|Year : 2018 | Volume
| Issue : 7 | Page : 1469-1475
Therapeutic approaches targeting cancer stem cells
Yunzhi Pan1, Sai Ma1, Kaiyue Cao2, Sufang Zhou3, Aiqin Zhao3, Ming Li1, Feng Qian1, Chuanwu Zhu1
1 The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, China
2 Tianjin First Center Hospital, Tianjin, China
3 The People's Hospital of SND, Suzhou, China
|Date of Web Publication||19-Dec-2018|
The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215007
Source of Support: None, Conflict of Interest: None
Increasing studies have demonstrated that most tumors consisted a subpopulation of cells with stem cell properties, known as cancer stem cells (CSCs). Accumulating evidence indicated that CSCs may be critical driving force for several types of cancer. Hence, it was necessary to develop therapeutic approaches specifically targeting CSCs. In this review, first, the biological properties of CSCs were introduced, including the self-renewal and differentiation, high tumorigenesis and invasiveness, resistance to chemotherapy and radiotherapy, genetic and epigenetic variations. Meanwhile, CSCs-targeted therapeutic strategies were summarized, including targeting cell surface markers, signaling pathways, CSC niches, differentiation therapy, and drug resistance for CSCs. Furthermore, clinical trials on anti-CSCs therapies supported the efficacy of these therapies, as well as their combination with conventional chemotherapy and radiotherapy. CSCs could be significantly eradicated, eventually resulting in inhibited tumor growth, metastasis, and recurrence. Thus, selectively targeting CSCs with various agents may be a novel and promising therapeutic strategy against cancer.
Keywords: Anti-cancer stem cells therapy, biological properties, cancer stem cells
|How to cite this article:|
Pan Y, Ma S, Cao K, Zhou S, Zhao A, Li M, Qian F, Zhu C. Therapeutic approaches targeting cancer stem cells. J Can Res Ther 2018;14:1469-75
| > Introduction|| |
In the past decades, the anticancer treatment has made considerable progress, but tumors remained refractory mainly because of recurrence or drug resistance. Conventional tumor therapies, including chemotherapy and radiotherapy, mainly aimed to decrease the tumor burden thus making limited efficacy in fighting cancers. Increasing evidence suggested that tumors were composed of phenotypically and functionally diverse populations of neoplastic cells. Furthermore, of which, the cell subpopulation with stem cell properties – cancer stem cells (CSCs) were closely related to cancer development, metastasis, and resistance to therapy.,, Hence, CSCs have been considered as the potential target or drug receptors in the treatment of malignancy.
The CSCs theory was initially proposed by Moore et al. in 1973. In a study on acute myeloid leukemia, CSCs were first identified. According to the hypothesis, CSCs have been a small proportion of cancer cells with powerful tumorigenesis ability, self-renewal capacity, as well as chemotherapy and radiotherapy resistance. In addition, different studies demonstrated that CSCs were successfully isolated from a multiple of solid tumors including breast, colon, prostate, and brain cancers [Table 1]. Currently, global researchers have made great efforts to understand biological properties of CSCs and develop correspondingly therapeutic approaches targeting CSCs.
|Table 1: Markers used for the identification of cancer stem cells in different cancers|
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| > Biological Properties of Cancer Stem Cells|| |
Clarifying biological properties of CSCs would bring tremendous value for exploring targeted therapies. Based on numerous studies, there were several characteristics, which may be significant to CSCs-targeted therapeutic strategies.
Self-renewal and differentiation capacity
Like normal stem cells, CSCs showed the ability of self-renew. However, unlike normal stem cells, CSCs would be strictly influenced by both internal and external factors while the balance could not be maintained, leading to hyperproliferation and even metastasis.
The differentiation potential was another important property of CSCs both in vitro and in vivo. To analyze the differentiation features of CSCs, a series of studies demonstrated that CSCs showed phenotypic characteristics or corresponding markers. For example, liver CSCs could differentiate into cancer cells containing alpha-fetoprotein, albumin, CK8, CK18, CK7, and other markers.
