• The Korean Journal of Physiology and Pharmacology
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• v.16 no.1
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• pp.11-16
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• 2012

Cancer stem cells (CSCs) are often characterized by the elevated expression of drug-resistance related stem-cell surface markers, such as CD133 and ABCG2. Recently, we reported that CSCs have a high level of expression of the IL-6 receptor (IL-6R). The purpose of this study was to investigate the effect of anticancer drugs on the expression of the drug resistance-related cancer stem cell markers, ABCG2, IL-6R, and CD133 in non-small cell lung cancer (NSCLC) cell lines. A549, H460, and H23 NSCLC cell lines were treated with the anticancer drugs 5-fluorouracil (5-FU; $25{\mu}g/ml$) and methotrexate (MTX; $50{\mu}g/ml$), and the expression of putative CSC markers was analyzed by fluorescent activated cell sorter (FACS) and the gene expression level of abcg2, il-6r and cd133 by reverse transcriptase-polymerase chain reaction (RT-PCR). We found that the fraction of ABCG2-positive(+) cells was significantly increased by treatment with both 5-FU and MTX in NSCLC cells, and the elevation of abcg2, il-6r and cd133 expressions in response to these drugs was also confirmed using RT-PCR. Also, the number of IL-6R(+) cells was increased by MTX in the 3 cell lines mentioned and increased by 5-FU in the H460 cell line. The number of CD133(+) cells was also significantly increased by both 5-FU and MTX treatment in all of the cell lines tested. These results indicate that 5-FU and MTX considerably enhance the expression of drug-resistance related CSC markers in NSCLC cell lines. Thus, we suggest that antimetabolite cancer drugs, such as 5-FU and MTX, can lead to the propagation of CSCs through altering the expression of CSC markers.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.8549-8556
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• 2014

Head and neck squamous cell carcinoma (HNSCC) is one of the world top ten most common cancers with its highest occurrence in the Indian subcontinent and different aggressive and etiological behavioural patterns. The scenario is only getting worst with the 5 year survival rates dropping to 50%, persistent treatment failures and frequent cases of relapse/recurrence. One of the major reasons for these failures is the presence of cancer stem cells (CSCs), a small population of cancer cells that are highly tumourigenic, capable of self-renewal and have the ability to differentiate into cells that constitute the bulk of tumours. Notably, recent evidence suggests that cancer stem cells are especially resistant to conventional therapy and are the "drivers" of local recurrence and metastatic spread. Specific markers for this population have been investigated in HNSCC in the hope of developing a deeper understanding of their role in oral cancer pathogenesis, elucidating novel biomarkers for early diagnosis and newer therapeutic strategies. This review covers the fundamental relevance of almost all the CSC biomarkers established to date with a special emphasis on their impact in the process of oral tumourigenesis and their potential role in improving the diagnosis, prognosis and treatment of OSCC patients.

• BMB Reports
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• v.51 no.11
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• pp.596-601
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• 2018

Colon cancer is one of the most lethal and common malignancies worldwide. STK899704, a novel synthetic agent, has been reported to exhibit anticancer effects towards numerous cancer cells. However, the effect of STK899704 on the biological properties of colon cancer, including cancer cell migration and cancer stem cells (CSCs), remains unknown. Here, we examined the inhibitory effect of STK899704 on cell migration and CSC stemness. In the wound healing assay, STK899704 significantly inhibited the motility of colon cancer cells. Furthermore, STK899704 downregulated the mRNA expression levels of the cell migration mediator focal adhesion kinase (FAK). STK899704 also suppressed mitogen-activated protein kinase kinase and extracellular signal-regulated kinase, which are downstream signaling molecules of FAK. Additionally, STK899704 inhibited stemness gene expression and sphere formation in colon cancer stem cells. These results suggest that STK899704 can be used to treat human colon cancer.

• Korean Journal of Veterinary Research
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• v.58 no.4
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• pp.201-209
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• 2018

Canine mammary tumors are among the most frequently observed cutaneous tumors in female dogs. Cancer stem cells (CSCs), referred to as tumor-initiating cells, are thought to have properties similar to normal stem cells such as the ability to self-renewal and to differentiate into various cell types. Biological understanding of CSCs and the critical pathways involved in their maintenance are important in research and therapy for mammary tumors. We conducted the present study on sphere formation from REM134 cells by using methylcellulose to produce tumorspheres on a large scale and compared the specific markers of the spheres-formed and plating-cultured REM134 cells. The results revealed that the tumorspheres cultured in methylcellulose had higher seeding density and improved morphology compared to those produced in normal sphere formation medium. Expression levels of stemness markers and CSC-related markers were higher in tumorsphere-forming cells than in plating-cultured cells. Subsequently, we transplanted the tumorsphere-forming and plating-cultured cells into female nude mice to examine their tumorigenic potential. Tumor volume increased rapidly in mice transplanted with tumorsphere-derived cells compared to plating-cultured cells. We observed a novel sphere-forming condition for REM134 cells and showed that REM134 cell tumorspheres can exhibit improved CSC properties.

