• aptamers
• cancer stem cell markers
• targeted drug delivery

• Humans
• Aptamers, Nucleotide/administration & dosage
• Aptamers, Nucleotide/therapeutic use
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/drug effects
• Neoplasms/drug therapy
• Biomarkers, Tumor/metabolism
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/administration & dosage
• Drug Delivery Systems

• Cisplatin resistance
• EGFR
• EGFR inhibitor
• Lung cancer
• NSCLC
• Nrf2

• Humans
• NF-E2-Related Factor 2/metabolism
• NF-E2-Related Factor 2/genetics
• Cisplatin/pharmacology
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/genetics
• ErbB Receptors/genetics
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Drug Resistance, Neoplasm/drug effects
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Gene Silencing
• Tyrphostins/pharmacology
• Quinazolines/pharmacology
• Cell Survival/drug effects

• Biomarkers
• Cancer Stem Cells
• Circulating Tumor Cells
• Epithelial–Mesenchymal Transition (EMT)
• Lung Cancer
• Tumor heterogeneity
• Tumor microenvironment

• Humans
• Neoplastic Cells, Circulating/pathology
• Neoplastic Cells, Circulating/metabolism
• Lung Neoplasms/pathology
• Neoplastic Stem Cells/pathology
• Epithelial-Mesenchymal Transition
• Animals

• CSCs isolation
• Cancer stem cells (CSCs)
• Side population
• Spheres

• Neoplastic Stem Cells/pathology
• Neoplastic Stem Cells/metabolism
• Humans
• Neoplasms/pathology
• Neoplasms/metabolism
• Neoplasms/diagnosis
• Cell Separation/methods
• Animals
• Cell Culture Techniques/methods
• Biomarkers, Tumor/metabolism
• Flow Cytometry/methods

• cancer stem cells
• cell death
• colon and lung cancer cells
• multicellular tumor spheroids
• unsymmetrical bisacridines

• Humans
• Lung Neoplasms/metabolism
• Spheroids, Cellular
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/metabolism
• Tumor Cells, Cultured
• Neoplastic Stem Cells/metabolism
• Colon
• Cell Line, Tumor

• mini-grant no. 036053 Gdańsk University of Technology

• cancer stem cells
• non-small-cell lung cancer

• Humans
• Endothelial Cells/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• Pulmonary Disease, Chronic Obstructive/genetics
• Hypoxia/metabolism
• Carcinogenesis/metabolism
• Lung Neoplasms/pathology
• Extracellular Vesicles/metabolism
• Phenotype
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism

• Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia), 1731093
• Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
• Ministero della Salute (Ministry of Health, Italy)

• JADE2
• mutation
• non-small cell lung cancer
• overexpression
• prognosis
• tumor mutational burden
• tumor-infiltrating immune cells

• XXXX Pathological Society of Great Britain and Ireland

• Cancer
• Cell biology
• Molecular biology
• Transcriptomics

• epithelial-mesenchymal transition
• evodiamine
• non-small cell lung cancer
• transforming growth factor β

Ionizing radiation (IR) has been shown to play a crucial role in the treatment of glioblastoma (GBM; grade IV) and non-small-cell lung cancer (NSCLC). Nevertheless, recent studies have indicated that radiotherapy can offer only palliation owing to the radioresistance of GBM and NSCLC. Therefore, delineating the major radioresistance mechanisms may provide novel therapeutic approaches to sensitize these diseases to IR and improve patient outcomes. This review provides insights into the molecular and cellular mechanisms underlying GBM and NSCLC radioresistance, where it sheds light on the role played by cancer stem cells (CSCs), as well as discusses comprehensively how the cellular dormancy/non-proliferating state and polyploidy impact on their survival and relapse post-IR exposure.

• Cancer stem cells
• EGFR-TKI
• Lung cancer
• NSCLC
• Natural products

• CD133 expression
• Metastatic breast cancer
• cancer stem cells
• clinicopathological characteristics
• survival and response rate

