miR-214-Enriched Extracellular Vesicles Released by Acid-Adapted Melanoma Cells Promote Inflammatory Macrophage-Dependent Tumor Trans-Endothelial Migration

Abstract

The understanding of the molecular mechanisms leading to melanoma dissemination is urgently needed in view of the identification of new targets and the development of innovative strategies to improve patients’ outcomes. Within the complexity of tumor intercellular communications leading to metastatic dissemination, extracellular vesicles (EV) released by tumor cells are central players. Indeed, the ability to travel through the circulatory system conveying oncogenic bioactive molecules even at distant sites makes EV capable of modulating recipient cells to facilitate metastatic dissemination. The dynamic remodeling of the tumor microenvironment might influence, along with a number of other events, tumoral EV release. We observed that, in melanoma, extracellular acidosis increases the release of EV enriched in miR-214, an onco-miRNA involved in melanoma metastasis. Then, miR-214-enriched EV were found to induce a state of macrophage activation, leading to an overproduction of proinflammatory cytokines and nitric oxide. Such an inflammatory microenvironment was able to alter the endothelial cell permeability, thereby facilitating the trans-endothelial migration of melanoma cells, a crucial step in the metastatic cascade. The use of synthetic miR-214 inhibitors and miR-214 overexpression allowed us to demonstrate the key role of miR-214 in the EV-dependent induction of macrophage activation. Overall, our in vitro study reveals that the release of tumor miR-214-enriched EV, potentiated by adapting tumor cells to extracellular acidosis, drives a macrophage-dependent trans-endothelial migration of melanoma cells. This finding points to miR-214 as a potential new therapeutic target to prevent melanoma intravasation.

Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts

“…Extensive literature demonstrates how extracellular lactic acidosis sustains tumor progression by acting either directly on cancer cells, or indirectly, by reprogramming the stromal component within the tumor mass to guarantee cancer cell proliferation and survival even under prohibitive and hostile conditions. Briefly, the acidic TME promotes, on the one hand, the acquisition by cancer cells of high plasticity that renders them extremely adaptable to various scenarios they may encounter [ 10 ]; on the other one, extracellular acidosis is able to induce a pro-tumoral reprogramming in the stromal cells, for instance, by altering the capacity of natural and adaptive immune cells to face with the tumor [ 5 , 7 , 17 ], or by remodeling the vasculature rendering vessels more permeant and subsequently permissive to cancer cell intra/extravasation [ 33 ], or further, by inducing the generation of CAFs with all the pro-tumoral activity they are endowed with [ 12 ]. What is still not known, is the effect that the acidic TME may exert on the adipocyte compartment.…”

The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs

“…The Lactate Colorimetric Assay Kit (BioVision, purchased from Vinci-Biochem, Florence, Italy) was used according to the manufacturer's instructions to measure lactate production in the conditioned media of GC cells, as previously described [18].…”

The extracellular vesicles targeting tumor microenvironment: a promising therapeutic strategy for melanoma

“…A high TAM infiltration often leads to poor clinical outcomes in a great number of tumors, including melanoma (67,83,84). Besides, extracellular acidosis is another crucial aspect of the TME and Andreucci et al (85) observed that the acidic microenvironment stimulated the secretion of melanoma-EVs enriched with miR-214. Then, these EVs tended to induce a proinflammatory activation of macrophages by increasing the expression of COX-2 and the release of inflammatory cytokines, such as IL-1b, IL-6, TNF-a, and NO, so as to establish an inflammatory TME which in turn facilitated the progression of melanoma.…”