A Journey on Extracellular Vesicles for Matrix Metalloproteinases: A Mechanistic Perspective

Abstract

Matrix metalloproteinases (MMPs) are key players in matrix remodeling and their function has been particularly investigated in cancer biology. Indeed, through extracellular matrix (ECM) degradation and shedding of diverse cell surface macromolecules, they are implicated in different steps of tumor development, from local expansion by growth to tissue invasion and metastasis. Interestingly, MMPs are also components of extracellular vesicles (EVs). EVs are membrane-limited organelles that cells release in their extracellular environment. These “secreted” vesicles are now well accepted players in cell-to-cell communication. EVs have received a lot of interest in recent years as they are also envisioned as sources of biomarkers and as potentially outperforming vehicles for the delivery of therapeutics. Molecular machineries governing EV biogenesis, cargo loading and delivery to recipient cells are complex and still under intense investigation. In this review, we will summarize the state of the art of our knowledge about the molecular mechanisms implicated in MMP trafficking and secretion. We focus on MT1-MMP, a major effector of invasive cell behavior. We will also discuss how this knowledge is of interest for a better understanding of EV-loading of MMPs. Such knowledge might be of use to engineer novel strategies for cancer treatment. A better understanding of these mechanisms could also be used to design more efficient EV-based therapies.

Extracellular Vesicles: Biological Packages That Modulate Tumor Cell Invasion

“…Extracellular vesicles are known to contain proteases that are involved in proteolytic degradation of the extracellular matrix. Membrane type 1-matrix metalloproteinase (MT1-MMP) has been found as bioactive cargo in several classes of EVs [23,24]. Substrate targets of MT1-MMP include aggrecan, collagen types I, II, and III, fibronectin, gelatin, laminin-1 and -5, and vitronectin [24,25].…”

Characterizing the extracellular vesicle proteomic landscape of the human airway using in vitro organotypic multi-cellular models

“…A growing number of studies have also detected metalloproteases and integrins in EVs. 58 , 59 , 60 , 61 , 62 , 63 Metalloproteases are thought to contribute to EV biogenesis, modification, and EV uptake by recipient cells through the remodeling of the extracellular matrix (ECM) and the modification of EV and cell surface receptors. 62 , 63 Furthermore, EV-bound integrins are involved in adhesion to the ECM and EV uptake by recipient cells.…”

“… 58 , 59 , 60 , 61 , 62 , 63 Metalloproteases are thought to contribute to EV biogenesis, modification, and EV uptake by recipient cells through the remodeling of the extracellular matrix (ECM) and the modification of EV and cell surface receptors. 62 , 63 Furthermore, EV-bound integrins are involved in adhesion to the ECM and EV uptake by recipient cells. 60 , 61 While studies have shown these proteins’ involvement in EV biogenesis, migration through the ECM, and the homing of EVs to specific cell types in disease states such as cancer and kidney disease, these mechanisms and/or resulting biological consequences in the airway are still relatively unclear.…”

An integrative analysis reveals the prognostic and immunological role of TIMP gene family in pan-cancer

“…The process of metastasis involves the separation of malignant cells from the primary tumor, local invasion, angiogenesis, and the spread in the circulatory or lymphatic systems, through which they can transfer to distant organs [6]. When cancer spreads, the tissue matrix changes, creating an environment that fosters tumor development, migration, invasion, angiogenesis, and immune suppression [7,8]. MMPs, commonly referred to as matrix metalloproteinase, are present in the extracellular environment of cells and can degrade both matrix and non-matrix proteins.…”