• CART therapy
• COPD
• cancer stem cell
• inflammation
• small cell lung cancer

The stemness-associated markers OCT4, NANOG, SOX2, KLF4 and c-MYC are expressed in numerous cancer types suggesting the presence of cancer stem cells (CSCs). Immunohistochemical (IHC) staining performed on 12 lung adenocarcinoma (LA) tissue samples showed protein expression of OCT4, NANOG, SOX2, KLF4 and c-MYC, and the CSC marker CD44. In situ hybridization (ISH) performed on six of the LA tissue samples showed mRNA expression of OCT4, NANOG, SOX2, KLF4 and c-MYC. Immunofluorescence staining performed on three of the tissue samples showed co-expression of OCT4 and c-MYC with NANOG, SOX2 and KLF4 by tumor gland cells, and expression of OCT4 and c-MYC exclusively by cells within the stroma. RT-qPCR performed on five LA-derived primary cell lines showed mRNA expression of all the markers except SOX2. Western blotting performed on four LA-derived primary cell lines demonstrated protein expression of all the markers except SOX2 and NANOG. Initial tumorsphere assays performed on four LA-derived primary cell lines demonstrated 0–80% of tumorspheres surpassing the 50 µm threshold. The expression of the stemness-associated markers OCT4, SOX2, NANOG, KFL4 and c-MYC by LA at the mRNA and protein level, and the unique expression patterns suggest a putative presence of CSC subpopulations within LA, which may be a novel therapeutic target for this cancer. Further functional studies are required to investigate the possession of stemness traits.

• cancer stem cells
• embryonic stem cells
• induced pluripotent stem cells
• lung adenocarcinoma
• stemness-associated markers
• treatment resistance
• tumorsphere

Radioresistance conferred by cancer stem cells (CSCs) is the principal cause of the failure of cancer radiotherapy. Eradication of CSCs is a prime therapeutic target and a requirement for effective radiotherapy. Three dimensional (3D) cell-cultured model could mimic the morphology of cells in vivo and induce CSC properties. Emerging evidence suggests that microRNAs (miRNAs) play crucial roles in the regulation of radiosensitivity in cancers. In this study, we aim to investigate the effects of miRNAs on the radiosensitivity of 3D cultured stem-like cells. Using miRNA microarray analysis in 2D and 3D cell culture models, we found that the expression of miR-29b-3p was downregulated in 3D cultured A549 and MCF7 cells compared with monolayer (2D) cells. Clinic data analysis from The Cancer Genome Atlas database exhibited that miR-29b-3p high expression showed significant advantages in lung adenocarcinoma and breast invasive carcinoma patients’ prognosis. The subsequent experiments proved that miR-29b-3p overexpression decreased the radioresistance of cells in 3D culture and tumors in vivo through interfering kinetics process of DNA damage repair and inhibiting oncogenes RBL1, PIK3R1, AKT2, and Bcl-2. In addition, miR-29b-3p knockdown enhanced cancer cells invasion and migration capability. MiR-29b-3p overexpression decreased the stemness of 3D cultured cells. In conclusion, our results demonstrate that miR-29b-3p could be a sensitizer of radiation killing in CSC-like cells via inhibiting oncogenes expression. MiR-29b-3p could be a novel therapeutic candidate target for radiotherapy.

• miR-29b-3p
• oncogene axis
• radiosensitivity
• stemness
• three dimensional cultured cells

Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear.

MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors.

We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo.

Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.

The online version contains supplementary material available at 10.1186/s13046-021-02069-4.

Apatinib suppressed proliferation, induced cell cycle arrest and apoptosis, and inhibited malignancy in NSCLC in vitro and in vivo.

• Apatinib
• Apoptosis
• Autophagy
• NSCLC
• ROS/Nrf2/p62
• STAT3/PD-L1

There is growing evidence that cancer stem cells (CSCs), a small subpopulation of self-renewal cancer cells, are responsible for tumor growth, treatment resistance, and cancer relapse and are thus of enormous clinical interest. Here, we aimed to isolate new CSC-like cells derived from human primary non-small cell lung cancer (NSCLC) specimens and to analyze the influence of different inhibitors of NF-κB and MYC signaling on cell survival. CSC-like cells were established from three squamous cell carcinomas (SCC) and three adenocarcinomas (AC) of the lung and were shown to express common CSC markers such as Prominin-1, CD44-antigen, and Nestin. Further, cells gave rise to spherical cancer organoids. Inhibition of MYC and NF-κB signaling using KJ-Pyr-9, dexamethasone, and pyrrolidinedithiocarbamate resulted in significant reductions in cell survival for SCC- and AC-derived cells. However, inhibition of the protein–protein interaction of MYC/NMYC proto-oncogenes with Myc-associated factor X (MAX) using KJ-Pyr-9 revealed the most promising survival-decreasing effects. Next to the establishment of six novel in vitro models for studying NSCLC-derived CSC-like populations, the presented investigations might provide new insights into potential novel therapies targeting NF-κB/MYC to improve clinical outcomes in NSCLC patients. Nevertheless, the full picture of downstream signaling still remains elusive.

