Cancer Stem Cells In Carcinoma Research Articles

Novel C-Terminal Heat Shock Protein 90 Inhibitors (KU711 and Ku757) Are Effective in Targeting Head and Neck Squamous Cell Carcinoma Cancer Stem cells

Advanced head and neck squamous cell carcinoma (HNSCC) remains a therapeutic challenge due to the development of therapy resistance. Several studies have implicated the development of cancer stem cells as a possible mechanism for therapy resistance in HNSCC. Heat shock protein 90’s (Hsp90’s) molecular chaperone function is implicated in pathways of resistance in HNSCC. Therefore, in the present study, we investigated the efficacy of novel C-terminal Hsp90 inhibitors (KU711 and KU757) in targeting HNSCC cancer stem cells (CSCs). Treatment of HNSCC human cell lines MDA1986, UMSCC 22B, and UMSCC 22B cisplatin-resistant cells with the KU compounds indicated complete blockage of self-renewal for the resistant and parent cell lines starting from 20 μM KU711 and 1 μM KU757. Dose-dependent decrease in the cancer stem cell markers CD44, ALDH, and CD44/ALDH double-positive cells was observed for all cell lines after treatment with KU711 and KU757. When cells were treated with either drug, migration and invasion were downregulated greater than 90% even at the lowest concentrations of 20 μM KU711 and 1 μM KU757. Western blot showed >90% reduction in client protein “stemness” marker BMI-1 and mesenchymal marker vimentin, as well as increase in epithelial marker E-cadherin for both cell lines, indicating epithelial to mesenchymal transition quiescence. Several CSC-mediated miRNAs that play a critical role in HNSCC therapy resistance were also downregulated with KU treatment. In vivo, KU compounds were effective in decreasing tumor growth with no observed toxicity. Taken together, these results indicate that KU compounds are effective therapeutics for targeting HNSCC CSCs.

P1.02-066 Cancer Stem Cells in Pulmonary High Grade Neuroendocrine Carcinoma: a Series of 23 Cases from Eastern India

P1.02-066 Cancer Stem Cells in Pulmonary High Grade Neuroendocrine Carcinoma: a Series of 23 Cases from Eastern India

Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma

BackgroundThe relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive (EpCAM+) CSCs.MethodsTwo patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence.ResultsWhole exome sequencing on the sorted EpCAM+ and EpCAM− HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted EpCAM+ cells than in EpCAM− cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted EpCAM+ and EpCAM− cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation.ConclusionsOur data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs.

Lidamycin decreases CD133 expression in hepatocellular carcinoma via the Notch signaling pathway.

Cluster of differentiation (CD)133 is considered a molecular marker of cancer stem cells in hepatocellular carcinoma. In the present study, the effect of lidamycin (LDM) on CD133 expression in hepatocellular carcinoma (Huh7 cells) was evaluated and the potential molecular mechanism was investigated. Flow cytometry analysis, as well as sorting, sphere formation and western-blot assays, were performed in vitro to explore the effects of LDM on CD133 expression. A subcutaneous tumor model in nude mice was used to observe the effects of LDM on tumor volume and CD133 protein in vivo. To investigate the potential underlying molecular mechanism, Notch signaling pathway activity was detected by western blot analysis and reverse transcription-quantitative polymerase chain reaction. The proportion of CD133+ cells and the expression of CD133 protein were revealed to be downregulated by LDM. Sphere formation of sorted CD133+ cells was suppressed 7 days after LDM treatment. In addition, LDM inhibited tumor volume formed from sorted CD133+ cells and CD133 protein level in vivo. LDM decreased the mRNA level of NOTCH1, Hes1 (Hes family BHLH transcription factor 1) and Hey1 (Hes-related family BHLH transcription factor with YRPW motif 1) genes; consequently, the protein expression of NOTCH1, Notch intracellular domain, Hes1 and Hey1 was decreased by LDM. Downregulation of the Notch signaling pathway by LDM was enhanced through combination with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. In brief, these data suggest that LDM suppresses CD133 expression via the Notch signaling pathway, indicating the potential mechanism of LDM on CD133 and the benefits for further clinical application.

Identification of differentially expressed genes in oral squamous cell carcinoma TCA8113 cells.

