Journal of Cancer Research and Therapeutics

REVIEW ARTICLE
Year
: 2018  |  Volume : 14  |  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

Correspondence Address:
Chuanwu Zhu
The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215007
China

Abstract

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.



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;14:1469-1475


How to cite this URL:
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 [serial online] 2018 [cited 2019 Aug 20 ];14:1469-1475
Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1469/247736


Full Text



 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.[1],[2],[3] 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.[4] In a study on acute myeloid leukemia, CSCs were first identified.[5] 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.[6] 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}

 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.[7]

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.[8] 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.[9] 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.[10],[11]

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.[12]

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}

 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.{Table 3}

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.[13] 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.[14],[15] Other anti-CD44 mAbs such as P245, H4C4, GV5, and RO5429083 might show pronounced effects on eliminating CSCs in some cancers.[16],[17],[18],[19] An anti-CD133 mAb-induced specific, dose-dependent cytotoxic effects in CD133(+)-glioblastoma cells.[20] 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.[21] Encouraging data have revealed that mAbs against DLL4 were effective in eliminating CSCs.[22] 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.[23] 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).[24] 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.[25] 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.[26] SiRNA targeted to Notch4 rather than Notch1 was more effective in suppressing breast cancer recurrence.[27]

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.[28],[29] 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.[30],[31] In addition, studies demonstrated that GDC-0449 (also known as Vismodegib), an orally active SMO antagonist, presented bioavailability in basal cell carcinoma,[32] and brain cancer.[33] In the case of pancreatic tumor xenografts, the proportion of ALDHbri CSCs could be reduced with IPI269609, the SMO inhibitor.[34]

The combined Hh pathway inhibitor-targeted treatments and other therapeutic strategies have attracted general attention.[35],[36] 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.[37],[38]

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.[39] 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.[40],[41] Recently, Salinomycin, an antibiotic potassium ionophore, has been reported to inhibit breast CSCs and target the Wnt pathway by blocking the phosphorylation of LRP6.[42]

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.[43] 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.[44],[45] The application of anti-inflammatory drugs in cancer prevention and treatment was also supported with clinical and experimental data.[46] Thus, the specialized microenvironment seemed to be a crucial target for CSCs elimination.

Differentiation therapy

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.[47],[48] Oncostatin M, an interleukin 6-related cytokine, was reported to induce the differentiation of liver CSCs, from hepatoblasts to hepatocytes.[49] Bone morphogenetic proteins (BMPs), among which BMP7 elicited the strongest effects, triggered differentiation and reduced CSCs in human glioblastomas.[50]

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.[51] 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.[52] 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.[53]

Other therapeutics

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.[54] 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.[55] 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.[56],[57]

 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].{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.

