Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications

Abstract

Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.

IRE1a-Induced FilaminA Phosphorylation Enhances Migration of Mesenchymal Stem Cells Derived from Multiple Myeloma Patients

“…In virtue of their cancer-specific homing potential, HD-BMMSCs can be applied as an advanced cell therapy product potentially counteracting MM progression through the modification of the cancer microenvironment. To achieve a therapeutically relevant medicinal product, ex vivo modifications of BMM-SCs implementing their migration capacity are required [36]. Here, we showed that, in MM-BMMSCs, IRE1a can contribute to enhanced cell migration by binding active FLNA: such paradigm can be transferred to HD-BMMSCs.…”

Mesenchymal Stromal Cell-Based Targeted Therapy Pancreatic Cancer: Progress and Challenges

“…MSCs express various chemokines and cell adhesion molecules that coordinate the mobilization of MSCs to the damage locations [ 15 , 60 , 61 , 62 , 63 , 64 ]. Recent research has found that the tumor-homing capacity of MSCs could be regulated by the cooperation of cytokines, chemokines, and adhesion molecules [ 15 , 24 , 65 , 66 , 67 , 68 ].…”

Stem Cells for Cancer Therapy: Translating the Uncertainties and Possibilities of Stem Cell Properties into Opportunities for Effective Cancer Therapy

“…As such, it is evident that for MSC-based cancer therapy to remain applicable and relevant as a mainstream cancer therapy, a more homogenous form of MSCs with specific tumor-homing activity and more efficient drug delivery strategies to cancer cells are needed. [ 66 , 67 ] Although much is still unknown about the mechanisms by which exosomes and their miRNA interact with tumors, the advancement of gene engineering techniques provides opportunities to further develop these nano-size vesicles with improved targeting specificity for the delivery of anti-oncomirs [ 68 ]. For instance, exosomes have been shown to possess homing capabilities similar to that of MSC from which they were derived, and genetic modifications of membrane proteins on the exosomal surface could enhance its tumor targeting properties allowing the interaction of anti-oncomirs to be delivered in a more targeted manner [ 69 ].…”