Previous studies have demonstrated that cancer cells with increased levels of aldehyde dehydrogenase ‘bright’ activity (ALDHbr) exhibit stem cell properties compared with cells exhibiting decreased ALDH activity (ALDHlow). To screen possible biomarkers of cancer stem cells in tongue squamous cell carcinoma, ALDHbr and ALDHlow cells were isolated from the tongue squamous cell carcinoma TCA8113 cell line, and suppression subtractive hybridization was performed to identify differentially expressed genes in the two subpopulations. A total of 240 positive clones were randomly selected for sequencing and were functionally characterized using bioinformatical tools. The results of the present study identified the differential expression of 104 clones, 62 of which corresponded to known genes and 42 of which corresponded to unknown genes. Cluster analysis revealed that the known genes were involved in the regulation of the cell cycle and cell differentiation. In addition, analysis of 10 signaling pathways revealed that genes were markedly altered in the ALDHbr cell subpopulation. Additional study is required to identify the function that these genes serve in the biomolecular regulatory mechanisms of cancer stem cells and to assist in explaining the biological behavior of oral squamous cell carcinoma.

Gli1 is a potential cancer stem cell marker and predicts poor prognosis in ductal breast carcinoma

Glioma-associated oncogene homolog 1 (Gli1) maintains the cancer stem cell-like characteristics in various tumors. However, its expression in cancer stem cells (CSC) in ductal breast carcinoma has not been well studied. We aimed to characterize Gli1 as a potential CSC marker and investigate its clinical significance in ductal breast carcinoma. Immunohistochemical staining was used to study the relationship of Gli1 to clinicopathologic features, cell cycle regulation-related genes, and CSC markers. Gli1 was expressed to a greater extent in ductal breast carcinoma than in normal breast tissues (P=.002). Its expression was significantly correlated with tumor grade (P=.044), pT stage (P=.017), and molecular subtype (P=.008). Expression was associated, not only with the expression of HIF-1α (P<.001), but also with greater microvessel density (MVD; P=.012). Kaplan-Meier survival analysis revealed that Gli1 was significantly associated with lower overall survival (OS; P=.02). Univariate Cox regression analysis confirmed that Gli1 was a poor prognostic factor for OS (P=.037) and was associated with the expression of the cell cycle-related genes cyclin D1 (P=.011), p21 (P=.009), and pAkt-Thr308 (P=.038). Moreover, Gli1 expression correlated significantly with the expression of two CSC markers, Sox2 (P=.01) and LSD1 (P=.01). Gli1 could be a stem cell marker and an indicator of poor prognosis in patients with ductal breast carcinoma.

Diagnosis of human prostate carcinoma cancer stem cells enriched from DU145 cell lines changes with microscopic texture analysis in radiation and hyperthermia treatment using run-length matrix

Purpose: Hyperthermia and radiation have the ability to induce structural and morphological changes on both macroscopic and microscopic level. Normal and damage cells have a different texture but may be perceived by human eye, as having the same texture.Materials and methods: To explore the potential of texture analysis based on run-length matrix, a total of 32 sphere images for each group and treatment regime were used in this study. Cells were subjected to the treatment with different doses of 6 MeV electron radiation (0 2, 4 and 6 Gy), hyperthermia (at 43° C in 0, 30, 60 and 90 min) and radiation + hyperthermia (at 43 °C in 30 min with 2, 4 and 6 Gy dose), respectively. Twenty run-length matrix (RLM) features were extracted as descriptors for each selected region of interest for texture analysis. Linear discriminant analysis was employed to transform raw data to lower-dimensional spaces and increase discriminative power.Results: The features were classified by the first nearest neighbor classifier. RLM features represented the best performance with sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of 100% between 0 and 6 Gy radiation, 0 and 6 Gy radiation + hyperthermia, 0 and 90 min and 30 and 90 min hyperthermia groups. The area under receiver operating characteristic curve was 1 for these groups.Conclusion: RLM features have a high potential to characterize cell changes during different treatment regimes.