References

1López-Lázaro M. The stem cell division theory of cancer. Crit Rev Oncol Hematol 2018;123:95-113.
2Kaur S, Singh G, Kaur K. Cancer stem cells: An insight and future perspective. J Cancer Res Ther 2014;10:846-52.
3Afzali M, Vatankhah M, Ostad SN. Investigation of simvastatin-induced apoptosis and cell cycle arrest in cancer stem cells of MCF-7. J Cancer Res Ther 2016;12:725-30.
4Moore MA, Williams N, Metcalf D.In vitro colony formation by normal and leukemic human hematopoietic cells: Characterization of the colony-forming cells. J Natl Cancer Inst 1973;50:603-23.
5Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994;367:645-8.
6Ahmad G, Amiji MM. Cancer stem cell-targeted therapeutics and delivery strategies. Expert Opin Drug Deliv 2017;14:997-1008.
7Nio K, Yamashita T, Kaneko S. The evolving concept of liver cancer stem cells. Mol Cancer 2017;16:4.
8Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396-401.
9Camerlingo R, Ferraro GA, De Francesco F, Romano M, Nicoletti G, Di Bonito M, et al. The role of CD44+/CD24-/low biomarker for screening, diagnosis and monitoring of breast cancer. Oncol Rep 2014;31:1127-32.
10Hatina J, Parmar HS, Kripnerova M, Hepburn A, Heer R. Urothelial carcinoma stem cells: Current concepts, controversies, and methods. Methods Mol Biol 2018;1655:121-36.
11Balla MM, Ningthoujam RS, Kumar M, Bandekar JR, Pandey BN. Cellular and spectroscopic characterization of cancer stem cell-like cells derived from A549 lung carcinoma. J Cancer Res Ther 2016;12:1144-52.
12Fearon ER, Wicha MS. KRAS and cancer stem cells in APC-mutant colorectal cancer. J Natl Cancer Inst 2014;106:djt444.
13Naujokat C. Monoclonal antibodies against human cancer stem cells. Immunotherapy 2014;6:290-308.
14Vey N, Delaunay J, Martinelli G, Fiedler W, Raffoux E, Prebet T, et al. Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia. Oncotarget 2016;7:32532-42.
15Chen P, Huang H, Wu J, Lu R, Wu Y, Jiang X, et al. Bone marrow stromal cells protect acute myeloid leukemia cells from anti-CD44 therapy partly through regulating PI3K/Akt-p27(Kip1) axis. Mol Carcinog 2015;54:1678-85.
16Yang ZX, Sun YH, He JG, Cao H, Jiang GQ. Increased activity of CHK enhances the radioresistance of MCF-7 breast cancer stem cells. Oncol Lett 2015;10:3443-9.
17Li L, Hao X, Qin J, Tang W, He F, Smith A, et al. Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice. Gastroenterology 2014;146:1108-18.
18Masuko K, Okazaki S, Satoh M, Tanaka G, Ikeda T, Torii R, et al. Anti-tumor effect against human cancer xenografts by a fully human monoclonal antibody to a variant 8-epitope of CD44R1 expressed on cancer stem cells. PLoS One 2012;7:e29728.
19Cao K, Pan Y, Yu L, Shu X, Yang J, Sun L, et al. Monoclonal antibodies targeting non-small cell lung cancer stem-like cells by multipotent cancer stem cell monoclonal antibody library. Int J Oncol 2017;50:587-96.
20Kim JS, Shin DH, Kim JS. Dual-targeting immunoliposomes using angiopep-2 and CD133 antibody for glioblastoma stem cells. J Control Release 2018;269:245-57.
21Huang J, Li C, Wang Y, Lv H, Guo Y, Dai H, et al. Cytokine-induced killer (CIK) cells bound with anti-CD3/anti-CD133 bispecific antibodies target CD133(high) cancer stem cells in vitro and in vivo. Clin Immunol 2013;149:156-68.
22Lee D, Kim D, Choi YB, Kang K, Sung ES, Ahn JH, et al. Simultaneous blockade of VEGF and dll4 by HD105, a bispecific antibody, inhibits tumor progression and angiogenesis. MAbs 2016;8:892-904.
23Li CJ, Zhang X, Fan GW. Updates in colorectal cancer stem cell research. J Cancer Res Ther 2014;10:233-9.
24Wang C, Shen J, Yukata K, Inzana JA, O'Keefe RJ, Awad HA, et al. Transient gamma-secretase inhibition accelerates and enhances fracture repair likely via notch signaling modulation. Bone 2015;73:77-89.
25Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, et al. Therapeutic antibody targeting of individual notch receptors. Nature 2010;464:1052-7.
26Yao Z, Sherif ZA. The effect of epigenetic silencing and TP53 mutation on the expression of DLL4 in human cancer stem disorder. Oncotarget 2016;7:62976-88.
27Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 2010;70:709-18.
28Zhang C, Li C, He F, Cai Y, Yang H. Identification of CD44+CD24+gastric cancer stem cells. J Cancer Res Clin Oncol 2011;137:1679-86.
29Takezaki T, Hide T, Takanaga H, Nakamura H, Kuratsu J, Kondo T, et al. Essential role of the hedgehog signaling pathway in human glioma-initiating cells. Cancer Sci 2011;102:1306-12.
30Zhang B, Jiang T, Shen S, She X, Tuo Y, Hu Y, et al. Cyclopamine disrupts tumor extracellular matrix and improves the distribution and efficacy of nanotherapeutics in pancreatic cancer. Biomaterials 2016;103:12-21.
31Iovine V, Mori M, Calcaterra A, Berardozzi S, Botta B. One hundred faces of cyclopamine. Curr Pharm Des 2016;22:1658-81.
