A Review of Exosomes and their Role in The Tumor Microenvironment and Host-Tumor "Macroenvironment"

Abstract

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. Our lab has 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."

Keywords: Exosomes; Fibroblasts; Immunosuppression; Metabolic reprogramming; Tumor macroenvironment; Tumor microenvironment; miRNA.

Figure 1:. 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.