Can nanomedicines kill cancer stem cells?☆
Graphical abstract
Introduction
Tumors are heterogeneous tissues with abundant phenotypically and functionally distinct cell subpopulations each having different capacities to grow, differentiate, develop drug resistance and form metastases [1]. In 1977, Hamburger and Salmon have shown that cancer cells derived from multiple myeloma patients can be cloned in soft agar at a frequency of 1 clone for from 100 to 100,000 cells and hereby suggested that only a small portion of tumor cells are tumorigenic [2]. These rare cells are now sometimes called “cancer stem cells” (CSCs) as they share many characteristics with normal stem cells, such as self-renewal and differentiation. A growing body of evidence suggests that CSCs can play a major role in cancer initiation, progression, resistance, recurrence, and metastasis in selected cancers [1], [3], [4], [5]. CSCs are intrinsically drug resistant and often display same phenotypes as multidrug resistant (MDR) cells including expression of drug efflux transporters [6], activation of anti-apoptotic signaling pathways [7], [8], and reprogramming of metabolic processes [5]. Notably, treatment with most commonly used chemotherapeutic drugs often results in an increase of the CSCs fraction in the tumor, making it more likely that these cells survive and spread to distant sites (Table 1). Tumor relapses are often observed after the treatment with those chemotherapies, which kill only the bulk of the more sensitive tumor cells, while allowing more resistant CSCs to evade. As a result, CSCs can even constitute the greatest fraction of the remaining/recurrent tumors (Fig. 1).
Based on these considerations chemotherapeutic approaches targeting CSCs may be more successful in treating cancer. However, tumors display plasticity and therefore elimination and targeting of CSCs without killing other cancer cells (non-CSCs) may not result in the complete cure. It has been shown that CSC phenotype can be “dynamic” as under certain conditions non-CSCs tumor cells can reverse their phenotype and become CSCs. Therefore successful therapy must eliminate both the bulk tumor cells and rare CSCs (Fig. 1). Overall, further preclinical and clinical studies are needed to definitively assess how CSCs respond to therapy. The design of these studies should take into account diverse biomarkers of the CSCs phenotypes and parameters of the CSCs function to provide robust clinical data on the role of such cells in the disease progression and therapy.
Developing simple, effective and robust therapeutic strategies against CSCs is needed to increase the efficacy of cancer therapy. Although some anti-cancer agents proposed recently can efficiently kill CSCs, similar to other anticancer drugs, most such agents have limitations upon translation into clinical studies, such as off-target effect, poor water solubility, short circulation time, inconsistent stability, and unfavorable biodistribution. Nanotechnology has shown significant promise in development of drugs and drug delivery systems that can overcome such limitations and address urgent needs to improve efficacy of diagnosis and therapy of various diseases [15], [16]. There is an increasing number of nanoparticle-based carriers used in drug delivery systems (“nanocarriers”), such as polymeric micelles [17], [18], [19], [20], liposomes [21], [22], [23], dendrimers [24], [25], nanoemulsions [26], gold [27], [28] or metal nanoparticles [29], etc. (Fig. 2). Some nanocarrier-based therapeutic products (also termed “nanomedicines”) are already on the market for treatment of cancer, lipid regulation, multiple sclerosis, viral and fungal infections [30], [31] while others undergo clinical and preclinical evaluation. Specifically, in the field of cancer therapy, nanotechnology is applied to improve bioavailability and decrease systemic toxicity of anti-cancer agents [32], [33]. Successful examples of clinically approved nanomedicines for cancer therapy include liposomal doxorubicin Doxil®, albumin-bound paclitaxel Abraxane®, PEG-l-Asparaginase Oncaspar® and others. Doxil®, the first polyethylene glycol (PEG) modified (“PEGylated”) liposomal nanomedicine approved by the Food and Drug Administration (FDA) exhibits more than 100 times longer blood circulation half-life than that of free drug and decreases the risk of the cardio toxicity, which is a major side effect of the free drug [34], [35], [36].