High tumorigenesis and invasiveness
One of the most distinctive characters of CSCs was the high tumorigenesis and invasiveness. Reportedly, injection of as few as 100 CD133 + brain CSCs in nonobese diabetic, severe combined immunodeficient mouse would produce a tumor that could be serially transplanted, whereas injection of 105 CD133-cells engrafted without causing a tumor. As the most common malignancy in women, breast tumors were composed of phenotypically diverse populations of breast cancer cells. The tumorigenic cells as CD44 (+) CD24 (−/low) Lineage (−) were identified and successfully isolated. The tumors could be formed in mice with as few as 100 cells with this phenotype, whereas it failed to form tumor with tens of thousands of cells with alternate phenotypes. The capacity of tumorigenesis was different in other CSCs [Table 1].
Resistance to chemotherapy and radiotherapy
Currently, acquired multi-drug resistance almost invariably occurred in advanced and metastatic solid tumors, leading to disease progression and death. Increasing studies demonstrated that many cancers were resistant to chemotherapy and radiotherapy, and the existence of proliferatively quiescent CSCs would be one reason. Molecular mechanisms on chemotherapeutic and radiotherapy resistance included high expression of ABC transporters, enhanced DNA damage response, a hypoxic niche, apoptosis evasion, and so on.,
Genetic and epigenetic variations
Genetic and epigenetic factors of CSCs were complicated. For example, loss-of-function mutations of adenomatous polyposis coli (APC) and gain-of-function mutations of K-Ras were both common abnormalities in colon cancer. CSCs would be activated with K-Ras mutations, contributing to colorectal tumorigenesis and metastasis in CRC cells harboring APC mutations.
Taking above-mentioned factors into consideration, there were several characters of CSCs which raised the tremendous potential for therapeutic approaches targeting CSCs. Comparison of biological properties between CSCs and normal stem cells has been summarized [Table 2].
|Table 2: Biological properties of cancer stem cells and normal stem cells|
Click here to view
| > Targeted Therapies Against Cancer Stem Cells|| |
In the past decades, numerous therapeutic strategies for eradicating CSCs have been proposed [Table 3]. In general, the core idea could be envisaged: Eliminating the CSCs themselves by either killing or differentiating them and disrupting niche signaling.
Therapeutic approaches targeting cell surface markers
Various cell surface and transmembrane proteins were expressed by CSCs, including CD44, CD47, CD123, EpCAM (CD326), CD133, IGF receptor I, and proteins in the Notch and Wnt signaling pathways. Monoclonal antibodies (mAbs) against above-mentioned proteins have been demonstrated to exhibit significant anti-CSCs activity in mice with human cancer xenograft or in clinical studies.
Notably, H90, a mouse IgG1 mAb against human CD44, has been the first mAb targeting CSCs. H90 inhibited proliferation, induced terminal differentiation, and mediated apoptosis in human myeloid leukemia cell lines., Other anti-CD44 mAbs such as P245, H4C4, GV5, and RO5429083 might show pronounced effects on eliminating CSCs in some cancers.,,, An anti-CD133 mAb-induced specific, dose-dependent cytotoxic effects in CD133(+)-glioblastoma cells. BsAb was a chemical heteroconjugation of an anti-human-CD3 mouse IgG2a mAb (OKT3) and an anti-human CD133 mouse IgG1 mAb. BsAb was able to effectively and specifically kill human CD133 (high) pancreatic (SW1990) and CD133 (high) hepatic (Hep3B) cancer cells in co-culture experiments in vitro. Encouraging data have revealed that mAbs against DLL4 were effective in eliminating CSCs. From the above, it was possible that therapeutic approaches targeting cell surface markers appeared to be a promising strategy for eliminating CSCs in future cancer treatment.