PKC-δ attenuates the cancer stem cell among squamous cell carcinoma cells through down-regulating p63

Protein kinase C delta (PKC-δ) has been identified as a tumor suppressor. However, the effects of PKC-δ on the cancer stem cells in squamous cell carcinomas (SCC) have not been clarified. The purpose of this study was to detect the regulation of PKC-δ on cancer stem cell among SSC cells and the role of p63 during the regulation.Immunohistochemistry of human cutaneous SCC tissues was performed to detect the expression of PKC-δ. After the human SCC13 cells infected by recombinant adenoviruses, the cell proliferation were determined. The correlation of PKC-δ and p63 was detected by western blot. The colony forming activity and the number of cancer stem cells (CSCs) in SCC identified by double-staining with anti-integrin α6 and anti-CD71 antibodies were detected.The expression of PKC-δ was obviously decreased in SCC tissues compared with that in normal skin tissues. The higher protein level of p63 in SCC was attenuated by the transfection of PKC-δ. The higher proliferation capacity of SCC13 cells, the higher activity and expression of CSCs in SCC13 cells induced by p63 were significantly suppressed by the transfection of PKC-δ.In conclusion, PKC-δ played as a protective role in SCC partly by down-regulating p63, leading to the suppression of SCC cell proliferation, attenuation of the activity and expression of CSCs in SCC cells.

Cancer stem cells and epithelial-mesenchymal transition in urothelial carcinoma: Possible pathways and potential therapeutic approaches.

There is growing evidence of the presence of cancer stem cells in urothelial carcinoma. Cancer stem cells have the ability to self-renew and to differentiate into all cell types of the original heterogeneous tumor. A panel of diverse cancer stem cell markers might be suitable for simulation studies of urothelial cancer stem cells and for the development of optimized treatment protocols. The present review focuses on the advances in recognizing the markers of urothelial cancer stem cells and possible therapeutic targets. The commonly reported markers and pathways that were evaluated include CD44, CD133, ALDH1, SOX2 & SOX4, BMI1, EZH1, PD-L1, MAGE-A3, COX2/PGE2/STAT3, AR, and autophagy. Studies on the epithelial-mesenchymal transition-related pathways (Shh, Wnt/β-catenin, Notch, PI3K/Akt, TGF-β, miRNA) are also reviewed. Most of these markers were recognized through the expression patterns of cancer stem cell-rich side populations. Their regulative role in the development and differentiation of urothelial cancer stem cells was confirmed invitro by functional analyses (e.g. cell migration, colony formation, sphere formation), and invivo in xenograft experiments. Although a small number of these pathways are targeted by currently available drugs or drugs that are the currently being tested in clinical trials, a clear treatment approach has not been developed for most pathways. A greater understanding of the mechanisms that control the proliferation and differentiation of cancer stem cells is expected to lead to improvements in targeted therapy.

Abstract 4200: Targeting cancer stem cells in serous ovarian carcinoma using RP6530, a dual PI3k δ/γ inhibitor

Abstract Ovarian cancer is one of the most lethal gynecological malignancies as most patients are diagnosed at an advanced stage and have a poor prognosis. Several studies have prospectively isolated cancer stem cells (CSCs) from samples of tumor from patients with serous adenocarcinoma of the ovary (SOC). This has been achieved by using cell surface antigens or functional assays. Targeting this subpopulation could be critical to overcome drug resistance, recurrence, and hence improve the survival of patients. The PI3K pathway is deregulated in 37% of SOC with PI3Kδ and γ amplified in 16% of tumors (TCGA data). We have used a novel and selective PI3K γ/δ inhibitor (RP6530) with high potency against PI3Kγ (IC50=25 nM) and δ (IC50=33 nM) enzymes and selectivity over α (&amp;gt;300-fold) and β (&amp;gt;100-fold) isoforms. RP6530, an orally active and sensitive small molecule inhibitor, is currently being tested in Phase-1 trials in US and Europe to evaluate its safety and efficacy in patients with hematological malignancies. The objective of this study was to test the efficacy of RP6530 against CSCs of EOC. Spheroids, enriched for CSCs were employed as an approach to evaluate the specific potency of the drug. In the experiments, Salinomycin was used as a control drug that targets CSCs. Initially, we have analyzed 3 cell lines (PEO4, OVCAR-5 and CAOV-2) with and without addition of 5µM RP6530. RP6530 significantly inhibited spheroid formation in PEO4 (0.001) and OVCAR-5 (p&amp;lt;0.05) and CAOV-2 (p&amp;lt;0.01) (mean of ≥3 experiments in triplicate). In cell viability assay, RP6530 had no cytotoxic effect as compared to Cisplatin in any of the cell lines. To evaluate the effect of the compound on CSC, we performed analysis of side population (SP) with Hoechst 33342 at 355 nm by flow cytometry. RP6530 either caused a significant reduction (&amp;gt;50%) in the fraction of SP cells (PEO4 and CAOV-2) or was neutral (OVCAR-5) indicating that the compound preferentially targets CSC in ovarian cancer cell lines. Colony assay revealed significantly lesser number of colonies in RP6530 treated cells. Phosphorylation of Akt that is downstream of PI3 kinase was inhibited in a dose dependent manner in all three cell lines. Evaluation of drugs that are intended to target CSCs is different from that of conventional cytotoxic drugs. Taken together, the results indicate that RP6530 shows potent inhibitory effect on CSCs in ovarian cancer cell lines. Citation Format: Sneha S, Nivetha R, R P. Nagare, Srikant Viswanadha, Swaroop Vakkalanka, T S. Ganesan. Targeting cancer stem cells in serous ovarian carcinoma using RP6530, a dual PI3k δ/γ inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4200. doi:10.1158/1538-7445.AM2017-4200

