Arming Mesenchymal Stromal/Stem Cells Against Cancer: Has the Time Come?

Abstract

Since mesenchymal stromal/stem cells (MSCs) were discovered, researchers have been drawn to study their peculiar biological features, including their immune privileged status and their capacity to selectively migrate into inflammatory areas, including tumors. These properties make MSCs promising cellular vehicles for the delivery of therapeutic molecules in the clinical setting. In recent decades, the engineering of MSCs into biological vehicles carrying anticancer compounds has been achieved in different ways, including the loading of MSCs with chemotherapeutics or drug functionalized nanoparticles (NPs), genetic modifications to force the production of anticancer proteins, and the use of oncolytic viruses. Recently, it has been demonstrated that wild-type and engineered MSCs can release extracellular vesicles (EVs) that contain therapeutic agents. Despite the enthusiasm for MSCs as cyto-pharmaceutical agents, many challenges, including controlling the fate of MSCs after administration, must still be considered. Preclinical results demonstrated that MSCs accumulate in lung, liver, and spleen, which could prevent their engraftment into tumor sites. For this reason, physical, physiological, and biological methods have been implemented to increase MSC concentration in the target tumors. Currently, there are more than 900 registered clinical trials using MSCs. Only a small fraction of these are investigating MSC-based therapies for cancer, but the number of these clinical trials is expected to increase as technology and our understanding of MSCs improve. This review will summarize MSC-based antitumor therapies to generate an increasing awareness of their potential and limits to accelerate their clinical translation.

Anti-GD2 CAR MSCs against metastatic Ewing's sarcoma

“…The invasive nature of ES is an underlying cause for the failure of standard therapies [46] . The tumour-tropic ability of MSCs offers an alternative approach, in which these cells can be used as vehicles for the delivery of antitumour molecules [13] . MSCs are considered as putative cells of origin for ES and display an active role as progenitors of the tumour-supportive stroma [ 2 , 13 , 47 ].…”

“…Among the many potential strategies for increasing the therapeutic effects of TRAIL, the use of cells that express TRAIL looks promising [11] . MSCs have been identified as suitable vehicles for the delivery of anticancer molecules to tumour sites, including TRAIL [12] , [13] , [14] , [15] , [16] , [17] , [18] .…”

“…However, metastases represent a great challenge in ES patients; therefore, dedicated strategies designed to target MSCs to metastatic sites in ES, particularly the lungs, and to increase the in vivo persistence of MSCs remain necessary. A high level of MSC engraftment in the lung after systemic infusion, combined with novel targeting properties induced by gene modifications, could represent a novel and effective approach to treat ES, even after metastatic dissemination [ 13 , [20] , [21] , [22] , [23] , [24] ].…”

Mesenchymal Stem Cells as a Cornerstone in a Galaxy of Intercellular Signals: Basis for a New Era of Medicine

“…Moreover, research has investigated the strategy of producing MSC genetically manipulated to express specific enzymes, such as cytosine deaminase or herpes simplex virus thymidine kinase, which converts inactive systemically administrated prodrugs, such as fluorouracil and ganciclovir, into active cytotoxic agents, which increase tumor-directed chemotherapy activity minimizing systemic toxicity [ 270 , 271 ]. Other possibilities are to use MSC as carriers of oncolytic viruses that destroy cancer cells [ 272 , 273 ], or to carry out genetic modifications of MSC to express anticancer bioactive molecules [ 274 ].…”

Time-Dependent Internalization of S100B by Mesenchymal Stem Cells via the Pathways of Clathrin- and Lipid Raft-Mediated Endocytosis

“…Gliomas are malignant tumors with poor prognosis and a short median survival time and constitute the majority of neoplasms in the central nervous system ( Reifenberger et al, 2017 ). Mesenchymal stem cells (MSCs) are characterized by low immunogenicity and tumor tissue homing and are increasingly used as promising carriers in stem cell-based therapy for gliomas ( Smith et al, 2015 ; Li et al, 2019 ; Golinelli et al, 2020 ). However, malignant transformation of MSCs of both human and murine origin has been reported in many studies ( Sánchez et al, 2014 ; Cui et al, 2019 ; Dai et al, 2020 ), and a patient with ischemic stroke developed a primitive tumor similar to malignant glioma after receiving stem cell therapy ( Berkowitz et al, 2016 ).…”