• MYC
• NF-κB
• NSCLC
• adenocarcinoma
• cancer stem cell-like cells
• squamous cell carcinoma

• Adenocarcinoma/genetics
• Adenocarcinoma/pathology
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Cell Survival/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• NF-kappa B/metabolism
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Phenotype
• Proto-Oncogene Proteins c-myc/metabolism
• Signal Transduction/genetics
• Tumor Necrosis Factor-alpha/metabolism

• EGFR
• EMT
• NSCLC
• Notch1
• tumor spheres

• circulating cancer stem cells
• circulating tumor cells
• early diagnosis
• liquid biopsy
• microfluidic platform
• optical sensing

• NRF- 2019R1I1A1A01058888 National Research Foundation of Korea
• No.2019R1A2C3002300 National Research Foundation of Korea
• No.2016R1A6A1A03012845 National Research Foundation of Korea

• cancer stem cells
• predictive markers

• A549 Cells
• ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
• ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
• Animals
• Antibodies, Monoclonal/pharmacology
• Antineoplastic Agents, Immunological/pharmacology
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Calcineurin/metabolism
• Calcium Channel Blockers/pharmacology
• Calcium Channels/drug effects
• Calcium Channels/genetics
• Calcium Channels/metabolism
• Calcium Signaling
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Cell Proliferation
• Cell Self Renewal
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Mice, Inbred NOD
• Mice, SCID
• NFATC Transcription Factors/genetics
• NFATC Transcription Factors/metabolism
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Receptor, Notch3/genetics
• Receptor, Notch3/metabolism
• Tumor Burden
• Xenograft Model Antitumor Assays
• Mice

• National Natural Science Foundation of China (National Science Foundation of China)
• the National Key Research and Development Program of China 2016YFA0500303

Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1,BCL2,FZD1,GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs.

• CD44v6
• CD44v6 CRISPR/Cas9 knockout
• CD44v6-therapy
• CIC
• MDR1
• YB-1
• YB-1 CRISPR/Cas9 knockout
• colorectal cancer (CRC)
• stemness genes

• B cell precursor acute lymphoblastic leukemia
• Bone marrow mesenchymal stromal cell
• Cancer stem cell
• Cellular interaction
• Leukemic stem cell

• Colorectal cancer
• piRNA
• piwi-interacting RNA
• piwiRNA

• Cancer stem cells
• Chemoresistance
• butyrate
• colorectal cancer

• Biomarkers, Tumor/genetics
• Butyrates/pharmacology
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Drug Resistance, Neoplasm/genetics
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Microarray Analysis/methods
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Tumor Cells, Cultured

Previous studies have shown that lung cancer stem cells express CD133 and that certain cancer stem cells express cancer germline antigens (CGAs). The transcriptional regulation of CD133 is complicated and poorly understood. We investigated CD133 and CGA expression in a non-small cell lung cancer cell line.

The expression levels of CD133 and CGAs (MAGE-6, GAGE, SSX, and TRAG-3) were measured in an NCI-H292 lung cancer cell line. The methylation status of the CD133 gene promoter region was analyzed. The expression levels and promoter methylation statuses of CD133 and CGAs were confirmed by treatment with the demethylating agent 5-aza-2′-deoxycytidine (ADC).

After treatment with ADC, CD133 expression was no longer detected. MAGE-6 and TRAG-3 were detected before ADC treatment, while GAGE and SSX were not detected. ADC treatment upregulated MAGE-6 and TRAG-3 expression, while GAGE expression was still undetected after treatment, and only weak SSX expression was observed. GAGE expression was not correlated with expression of CD133, while the levels of expression of MAGE-6, TRAG-3, and SSX were inversely correlated with CD133 expression.

These results showed that CD133 expression can be regulated by methylation. Thus, the demethylation of the CD133 promoter may compromise the treatment of lung cancer by inactivating cancer stem cells and/or activating CGAs.

• Demethylation
• Lung neoplasms
• Neoplastic stem cells

• Cancer stem cell
• Digestive cancer
• Prognosis

Sorafenib remains the only approved molecular targeted agent for hepatocellular carcinoma (HCC); however, reliable biomarkers that predict its efficacy are still lacking. The aim of this study was to explore whether cancer stem cell (CSC) markers have a predictive role with regard to the sorafenib response in HCC patients.