Therapeutic approaches targeting signaling pathways
The strongest evidence to date were that the cell signaling pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin played important roles in cancer development. In most cases, inappropriate activation of signaling pathways stimulated proliferation, restricted differentiation, and prevented apoptosis. Hence, blockade of aberrant signaling pathways may provide a further avenue for the cancer therapeutic strategy targeting CSCs.
The notch pathway
Notch pathway was associated with CSCs in various cancers. CSCs in the breast cancer, medulloblastoma, and glioma, could be eliminated with inhibitors of γ-secretase, the protease required for Notch cleavage and activation, such as Gamma-secretase inhibitors (GSIs). However, GSIs were relatively nonselective drug and the Notch inhibition in intestinal stem cells were associated with dose-limiting gut toxicity (secretory diarrhea). Highly specialized mAbs that specifically antagonized Notch ligands and receptors provided single-target specificity. With anti-Delta-like 4 ligand (DLL4, a membrane-associated Notch ligand) antibody, either alone or in combination with the chemotherapeutic agent irinotecan, the frequency of CSCs (Ep-CAM+/CD44+/CD166+) could be reduced. SiRNA targeted to Notch4 rather than Notch1 was more effective in suppressing breast cancer recurrence.
The hedgehog pathway
Activation of the Hh pathway was involved in the maintenance and tumorigenesis of CSCs in many tumors including multiple myeloma, myeloid leukemia, colorectal cancer, gastric cancer, and glioma., Hence, several targeting therapies were developed on this basis. Cyclopamine, an antagonist of the Hh co-receptor Smoothened (SMO), could decrease CSCs proportion, or even eliminate CSCs and induce tumor regression in some cancer types, such as pancreatic cancer and brain cancer., In addition, studies demonstrated that GDC-0449 (also known as Vismodegib), an orally active SMO antagonist, presented bioavailability in basal cell carcinoma, and brain cancer. In the case of pancreatic tumor xenografts, the proportion of ALDHbri CSCs could be reduced with IPI269609, the SMO inhibitor.
The combined Hh pathway inhibitor-targeted treatments and other therapeutic strategies have attracted general attention., For example, a combination with cyclopamine and gemcitabine or a triple combination with cyclopamine, rapamycin, and chemotherapy could effectively diminish the number of pancreatic CSCs to be virtually undetectable levels in vitro and in vivo.,
The Wnt/β-catenin pathway
Aberrant activation of the Wnt/β-catenin pathway in CSCs was closely associated with tumorigenesis in many tissues. An antibody specific to frizzled7, a Wnt receptor, depleted clonogenicity, and tumorigenicity in tumors. Dickkopf-1 (Dkk1), a major secreted Wnt signaling antagonist, bound to the low-density lipoprotein receptor-related protein-6 (LRP6), an essential co-receptor for canonical Wnt signaling., Recently, Salinomycin, an antibiotic potassium ionophore, has been reported to inhibit breast CSCs and target the Wnt pathway by blocking the phosphorylation of LRP6.
Therapeutic approaches targeting cancer stem cells niches
Various factors involved in the tumor microenvironment including cancer-associated fibroblasts, endothelial cells, angiogenic vascular cells, cancer cells, and inflammatory cells. All these factors have made a direct influence on CSCs properties. The humanized mAb (Sibrotuzumab) have provided good clinical benefits for non-small cell lung cancer, which blocked the activity of fibroblast activation protein α expressed by carcinoma-associated fibroblasts. Meanwhile, anti-angiogenic therapies have also been studied in preclinical and clinical trials, such as anti-vascular endothelial growth factor antibodies and tyrosine kinase inhibitors., The application of anti-inflammatory drugs in cancer prevention and treatment was also supported with clinical and experimental data. Thus, the specialized microenvironment seemed to be a crucial target for CSCs elimination.