In the past two decades, examples of nanotechnology-based approaches to tackle the CSCs problem have been accumulating [37], [38]. In general, nanoparticles were applied to target CSCs in three broad and overlapping areas: 1) as “beacons” to label CSCs by their biological signatures [39], [40]; 2) as nanocarriers to deliver “non-druggable” (for example insoluble or unstable) anti-CSCs agents to CSCs [41], [42] and 3) as therapeutic modality on its own to wipe out CSCs without harming normal, healthy stem cells [43], [44], [45]. Recently, some groups have successfully applied nanomedicines to target the CSCs to eliminate the tumor and prevent its recurrence. However, the challenges of targeting CSCs by nanomedicines still exist and leave plenty of room for developing future therapies.
CSCs exhibit specific phenotypes that are different from other tumor cells, and can be identified by the overexpression of certain biomarkers, such as, CD133 +, CD44 + CD24 −, aldehyde dehydrogenase (ALDH +) and many others. High expression levels of these markers are associated with poor prognosis in patients [46], [47]. However, using these markers to target anti-cancer agents to CSCs is associated with several pitfalls. First, the markers differ from one type of cancer to another and there is no universal marker that can be used for all cancers [48], [49]. Second, multiple pools of biologically distinct CSCs can exist within one tumor as was shown both for acute myeloid leukemia [50], [51], as well as solid tumors [52]. Finally, CSCs share the markers' expression profiles with normal stem cells and therefore, there is a risk of affecting normal stem cells when targeting chemotherapeutic drug to CSCs. Moreover, since the CSCs phenotype is not a stable trait killing only the CSCs may not be sufficient for eliminating the tumors.
Thus, development of successful therapeutic modalities that can kill CSCs will require a comprehensive understanding of the characteristics of CSCs and relevant mechanisms (Fig. 1) as well as applying modern technologies for drug delivery. In this review we will summarize particular biological processes that are related to CSCs, and overview specific nanomedicine-based therapeutic approaches to ascertain the key question: can nanomedicines make difference in killing CSCs?
Section snippets
CSCs vs. clonal evolution hypothesis
There is an overwhelming body of evidence suggesting that similar to normal tissues, tumors are comprised of heterogeneous cell populations with varying metastatic potential [53], [54], [55], angiogenic potential [56] and drug resistance [57], [58]. M. Gerlinger and colleagues studied the tumor heterogeneity from multiple regions within a single patient's tumor by exome sequencing, chromosome aberration analysis, and ploidy profiling. They observed that about 63–69% of the mutations found in
Nanomedicine-based therapies against CSCs
Despite being noted as one of the most important developments in the treatment of tumor relapse [191], nanocarrier-mediated drug delivery systems to overcome tumor drug resistance leave plenty of room for improvements, especially for targeting drug resistant CSCs. Nanomedicines offer a fundamental advantage over current therapeutic agents that are limited in use due to problems of degradation, solubility, rapid clearance from the body and poor cellular uptake. Nanomedicines commonly display
Generalizations and future directions
The overview of the current state of the art suggests that there is a clear rationale and promise in application of the nanomedicines and drug delivery technologies to develop novel anti-CSCs therapies. Among all different kinds of drug delivery systems, polymer-based nanomaterials and nanocarriers are of special interest. They include polymeric micelles, polyelectrolyte complexes with DNA, RNA, proteins and peptides, soft polymer nanogels, solid polymer nanoparticles, polymer coated inorganic
Conclusions
Numerous drugs and treatment regimens have emerged since 1950s when chemotherapy was first applied to treat cancer patients. However in many cancers the treatment efficiencies of chemotherapy have rapidly leveled off. The current success in fight against cancer has been mostly accounted for the better screening and early detection methods rather to more effective treatments available. In this review we summarized the current views on CSCs models and described attempts to develop anti-CSCs
Acknowledgments
This work was supported in part by the grants from the National Institutes of Health 2RO1 CA89225, UO1 CA151806, an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant P20GM103480, the China Scholarship Council PhD Scholarship (to YZ) as well as The Carolina Partnership, a strategic partnership between the UNC Eshelman School of Pharmacy and The University Cancer Research Fund through the Lineberger
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Nanotechnology and drug resistance”.
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Authors contributed equally to this work.