• Journal of Life Science
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• v.26 no.10
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• pp.1214-1217
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• 2016

Rebamipide is a mucosal-protective antiulcer drug, but its mechanism of action in gastric cancer remains elusive. CagA, a major virulence factor of Helicobacter pylori (H. pylori), is associated with the risk of gastric cancer. CagA protein is injected into gastric epithelial cells and deregulates a variety of cellular signaling molecules. CagA from H. pylori induces phospholipase D1 (PLD1) expression through NFκB activation in gastric epithelial cells, followed by invasion and proliferation of gastric epithelial cancer cells. Infection with cagA-positive H. pylori and expression of CagA enhances the binding of NFκB to the PLD1 promoter. Rebamipide abolishes H. pylori cagA-induced PLD1 expression via inhibition of binding of NFκB to the PLD1 promoter and also inhibits PLD activity. Moreover, rebamipide abolishes H. pylori CagA-induced β-catenin and the expression of a target cancer stem cell (CSC) marker gene via upregulation of miRNA-320a and -4496, followed by attenuation of self-renewal capacity of H. pylori CagA-infected gastric CSCs. In addition, rebamipide increases the chemosensitivity of CagA-expressed gastric CSCs and suppresses gastric carcinogenesis. Thus, it is speculated that rebamipide might show a potent efficacy as chemotherapeutic drug against gastric cancer cells. In this review, we summarizes recent results regarding the novel insights for the efficacy of rebamipide in gastric cancer cells.

• Korean Journal of Pharmacognosy
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• v.45 no.2
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• pp.174-180
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• 2014

D-Pinitol, an anti-diabetic substance, is a naturally occurring compound found in legumes. In this study, we investigated the inhibitory effect of D-pinitol on growth and recurrence of breast cancer. When D-pinitol was treated on MDA-MB-231 or MCF-7 breast cancer cells, it was observed that the viability of the two cancer cell lines was reduced in MTT assay. In order to examine the effect on the growth of breast tumor, mouse xenograft assay was carried out. On day 0, nine millions cells of MDA-MB-231 were injected subcutaneously into nude mouse and D-pinitol was administered orally at the dose of 500 mg/kg or 1000 mg/kg body weight for consecutive 45 days. Tumor size was reduced in dose-dependent manner upto 95.4% in 1000 mpk-treated group, compared with the non-treated control group. When D-pinitol was co-administrated with $4{\mu}g$ of doxorubicin, recurrence of breast tumor was delayed by two weeks, compared with the mouse group of doxorubicin monotherapy. Consistent with this data, it was observed that the population of cancer stem cells (CSCs), responsible for recurrence of cancer, within tumor mass was significantly reduced. Taken together, D-pinitol inhibits the growth of breast cancer and relapse of the tumor by suppressing the proliferation of CSCs.

• Journal of Life Science
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• v.29 no.4
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• pp.499-508
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• 2019

Cancer stem cells (CSCs), which are primarily responsible for metastasis and recurrence, have self-renewal, differentiation, therapeutic resistance, and tumor formation abilities. Numerous studies have demonstrated the signaling pathways essential for the acquisition and maintenance of CSC characteristics, such as WNT/${\beta}$-catenin, Hedgehog, Notch, B lymphoma Mo-MLV insertion region 1 homolog (BMI1), Bone morphogenetic protein (BMP), and TGF-${\beta}$ signals. However, few therapeutic strategies have been developed that can selectively eliminate CSCs. Recently, neutralizing antibodies against Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1), immune checkpoint inhibitors (ICIs), have shown promising outcomes in clinical trials of melanoma, lung cancer, and pancreatic cancer, as well as in hematologic malignancies. ICIs are considered to outperform conventional anticancer drugs by maintaining long-lasting anti-cancer effects, with less severe side effects. Several studies reported that ICIs successfully blocked CSC properties in head and neck squamous carcinomas, melanomas, and breast cancer. Together, these findings suggest that novel and effective anticancer therapeutic modalities using ICIs for selective elimination of CSCs may be developed in the near future. In this review, we highlight the origin and characteristics of CSCs, together with critical signaling pathways. We also describe progress in ICI-mediated anticancer treatment to date and present perspectives on the development of CSC-targeting ICIs.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.10
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• pp.4177-4183
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• 2015

