMEX) associated miRNAs contribute to the metabolic reprogramming of normal stroma. This mini-review highlights the role of TEX in the tumor microenvironment (TME) and the hypothesis that exosomes may also generate a host-tumor “macroenvironment” beyond the TME through their miRNA and protein payloads, so to speak “fertilizing the soil for cancer seeding.”
Roles of cancer-derived exosomes in generation of
tumor “microenvironment” and “macroenvironment.”
Cancer-derived exosomes participate in the generation of a tumor microenvironment (TME) through paracrine signaling and in an endocrine pathway that can influence other parts of the body, referred to as a tumor macroevironment (TMaE). Here, we use a human melanoma model to demonstrate the mechanisms in which human melanoma-derived exosomes (HMEX) use in developing a pre-metastatic niche. In the immediate TME, HMEX are released from the primary tumor to convey immunosuppression. (A) HMEX contributes to the transition of normal fibroblasts to cancer-associated fibroblasts (CAFs). (B) They also suppress monocyte maturation and induce a monocytic myeloidsuppressor cell phenotype. (C) Moreover, they display ligands (ex. programmed death-ligand 1 (PD-L1)), that inactivate T-cells through direct binding. (D) We also hypothesize that HMEX promote a pre-metastatic niche at a distant site (ex. liver) through bloodstream and lymphatic drainage to promote vascular permeability, immunosuppression and metastasis. (E-G) There, HMEX act on normal stroma by translocation of growth factor receptors (ex. EGFR) and metabolic reprogramming using microRNA (miRNA) payloads (ex. miR-155, miR-210), exhibiting a reverse Warburg effect and promoting extracellular acidification that contribute to the anergy of CD8+ T cells. In conclusion, HMEX not only create a favorable immediate environment but a macroenvironment to facilitate the metastatic process.