Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood–Brain Barrier

Abstract

Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood–brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis.

Non-coding RNAs: the extensive and interactive regulators of the blood-brain barrier permeability

“…In contrast, the astrocyte-derived protective factors include Apolipoprotein E, Sonic hedgehog, Angiopoietin-1, Glial-derived neurotrophic factor, Retinoic acid, and Insulin-like growth factor-1. 108,109 Meanwhile, pericytes are also recognized as key players in BBB genesis and vessel stabilization.…”

Tumour brain: Pretreatment cognitive and affective disorders caused by peripheral cancers

“…In response to peripheral tumour growth, BBB integrity is thought to be corrupted via the release of proinflammatory cytokines (e.g., TNFα and IL-1β) and matrix metalloproteinases (MMPs) (Wardill et al, 2016). Increased fibrin deposition, immune cell infiltration and the transcytosis of tumour-associated extracellular vesicles (EVs) could cause further tight junction and basal membrane disruption (Koh et al, 2020;Morad et al, 2020;Demers et al, 2018;Burfeind et al, 2020a). However, the exact impact of tumour-induced disruption of BBB integrity on cognitive and affective brain function requires further elucidation.…”

“…Using a mouse model of triple-negative MDA-MB-231 cancer cells, the tumour-derived EVs were shown to downregulate the expression of the late endosomal marker Ras-related protein 7 (Rab7) in brain endothelial cells, demonstrating the ability of tumour-derived EVs to compromise BBB integrity and enhance EV-mediated communication between the systemic circulation and CNS parenchyma (Morad et al, 2019). In a subsequent study, the group worked on elucidating the functional consequences of tumour-derived EV transport across the BBB (Morad et al, 2020).…”

The role of extracellular vesicles in the physiological and pathological regulation of the blood–brain barrier

“…Cancer‐derived EVs have been unequivocally linked to the development and progression of primary and metastatic brain tumors 26–28 providing further evidence in support of EV interactions with the BBB 1,11,25,29 …”

“…Receptor‐based and adsorptive transcytosis are the two currently known routes through which complex circulating nanoparticles are transported through the BBB to the brain. Given the critical role that EV trafficking across the BBB plays during such significant pathological processes such as primary and metastatic brain tumors and some neurodegenerative diseases, 11,16,17,25 understanding the transcytosis of circulating EVs and their role in brain homeostasis remains an important research opportunity.…”