32Dessinioti C, Plaka M, Stratigos AJ. Vismodegib for the treatment of basal cell carcinoma: Results and implications of the ERIVANCE BCC trial. Future Oncol 2014;10:927-36.
33Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, et al. Vismodegib exerts targeted efficacy against recurrent sonic hedgehog-subgroup medulloblastoma: Results from phase II pediatric brain tumor consortium studies PBTC-025B and PBTC-032. J Clin Oncol 2015;33:2646-54.
34Fu Q, Liu P, Sun X, Huang S, Han F, Zhang L, et al. Ribonucleic acid interference knockdown of IL-6 enhances the efficacy of cisplatin in laryngeal cancer stem cells by down-regulating the IL-6/STAT3/HIF1 pathway. Cancer Cell Int 2017;17:79.
35Ulasov IV, Nandi S, Dey M, Sonabend AM, Lesniak MS. Inhibition of sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy. Mol Med 2011;17:103-12.
36Bahra M, Kamphues C, Boas-Knoop S, Lippert S, Esendik U, Schüller U, et al. Combination of hedgehog signaling blockage and chemotherapy leads to tumor reduction in pancreatic adenocarcinomas. Pancreas 2012;41:222-9.
37Hu K, Zhou H, Liu Y, Liu Z, Liu J, Tang J, et al. Hyaluronic acid functional amphipathic and redox-responsive polymer particles for the co-delivery of doxorubicin and cyclopamine to eradicate breast cancer cells and cancer stem cells. Nanoscale 2015;7:8607-18.
38Piérard-Franchimont C, Hermanns-Lê T, Paquet P, Herfs M, Delvenne P, Piérard GE, et al. Hedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas. Future Oncol 2015;11:2997-3002.
39Nickho H, Younesi V, Aghebati-Maleki L, Motallebnezhad M, Majidi Zolbanin J, Movassagh Pour A, et al. Developing and characterization of single chain variable fragment (scFv) antibody against frizzled 7 (Fzd7) receptor. Bioengineered 2017;8:501-10.
40Jin H, Wang B, Li J, Xie W, Mao Q, Li S, et al. Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling. Bone 2015;71:63-75.
41Zhang J, Zhang X, Zhao X, Jiang M, Gu M, Wang Z, et al. DKK1 promotes migration and invasion of non-small cell lung cancer via β-catenin signaling pathway. Tumour Biol 2017;39:1010428317703820.
42An H, Kim JY, Lee N, Cho Y, Oh E, Seo JH, et al. Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway. Biochem Biophys Res Commun 2015;466:696-703.
43Faivre S, Demetri G, Sargent W, Raymond E. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007;6:734-45.
44Vanrell MDM, Armstrong ME, Prieto P. Experimental evidence for the role of intonation in evidential marking. Lang Speech 2017;60:242-59.
45Ranieri G, Gadaleta-Caldarola G, Goffredo V, Patruno R, Mangia A, Rizzo A, et al. Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: From discovery to clinical development. Curr Med Chem 2012;19:938-44.
46Siddikuzzaman, Berlin GV. Evaluation of immunomodulatory and antitumor activity of all trans retinoic acid (ATRA) in solid tumor bearing mice. Immunopharmacol Immunotoxicol 2013;35:110-8.
47Karsy M, Albert L, Murali R, Jhanwar-Uniyal M. The impact of arsenic trioxide and all-trans retinoic acid on p53 R273H-codon mutant glioblastoma. Tumour Biol 2014;35:4567-80.
48Schmoch T, Gal Z, Mock A, Mossemann J, Lahrmann B, Grabe N, et al. Combined treatment of ATRA with epigenetic drugs increases aggressiveness of glioma xenografts. Anticancer Res 2016;36:1489-96.
49El-Kehdy H, Sargiacomo C, Fayyad-Kazan M, Fayyad-Kazan H, Lombard C, Lagneaux L, et al. Immunoprofiling of adult-derived human liver stem/Progenitor cells: Impact of hepatogenic differentiation and inflammation. Stem Cells Int 2017;2017:2679518.
50González-Gómez P, Crecente-Campo J, Zahonero C, de la Fuente M, Hernández-Laín A, Mira H, et al. Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma. Oncotarget 2015;6:10950-63.
51Ferguson PJ, Vincent MD, Koropatnick J. Synergistic antiproliferative activity of the RAD51 inhibitor IBR2 with inhibitors of receptor tyrosine kinases and microtubule protein. J Pharmacol Exp Ther 2018;364:46-54.
52Zhong Q, Liu ZH, Lin ZR, Hu ZD, Yuan L, Liu YM, et al. The RARS-MAD1L1 fusion gene induces cancer stem cell-like properties and therapeutic resistance in nasopharyngeal carcinoma. Clin Cancer Res 2018;24:659-73.
53Pal D, Kolluru V, Chandrasekaran B, Baby BV, Aman M, Suman S, et al. Targeting aberrant expression of Notch-1 in ALDH + cancer stem cells in breast cancer. Mol Carcinog 2017;56:1127-36.
54Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69:7507-11.
55Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, et al. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2017;35:3662-70.
56Chung SS, Vadgama JV. Curcumin and epigallocatechin gallate inhibit the cancer stem cell phenotype via down-regulation of STAT3-NFκB signaling. Anticancer Res 2015;35:39-46.
57Park SH, Sung JH, Chung N. Berberine diminishes side population and down-regulates stem cell-associated genes in the pancreatic cancer cell lines PANC-1 and MIA PaCa-2. Mol Cell Biochem 2014;394:209-15.