We enrolled 47 patients with HCC for whom tumor samples obtained before starting sorafenib treatment were available. RNA was extracted from formalin-fixed, paraffin-embedded samples, and real-time polymerase chain reaction was used to quantify mRNA expression of the CSC genes EpCAM, CD13, CK8, CD24, CD44, CD90, CD133, SALL4, ALDH1A1, ALB, and AFP.

Of 47 patients, 14.9% and 74.5% had vascular invasion and extrahepatic spread, respectively. Patients with low CD133 expression tended to have longer progression-free survival (PFS) than those with high CD133 expression (5.5 months vs 4.0 months), although without statistical significance. The expression levels of other markers were not associated with PFS. When examining markers in combination, patients with high CD133 and CD90 expression had shorter PFS rates than those with low expression (2.7 months vs 5.5 months; p=0.04). Patients with low CD133 and EpCAM expression demonstrated better PFS than those with high expression (7.0 months vs 4.2 months; p=0.04). Multivariable analysis indicated that an Eastern Cooperative Oncology Group performance status score of 1 and high CD133/CD90 expression were significantly associated with shorter PFS.

Overexpression of the CSC markers CD133 and CD90 in HCC was associated with poorer response to sorafenib. These two genes may serve as predictive biomarkers for sorafenib therapy.

• Biomarkers
• Cancer stem cells
• Carcinoma
• Prognosis
• Sorafenib
• hepatocellular

• aldehyde dehydrogenase
• cancer stem cell
• side population
• spheroid formation assay
• surface marker

The epithelial-mesenchymal transition (EMT) plays a key role in tumor progression, drug resistance and metastasis. Recently, numerous microRNA (miRNA) have been described to regulate EMT in tumor progression. In this study, we found that conditioned medium from the LC212 non-small-cell lung cancer (NSCLC) cell line (LC212-CM) induces morphological changes and overexpression of Vimentin, CD90, SMAD 2/3, SLUG and TWIST in A549 NSCLC cells, consistent with a mesenchymal phenotype. To identify the soluble mediators in LC212-CM involved in this phenomenon, we performed miRNA profiling and TGF-β1 quantification. We found that LC212-CM contains high levels of TGF-β1 as well as different secreted miRNAs. We focused our attention on Homo sapiens-microRNA21 (hsa-miR21), one of most relevant miRNA associated with lung cancer progression, metastasis and EMT. An hsa-miR21 antagomiR was able to prevent the LC212-CM-induced EMT phenotype in A549 cells. Furthermore, we found that TGF-β1 and hsa-miR21 cooperate in the induction of EMT in A549 cells. Intriguingly, TGF-β1 was found to induce hsa-miR21 expression in A549 cell, thus suggesting that the hsa-miR21 mediates at least in part the pro-EMT effects of TGF-β1. In conclusion, hsa-miR21 and TGF-β1 are involved in autocrine and paracrine circuits that regulate the EMT status of lung cancer cells.

• A549 Cells
• Cell Shape/drug effects
• Culture Media, Conditioned/pharmacology
• Epithelial-Mesenchymal Transition/drug effects
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Silencing/drug effects
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Phenotype
• Transforming Growth Factor beta1/metabolism

• P30 CA008748 NCI NIH HHS

Background: Pancreatic ductal adenocarcinoma (PDAC) requires multimodal therapeutic approaches and disease monitoring for effective treatment. Liquid biopsy biomarkers, including circulating tumor cells (CTCs) and cancer stem-like cells (CSCs), hold promise for evaluating treatment response promptly and guiding therapeutic modifications.

Methods: From 24 patients with metastatic PDAC (stage IV, M1) undergoing active systemic treatment, we collected 78 blood samples at different time points for CTC and CSC isolation using a microfluidic platform functionalized with antibodies against a CTC biomarker, epithelial cell adhesion molecule (EpCAM), or a CSC biomarker, CD133. These isolated cells were further verified, via fluorescent staining and imaging, using cytokeratin (CK), CD45, and nucleic acid stain 4',6-diamidino-2-phenylindole (DAPI).

Results: The majority (84.4%) of patient blood samples were positive for CTCs (EpCAM⁺CK⁺CD45^-DAPI⁺) and 70.8% of patient blood samples were positive for CSCs (CD133⁺CK⁺CD45^-DAPI⁺), using the highest baseline value of healthy samples as threshold. The CTC subtypes (EpCAM⁺CK⁺CD45^-DAPI⁺CD133⁺ and EpCAM⁺CK⁺CD45^-DAPI⁺CD133^-) and CSC subtypes (CD133⁺CK⁺CD45^-DAPI⁺EpCAM⁺ and CD133⁺CK⁺CD45^-DAPI⁺EpCAM^-) were also analyzed using immunochemical methods. In several cases, CSCs exhibited cytokeratin expression that did not express EpCAM, indicating that they will not be detected using EpCAM-based isolation.