Background: Gastric cancer is the second leading cause of cancer-related death in Asia, and the majority type is gastric adenocarcinoma (GAC). Most GAC patients die of recurrence and metastasis. Cancer stem cells (CSCs) have been thought to be responsible for the initiation, development, metastasis, and ultimately recurrence of cancer. In this study, we aimed to investigate expression and clinical significance of CSCs markers, CD133 and Lgr5, and vasculogenic mimicry (VM) in primary GAC. Materials and Methods: Specimens from 261 Chinese patients with follow-up were analyzed for CD133, Lgr5 protein expression and VM by immunohistochemical and histochemical staining. The Pearson Chi's square test was used to assess the associations among the positive staining of these markers and clinicopathological characteristics. Postoperative overall survival time was were studied by univariate and multivariate analyses. Results: In GAC tissues, positive rates of 49.0%, 38.7%, and 26.8% were obtained for CD133, Lgr5, and VM, respectively. The mean score of microvessel density (MVD) was $21.7{\pm}11.1$ in GAC tissues. There was a significantly difference between the positive and negative groups. There was a positive relationship between the VM, the expression of CD133 and Lgr5, and the score of MVD and the grades of tumor, lymph node metastasis, TNM stages (all p<0.05). The overall mean survival time of the patients with CD133, Lgr5, VM, and MVD (${\geq}22$) positive expression was lower than that of patients with negative expression. The score of MVD, positive expression of CD133 and VM were independent prognostic factors of GAC (p<0.05). Conclusions: VM, and expression of CD133, Lgr5, and the score of MVD are related to grades of tumor, lymph node metastasis, TNM stages, and overall mean survival time. It is suggested that CSCs and VM could play an important role in the evolution of GAC.

• Molecules and Cells
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• v.44 no.7
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• pp.481-492
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• 2021

Tribbles homolog 2 (TRIB2) is implicated in tumorigenesis and drug resistance in various types of cancers. However, the role of TRIB2 in the regulation of tumorigenesis and drug resistance of cancer stem cells (CSCs) is still elusive. In the present study, we showed increased expression of TRIB2 in spheroid-forming and aldehyde dehydrogenase-positive CSC populations of A2780 epithelial ovarian cancer cells. Short hairpin RNA-mediated silencing of TRIB2 expression attenuates the spheroid-forming, migratory, tumorigenic, and drug-resistant properties of A2780 cells, whereas overexpression of TRIB2 increases the CSC-like characteristics. TRIB2 overexpression induced GSK3β inactivation by augmenting AKT-dependent phosphorylation of GSK3β at Ser9, followed by increasing β-catenin level via reducing the GSK3β-mediated phosphorylation of β-catenin. Treatment of TRIB2-ovexpressed A2780 cells with the phosphoinositide3-kinase inhibitor LY294002 abrogated TRIB2-stimulated proliferation, migration, drug resistance of A2780 cells. These results suggest a critical role for TRIB2 in the regulation of CSC-like properties by increasing the stability of β-catenin protein via the AKT-GSK3β-dependent pathways.

• Biomolecules & Therapeutics
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• v.30 no.3
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• pp.213-220
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• 2022

Although there have been advances in cancer therapy and surgical improvement, lung cancer has the lowest survival rate (19%) at all stages. This is because most patients are diagnosed with concurrent metastasis, which occurs due to numerous related reasons. Especially, lung cancer is one of the most common and malignant cancers in the world. Although there are advanced therapeutic strategies, lung cancer remains one of the main causes of cancer death. Recent work has proposed that epithelial-mesenchymal transition (EMT) is the main cause of metastasis in most cases of human cancers including lung cancer. EMT involves the conversion of epithelial cells, wherein the cells lose their epithelial abilities and become mesenchymal cells involved in embryonic development, such as gastrulation and neural crest formation. In addition, recent research has indicated that EMT contributes to altering the cancer cells into cancer stem cells (CSCs). Although EMT is important in the developmental stages, this process also activates lung cancer progression, including complicated and diverse signaling pathways. Despite the numerous investigations on signaling pathways involved in the progression of lung cancer, this malignancy is considered critical for treatment. EMT in lung cancer involves many transcription factors and inducers, for example, Snail, TWIST, and ZEB are the master regulators of EMT. EMT-related factors and signaling pathways are involved in the progression of lung cancer, proposing new approaches to lung cancer therapy. In the current review, we highlight the signaling pathways implicated in lung cancer and elucidate the correlation of these pathways, indicating new insights to treat lung cancer and other malignancies.