Abstract 928: Combined treatment by manuka honey and metformin inhibited growth and inducted apoptosis in CD133+and CD90+ subpopulation hepatocellular carcinoma cancer stem cells

Abstract Manuka honey is well known for its anti-bacterial and wound healing properties but its anticancer role against cancer stem cells (CSC) in hepatocellular carcinoma (HCC) cell lines and the underlying molecular mechanisms remain uninvestigated. Recently, we identified a CSC subpopulation in HCC cell lines characterized by their CD133+ and CD90+ phenotype. The CD133+/ CD90+cells demonstrated a more aggressive phenotype than the CD133-/ CD90- counterpart and formed metastatic lesions in the lung of immunodeficient mice. In order to evaluate the effect of Manuka honey alone or in combined treatment with Metformin, a biguanide that has been widely used to treat type 2 diabetes, on cell viability and apoptosis induction in human HCC cell lines, isolated and identified CD133+/ CD90+subpopulation CSC were used. Cell viability was monitored using an MTT assay. In addition, apoptosis induction was labeled by Annexin V-fluorescein isothiocyanate/propidium iodide and measured using flow cytometry. Western blotting was used to examine the protein expression of p53, Bcl-2, Bax, Bcl-2-associated death promoter (Bad), Bcl-2 homologous antagonist/killer (Bak) and cleaved-caspases-3 and -9. The results of the present study revealed that Manuka honey alone or in combined treatment with Metformin suppressed the cell viability of CD133+/CD90+cells in a concentration-dependent manner and the maximum effect was detected in combined treatment after 24 h. In addition, Manuka honey alone or in combined treatment with Metformin induced a significant apoptosis in the tested cells. Furthermore, it was demonstrated that combined treatment increased the expression of proapoptotic proteins, including p53, Bax, Bad and Bak, while it decreased the protein level of antiapoptotic protein Bcl-2 compared to control, Manuka honey or Metformin alone. Furthermore, the combined treatment strongly inhibited stemness characteristics of CSC subpopulation, colony formation and dramatically inhibited CD133+/CD90+tumor growth in vivo. Our data demonstrated that combined treatment induced apoptosis in CD133+/CD90+ subpopulation through G1 arrest in the cell-cycle and regulating p53/Bcl-2/caspase-3 signaling pathway. In conclusion, our results suggested that Monuka honey alone or combined treatment with Metformin may be a potential treatment for apoptosis induction in CSC and may provide a novel therapeutic model for HCC. Citation Format: Amira S. Fyala, Ahmed S. Sultan. Combined treatment by manuka honey and metformin inhibited growth and inducted apoptosis in CD133+and CD90+ subpopulation hepatocellular carcinoma cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 928. doi:10.1158/1538-7445.AM2017-928

Cancer Stem Cells in Oral Cavity Squamous Cell Carcinoma: A Review.

Cancer stem cells (CSCs) have been identified in oral cavity squamous cell carcinoma (OCSCC). CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells and cancer cells that drive tumor growth. Studies of many cancer types including OCSCC have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple CSC subtypes within OCSCC, making investigation reliant on the use of multiple markers. This review examines the current knowledge in CSC markers OCT4, SOX2, NANOG, ALDH1, phosphorylated STAT3, CD44, CD24, CD133, and Musashi-1, specifically focusing on their use and validity in OCSCC CSC research and how they may be organized into the CSC hierarchy. OCSCC CSCs also express components of the renin–angiotensin system (RAS), which suggests CSCs may be novel therapeutic targets by modulation of the RAS using existing medications.