Increasing cases suggested that tumor growth would be unsustainable if CSCs were induced to differentiate. All-trans retinoic acid (ATRA), a natural compound derived from vitamin A, has been considered as a potent differentiating agent. ATRA was extensively applied in eliminating CSCs from glioblastomas, and head and neck cancer., Oncostatin M, an interleukin 6-related cytokine, was reported to induce the differentiation of liver CSCs, from hepatoblasts to hepatocytes. Bone morphogenetic proteins (BMPs), among which BMP7 elicited the strongest effects, triggered differentiation and reduced CSCs in human glioblastomas.
Therapeutic approaches targeting overcoming drug resistance in cancer stem cells
Currently, many researchers have strived to propose therapeutic approaches targeting drug resistance in CSCs. Verapamil, a classical P-glycoprotein inhibitor, was able to enhance the chemo-sensitivity of CSCs in squamous cell cancers. Difluorinated-curcumin, a novel analog of the dietary ingredient of Curcumin, could be an effective treatment strategy for preventing chemo-resistant CSCs. These effects were associated with the down-regulation of ABCG2. In addition, the sensitivity of traditional anti-cancer treatments could be enhanced with the down-regulation of ALDH in some cancer types, such as liver cancer and breast cancer.
In addition to the above-mentioned targeting therapeutics, there were other therapeutic strategies proposed in recent years such as metformin, natural compounds, telomerase inhibitors, oncolytic viruses, MicroRNA, and interferon. In a study from Hirsch et al., low doses of metformin inhibited cellular transformation and selectively killed CSCs in four types of breast cancer with genetic diversity. Imetelstat, as a telomerase inhibition, has been applied in clinical treatment for breast cancer, non-small cell lung cancer, multiple myeloma, and chronic lymphocytic leukemia. Some natural compounds including sulforaphane, epigallocatechin gallate, quercetin, curcumin, berberine, gamma-tocotrienols (gamma-T3), and parthenolide, showed biological activities in CSCs-targeted anti-tumor therapies.,
| > Clinical Research|| |
As described above, worldwide researchers have devoted to exploring new anti-CSCs drug, although there are many challenges and difficulties to overcome. According to ClincalTrials.gov., numerous anti-CSCs compounds have been already completed different phases of testing and successfully entered human clinic trials [Table 4].
| > Conclusion and Future Expectations|| |
Although there has been still controversy regarding the origin and certain features of CSCs, it was undoubted that CSCs showed stem-cell characteristics and were resistant to chemotherapy and radiotherapy. Hence, therapies targeting CSCs bring new hopes for future anti-tumor treatment.
Based on the current knowledge, CSCs-targeted therapies mainly aimed at controlling cell proliferation and growth, unable to eradicate the tumor cell mass. Chemotherapy and radiotherapy may bring better therapeutic response on the tumor bulk. Hence, it was noted that targeting any single molecular pathway or cell type could not realize efficient anticancer efficacy, neither avoiding the acquisition of resistance to treatment. A combination of classical chemotherapy and radiotherapy with novel therapies targeting CSCs may exert better therapeutic effects than that of single therapy.
Clinical and experimental data demonstrated that cancer therapy was effective only when CSCs could be completely eradicated. Unfortunately, the currently reported innovative therapies were not highly specific for CSCs. One potential reason may be that the differences among various cell populations in tumors were difficult to find, and there were several signaling pathways involved in the regulation of both CSCs and normal stem cells. Another reason may be that cancers could be triggered by several oncogenic mutations or there could be multiple mutations in CSCs. Due to the complexity, it was critically important to further improve our knowledge and understanding on CSCs properties and tumorous biology.
In general, therapeutic approaches targeting CSCs have great significance on the cancer treatment, but there are still several issues requiring extensive investigations in the future. For example, how do we find new markers with optimal specificity and sensitivity? What are the exact mechanisms of therapeutic strategies targeting CSCs? How do we combine these new CSCs-targeted agents with conventional chemo- and radio-therapies to achieve better efficacy? Approaches for solving these issues will ultimately contribute to improving the efficacy of targeted therapeutic strategies for the eradication of CSCs.
Financial support and sponsorship
The clinic medical center of infectious diseases in Suzhou (SZZX201508).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]