Conclusion: The microfluidic platform enabled the reliable isolation of CTCs and CSCs from PDAC patient samples, as well as their subtypes. Complementary assessment of both CTCs and CSCs appears advantageous to assess the profile of tumor progressing in some cases. This research has important implications for the application and interpretation of approved methods to detect CTCs.

• cancer stem-like cells
• circulating tumor cells
• microfluidics
• pancreatic cancer

Lung cancer stem cells have the ability to self-renew and are resistant to conventional chemotherapy. MicroRNAs (miRNAs) regulate and control the expression and function of many target genes; therefore, miRNA disorders are involved in the pathogenesis of human diseases, such as cancer. However, the effects of miRNA dysregulation on tumour stemness and drug resistance have not been fully elucidated. miR-181b has been reported to be a tumour suppressor miRNA and is associated with drug-resistant non-small cell lung cancer.

Cancer stem cell (CSC)-like properties were tested by a cell proliferation assay and flow cytometry; miR-181b expression was measured by real-time PCR; and Notch2 and related proteins were detected by Western blotting and immunohistochemistry. A mouse xenograft model was also established.

In this study, we found that ectopic miR-181b expression suppressed cancer stem cell properties and enhanced sensitivity to cisplatin (DDP) treatment by directly targeting Notch2. miR-181b could inactivate the Notch2/Hes1 signalling pathway. In addition, tumours from nude mice treated with miR-181b were significantly smaller than tumours from mice treated with control agomir. Decreased miR-181b expression and increased Notch2 expression were observed to have a significant relationship with overall survival (OS) and CSC-like properties in non-small cell lung cancer (NSCLC) patients.

This study elucidates an important role of miR-181b in the regulation of CSC-like properties, suggesting a potential therapeutic target for overcoming drug resistance in NSCLC.

The online version of this article (10.1186/s13287-018-1072-1) contains supplementary material, which is available to authorized users.

• Cancer stem cell-like properties
• Chemosensitivity
• MicroRNA-181b
• Non-small cell lung cancer (NSCLC)
• Notch2

• Cancer stem cells
• DATS
• Tobacco smoke
• Wnt/β-catenin

• Allyl Compounds/pharmacology
• Bronchi/cytology
• Bronchi/drug effects
• Carcinogenesis
• Cell Line, Tumor
• Cell Transformation, Neoplastic/drug effects
• Epithelial Cells/drug effects
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms/physiopathology
• Neoplastic Stem Cells/drug effects
• Smoking/adverse effects
• Sulfides/pharmacology
• Wnt Signaling Pathway/drug effects
• Wound Healing/drug effects
• beta Catenin/drug effects

Through the specific identification and direct targeting of cancer stem cells (CSCs), it is believed that a better treatment efficacy of cancer may be achieved. Hence, the present study aimed to identify a CSC subpopulation from adenocarcinoma cells (A549) as a model of non-small cell lung cancer (NSCLC). Initially, we sorted two subpopulations known as the triple-positive (EpCAM⁺/CD166⁺/CD44⁺) and triple-negative (EpCAM⁻/CD166⁻/CD44⁻) subpopulation using fluorescence-activated cell sorting (FACS). Sorted cells were subsequently evaluated for proliferation and chemotherapy-resistance using a viability assay and were further characterized for their clonal heterogeneity, self-renewal characteristics, cellular migration, alkaline dehydrogenase (ALDH) activity and the expression of stemness-related genes. According to our findings the triple-positive subpopulation revealed significantly higher (P<0.01) proliferation activity, exhibited better clonogenicity, was mostly comprised of holoclones and had markedly bigger (P<0.001) spheroid formation indicating a better self-renewal capacity. A relatively higher resistance to both 5-fluouracil and cisplatin with 80% expression of ALDH was observed in the triple-positive subpopulation, compared to only 67% detected in the triple-negative subpopulation indicated that high ALDH activity contributed to greater chemotherapy-resistance characteristics. Higher percentage of migrated cells was observed in the triple-positive subpopulation with 56% cellular migration being detected, compared to only 19% in the triple-negative subpopulation on day 2. This was similarly observed on day 3 in the triple-positive subpopulation with 36% higher cellular migration compared to the triple-negative subpopulation. Consistently, elevated levels of the stem cell genes such as REX1 and SSEA4 were also found in the triple-positive subpopulation indicating that the subpopulation displayed a strong characteristic of pluripotency. In conclusion, our study revealed that the triple-positive subpopulation demonstrated similar characteristics to CSCs compared to the triple-negative subpopulation. It also confirmed the feasibility of using the triple-positive (EpCAM⁺/CD166⁺/CD44⁺) marker as a novel candidate marker that may lead to the development of novel therapies targeting CSCs of NSCLC.