Abstract NTOC-106: FAK INHIBITION RE–SENSITIZES PLATINUM–RESISTANT SEROUS OVARIAN CANCER

Abstract Most ovarian cancer patients respond well to surgical debulking and platinum-taxol chemotherapy. However, ~80% of patients with a complete response to therapy will exhibit tumor recurrence, and in time develop platinum and chemotherapy-resistant disease. It is hypothesized that recurrent disease emanates from the regrowth of microscopic clusters of chemotherapy-resistant tumor cells - also termed cancer stem cells (CSCs). Here, we find that cisplatin chemotherapy elevates focal adhesion (FAK) tyrosine kinase phosphorylation (Y397 FAK) in 3D ovarian tumor spheroids. Notably, FAK is not known as a DNA-damage sensing kinase. Instead, FAK is linked to integrin adhesion-, migration-, and CSC-promoting signaling pathways. In mouse tumors, CP-taxol chemotherapy increases FAK Y397 phosphorylation and aldehyde dehydrogenase (ALDH-1A1, a known markers of CSCs) in tumor areas not associated with necrosis. FAK Y397 phosphorylation is constitutively-elevated in CP-resistant ovarian cancer cells and nanomolar levels of FAK inhibitor (VS-4718) block 3D colony cell growth. Oral VS-4718 administration to mice reduces CP-resistant orthotopic tumor burden with a concomitant decrease in tumor-associated ALDH activity and secondary tumor-initiating capacity. CRISPR-mediated FAK knockout or VS-4718 treated ovarian carcinoma cells exhibit diminished ALDH-1A1 expression. Importantly, co-administration of VS-4718 enhances the anti-tumor effectiveness of CP-taxol chemotherapy in an orthotopic CP-resistant mouse tumor model. As CP activates FAK and FAK signaling sustains ovarian carcinoma CSC phenotypes, our results support the future testing of FAK inhibitors in combination with CP to prevent recurrent and chemo-resistant ovarian cancer. Citation Format: Lisa M. Bean, Florian J. Sulzmaier, Kristen M. Anderson, Isabelle Tancioni, Cheyenne R. Butcher, Sean Uryu, Christine Jean, Christine Lawson, Xiao Lei Chen, Elizabeth G. Kleinschmidt, Vihren N. Kolev, Jonathan A. Pachter, Dwayne G. Stupack, and David D. Schlaepfer. FAK INHIBITION RE–SENSITIZES PLATINUM–RESISTANT SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-106.

110 Basal cell carcinoma cancer stem cells promote immune evasion

110 Basal cell carcinoma cancer stem cells promote immune evasion

Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma.

Purpose: Gastric carcinomas are heterogeneous, and the current therapy remains essentially based on surgery with conventional chemotherapy and radiotherapy. This study aimed to characterize biomarkers allowing the detection of cancer stem cells (CSC) in human gastric carcinoma of different histologic types.Experimental Design: The primary tumors from 37 patients with intestinal- or diffuse-type noncardia gastric carcinoma were studied, and patient-derived tumor xenograft (PDX) models in immunodeficient mice were developed. The expressions of 10 putative cell surface markers of CSCs, as well as aldehyde dehydrogenase (ALDH) activity, were studied, and the tumorigenic properties of cells were evaluated by in vitro tumorsphere assays and in vivo xenografts by limiting dilution assays.Results: We found that a subpopulation of gastric carcinoma cells expressing EPCAM, CD133, CD166, CD44, and a high ALDH activity presented the properties to generate new heterogeneous tumorspheres in vitro and tumors in vivo CD44 and CD166 were coexpressed, representing 6.1% to 37.5% of the cells; ALDH activity was detected in 1.6% to 15.4% of the cells; and the ALDH+ cells represented a core within the CD44+/CD166+ subpopulation that contained the highest frequency of tumorigenic CSCs in vivo The ALDH+ cells possessed drug efflux properties and were more resistant to standard chemotherapy than the ALDH- cells, a process that was partially reversed by verapamil treatment.Conclusions: CD44 and ALDH are the most specific biomarkers to detect and isolate tumorigenic and chemoresistant gastric CSCs in noncardia gastric carcinomas independently of the histologic classification of the tumor. Clin Cancer Res; 23(6); 1586-97. ©2016 AACR.

Self-targeted salinomycin-loaded DSPE-PEG-methotrexate nanomicelles for targeting both head and neck squamous cell carcinoma cancer cells and cancer stem cells.

