Mesenchymal stem cells engineered for cancer therapy

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Abstract

Recent pre-clinical and clinical studies have shown that stem cell-based therapies hold tremendous promise for the treatment of human disease. Mesenchymal stem cells (MSC) are emerging as promising anti-cancer agents which have an enormous potential to be utilized to treat a number of different cancer types. MSC have inherent tumor-trophic migratory properties, which allows them to serve as vehicles for delivering effective, targeted therapy to isolated tumors and metastatic disease. MSC have been readily engineered to express anti-proliferative, pro-apoptotic, anti-angiogenic agents that specifically target different cancer types. Many of these strategies have been validated in a wide range of studies evaluating treatment feasibility or efficacy, as well as establishing methods for real-time monitoring of stem cell migration in vivo for optimal therapy surveillance and accelerated development. This review aims to provide an in depth status of current MSC-based cancer therapies, as well as the prospects for their clinical translation.

Introduction

Malignant disease is estimated to account for 1 in each 4 human deaths over all age groups in the United States in 2007 [1]. In recent years, the early detection of some cancer types combined with the advent of cancer specific drugs has increased median survival in cancer patients. However, the short half life of a number of cancer specific drugs, their limited delivery to some tumor types and their detrimental effects on vital non-tumor bodily tissues and functions are major hindrances in precluding cure. A number of adult stem or progenitors cells have been isolated from different tissues including brain, heart, and kidney and have emerged as attractive candidates to treat a wide range of diseases (reviewed in [2], [3]). The ability of MSC to develop into various cell types, and the ease with which they can be expanded in culture, have led to a great deal of interest in their use as therapeutic agents to treat a wide range of diseases. They can be isolated from adult human tissues, have the capability for self-renewal and differentiation into mesenchymal lineages-osteocytic, chondrocytic, and adipogenic. They can be expanded and manipulated in vitro, and subsequently re-grafted. Following re-implantation, they have been found to suppress the immune system, reintegrate into tissue architecture and give rise to progeny consisting of both stem cells and lineage restricted daughter cell types [2]. Most importantly, MSC exhibit potent pathotropic migratory properties, rendering them attractive for use as targeted delivery vectors in tumor therapy [2], [3]. Besides offering high site-specificity, this treatment modality also efficiently remedies potential problems sprouting from limited biological drug half-life as drug secretion can be engineered to be continuous. This review sheds light on the utilization of engineered MSC in cancer therapy and their hopes and hurdles in translating MSC based therapies to clinics in cancer patients.

Section snippets

MSC: sources

Stem cells are the natural sources of embriogenetic tissue generation and continuous regeneration throughout adult life. Adult stem cells have been studied extensively and are already a successful source of FDA-approved treatments for a number of diseases including Parkinson's disease and juvenile diabetes [4]. MSC have been successfully isolated from a number of organs including brain, liver, kidney, lung, bone marrow, muscle, thymus, pancreas, skin, adipose tissue, fetal tissues, umbilical

MSC for tumor therapy

The unmodified MSC have been shown to have anti-tumor effects both in vitro and in different mouse models of cancer. This is attributed to the factors released by MSCs that have antitumor properties reducing the proliferation of glioma, melanoma, lung cancer, hepatoma, and breast cancer cells [33], [34], [35], [36]. Human mesenchymal stem cells (MSCs) injected intravenously (i.v.) in a mouse model of Kaposi's sarcoma were shown to home to sites of tumorigenesis and potently inhibit tumor growth

Synergistic approaches utilizing MSC based therapeutics with other anti-tumor agents

Given the heterogeneity of tumors in general, it is unlikely that any one effective strategy will provide a satisfactory treatment regimen for tumors. The advent of molecular theragnostics and personalized medicine might largely remedy the differences in nature and therapeutic resistance between different tumors [2], [90], but cannot provide adequate answers to the existence of profound intratumoral heterogeneity, as is observed, for instance, in gliomas [91]. A realist approach would be to

In vivo imaging of MSC fate, anti-tumor agent pharmacokinetics and therapeutic efficacy

The clinical translation of MSC based therapies will depend on how successfully the robust surveillance systems are designed to simultaneously monitor the long term fate of MSC, the pharmacokinetics of MSC delivered therapeutics and ultimately the therapeutic efficacy of MSC in vivo. Several strategies can be pursued to visualize stem cell behavior in vivo.

Prospects and caveats on the way to the clinics

The ability of MSCs to preferentially migrate towards local and disseminated malignant disease, interact with different tissue environments in addition to their easy availability, non immunogenic nature, relative ease of manipulation in vitro without requiring immortalization presents them as the most attractive candidates for cell based therapies in humans. The clinical translation of umbilical cord blood derived MSC will be limited by their unreliable and often low isolation efficiency and

Acknowledgments

This work was supported in part by National Institutes of Health (CA138922-01A2; KS), American Cancer Society (KS) and James McDonnel Foundation (KS).

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Therapeutic Strategies for Controlling Metastasis and Recurrence of Cancers; Contribution of Drug Delivery Technologies”.

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