The ribosome has long been considered as a consistent molecular factory, with a rather passive role in the translation process. Recent findings have shifted this obsolete view, revealing a remarkably complex and multifaceted machinery whose role is to orchestrate spatiotemporal control of gene expression. Ribosome specialization discovery has raised the interesting possibility of the existence of its malignant counterpart, an 'oncogenic' ribosome, which may promote tumor progression. Here we weigh the arguments supporting the existence of an 'oncogenic' ribosome and evaluate its role in cancer evolution. In particular, we provide an analysis and perspective on how the ribosome may play a critical role in the acquisition and maintenance of cancer stem cell phenotype.

• CSC-specific therapies
• Cancer stem cells
• Cancer-associated fibroblasts
• Epithelial-to-mesenchymal transition
• Exosomes
• Lung cancer
• Microenvironment
• Non-small cell lung carcinoma

• Cancer-Associated Fibroblasts/pathology
• Cancer-Associated Fibroblasts/physiology
• Carcinoma, Non-Small-Cell Lung/pathology
• Cell Communication/physiology
• Epithelial-Mesenchymal Transition/physiology
• Exosomes/physiology
• Female
• Humans
• Lung Neoplasms/pathology
• Male
• Neoplastic Stem Cells/pathology
• Neoplastic Stem Cells/physiology
• Tumor Microenvironment/physiology

• CD133
• CSCs
• EGFR
• NSCLC
• meta-analysis

• Animals
• Cell Hypoxia
• Cell Line, Tumor
• Exosomes/metabolism
• Gene Expression Profiling
• HSP90 Heat-Shock Proteins/metabolism
• Humans
• Lymphatic Metastasis
• Mice
• Nanotechnology
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Organoids/metabolism
• Organoids/pathology

• R01 CA047407 NCI NIH HHS
• R01 CA119045 NCI NIH HHS
• Ryobi Teien Memorial Foundation
• Japan Society for the Promotion of Science
• Japan Society for the Promotion of Science (JP)

The Sonic Hedgehog (Shh) pathway is physiologically involved during embryogenesis, but is also activated in several diseases, including solid cancers. Previous studies have demonstrated that the Shh pathway is involved in oncogenesis, tumor progression and chemoresistance in lung cancer and mesothelioma. The Shh pathway is also closely associated with epithelial-mesenchymal transition and cancer stem cells. Recent findings have revealed that a small proportion of lung cancer cells expressed an abnormal full-length Shh protein, associated with cancer stem cell features. In this paper, we review the role of the Shh pathway in thoracic cancers (small cell lung cancer, non-small cell lung cancer, and mesothelioma) and discuss the new perspectives of cancer research highlighted by the recent data of the literature.

• Sonic Hedgehog
• cancer stem cell
• chemoresistance
• lung cancer
• mesothelioma

• Lung cancer stem cells
• Lung neoplasms
• Molecular targeted therapy
• Neoplastic stem cells

Cancer stem-like cells (CSCs) have been reported to play major roles in tumorigenesis, tumor relapse, and metastasis after therapy against colorectal carcinoma (CRC). Therefore, identification of colorectal CSC regulators could provide promising targets for CRC. Ligand-of-Numb protein X1 (LNX1) is one E3 ubiquitin ligase which mediates the ubiquitination and degradation of Numb. Although several studies indicate LNX1 could be a potential suppressor of cancer diseases, the functions of LNX1 in mediating cancer stemness remain poorly understood. In this study, LNX1 was identified as a negative regulator of cancer stemness in CRC, which was downregulated in colonospheres or side population (SP) cells. Furthermore, the coxsackievirus and adenovirus receptor (CXADR) was found to be one critical downstream mediator of cancer stemness regulated by LNX1. Interestingly, the anti-breast cancer drug tamoxifen was found to be an agonist of LNX1 and suppress cancer stemness in CRC. In sum, this study provided the evidences that LNX1 signaling plays important roles in regulating the stemness of colon cancer cells.