To target both head and neck squamous cell carcinoma (HNSCC) cells and cancer stem cells (CSCs) by salinomycin-loaded DSPE-PEG-MTX (synthesized using DSPE-PEG2000-NH2 and methotrexate) nanomicelles (M-SAL-MTX). The characterization, antitumor activity and mechanism of M-SAL-MTX were evaluated. M-SAL-MTX showed enhanced inhibitory effect toward both HNSCC CSCs and non-CSCs compared with a single treatment of methotrexate and salinomycin. In nude mice-bearing HNSCC xenografts, M-SAL-MTX suppressed tumor growth more effectively than other controls including combination of methotrexate and salinomycin. Therefore, M-SAL-MTX may provide a strategy for treating HNSCC by targeting both HNSCC CSCs and HNSCC cells.

Cancer Stem Cells in Head and Neck Carcinomas: Identification and Possible Therapeutic Implications.

The recurrence and/or lack of response of certain tumors to radio- and chemotherapy has been attributed to a small subpopulation of cells termed cancer stem cells (CSCs). CSCs have been identified in many tumors (including solid and hematological tumors). CSCs are characterized by their capacity for self-renewal, their ability to introduce heterogeneity within a tumor mass and its metastases, genomic instability, and their insensitivity to both radiation and chemotherapy. The latter highlights the clinical importance of studying this subpopulation since their resistance to traditional treatments may lead to metastatic disease and/or tumor relapse. Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignancy worldwide with the highest incidence occurring in East Asia and eastern and southern Africa. Several cellular subpopulations believed to have CSC properties have been isolated from HNSCCs, but at present, identification and characterization of CSCs remains an experimental challenge with no established or standardized protocols in place to confirm their identity. In this review we discuss current approaches to the study of CSCs with a focus on HNSCCs, particularly in the context of what this might mean from a therapeutic perspective.

Cancer stem cells in esophageal squamous cell carcinoma and mechanisms of their drug resistance

Cancer stem cells in esophageal squamous cell carcinoma and mechanisms of their drug resistance

Using stem cell biology to study and treat ophthalmologic and oculoplastic diseases.

With the rapid growth of the stem cell biology field, the prospect of regenerative medicine across multiple tissue types comes closer to reality. Several groundbreaking steps paved the way for applying stem cell biology to the several subfields within ophthalmology and oculoplastic surgery. These steps include the use of stem cell transplants as well as studies of various ophthalmologic pathologies at the molecular level. The necessity of stem cell transplant is readily apparent, having already been used for several studies such as artificial lacrimal gland design and eyelid reconstruction. Investigating the stem cell biology behind oncological diseases of the eye has also developed recently, such as with the identification of specific markers to label cancer stem cells in orbital adenoid cystic carcinoma. The advent of induced pluripotent stem cells led to a burst of productivity in the field of regenerative medicine, making it possible to take a patient's own cells, reprogram them, and use them to either study patient-specific pathology in vitro or use them for eventual patient specific therapeutics. Patient-specific adipose-derived stem cells (ASCs) have been used for a variety of treatments, such as wound healing and burn therapies. As the fields of stem cell biology and regenerative medicine continue to progress, its use will become a mainstay of patient-specific cell therapies in the future.

Activation of D2 Dopamine Receptors in CD133+ve Cancer Stem Cells in Non-small Cell Lung Carcinoma Inhibits Proliferation, Clonogenic Ability, and Invasiveness of These Cells

Lung carcinoma is the leading cause of cancer-related death worldwide, and among this cancer, non-small cell lung carcinoma (NSCLC) comprises the majority of cases. Furthermore, recurrence and metastasis of NSCLC correlate well with CD133+ve tumor cells, a small population of tumor cells that have been designated as cancer stem cells (CSC). We have demonstrated for the first time high expression of D2 dopamine (DA) receptors in CD133+ve adenocarcinoma NSCLC cells. Also, activation of D2 DA receptors in these cells significantly inhibited their proliferation, clonogenic ability, and invasiveness by suppressing extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT, as well as down-regulation of octamer-binding transcription factor 4 (Oct-4) expression and matrix metalloproteinase-9 (MMP-9) secretion by these cells. These results are of significance as D2 DA agonists that are already in clinical use for treatment of other diseases may be useful in combination with conventional chemotherapy and radiotherapy for better management of NSCLC patients by targeting both tumor cells and stem cell compartments in the tumor mass.