• 82460555 National Natural Science Foundation of China (National Science Foundation of China)

• cancer
• cancer-associated cells
• tumor microenvironment

• Humans
• Neoplasms/pathology
• Neoplasms/immunology
• Neoplasms/metabolism
• Tumor Microenvironment
• Disease Progression
• Animals
• Cell Communication

• transcription
• breast cancer
• cancer stem cells

• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Humans
• Cyclin-Dependent Kinase Inhibitor p27/metabolism
• Cyclin-Dependent Kinase Inhibitor p27/genetics
• Animals
• STAT3 Transcription Factor/metabolism
• STAT3 Transcription Factor/genetics
• Female
• Phosphorylation
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Hyperplasia/metabolism
• Mice
• Gene Expression Regulation, Neoplastic
• Cell Self Renewal/genetics
• Cell Line, Tumor
• Mammary Glands, Animal/metabolism
• Mammary Glands, Animal/pathology
• Mammary Glands, Animal/cytology
• Jagged-1 Protein/metabolism
• Jagged-1 Protein/genetics

• R01 GM141349 NIGMS NIH HHS
• R01CA253111 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
• R01GM113256 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
• R01 GM146409 NIGMS NIH HHS
• R01 CA253111 NCI NIH HHS
• SPEC-23-023 Breast Cancer Research Foundation (BCRF)
• R01 GM113256 NIGMS NIH HHS
• W81XWH-17-1-0456 Breast Cancer Research Foundation (BCRF)
• R01GM146409 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

• DFMO
• ELDA
• cell cycle
• neuroblastoma
• neurosphere
• senescence
• xenograft

• Neuroblastoma/drug therapy
• Neuroblastoma/pathology
• Neuroblastoma/metabolism
• Humans
• Animals
• Cell Line, Tumor
• Mice
• Apoptosis/drug effects
• Eflornithine/pharmacology
• Eflornithine/therapeutic use
• Xenograft Model Antitumor Assays
• Cell Survival/drug effects
• Carcinogenesis/drug effects
• Cell Cycle/drug effects
• Cell Proliferation/drug effects
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Female

• Beat Childhood Cancer Foundation
• Ethan's Rodeo, Meryl and Charles Witmer Foundation
• Brooke's Blossoming Hope Foundation

• Cancer Stem Cell
• Hypoxia
• MCF7
• Vitamin C

• Cancer
• Circular RNA
• N6-methyladenosine
• Therapy
• m6A

• colorectal cancer
• immune
• layer analyses
• molecular characterization
• personalized therapies

• PTQ2018-009760 Spanish Economy and Competitiveness Ministry
• Jesús Antolín Garciarena fellowship IdiPAZ

• Cancer
• Diagnosis
• SNHG9
• ceRNA
• lncRNA

• circular RNAs
• head and neck squamous cell carcinoma
• miRNA sponge function
• tumor microenvironment
• tumor regulation

Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glutathione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.

• Medulloblastoma
• Cancer stem cells
• Stemness
• Metabolism
• Glycolysis
• Lipids

• Biomarkers
• Cancer stem cell
• Chemoresistance
• Colon adenocarcinoma
• Prognosis

• Adenocarcinoma/drug therapy
• Biomarkers, Tumor/genetics
• Carcinogenesis/genetics
• Colonic Neoplasms/drug therapy
• Drug Resistance
• Gene Expression Regulation, Neoplastic
• Humans
• Prognosis

• CD44
• Cancer
• HAS
• Hyaluronan
• Targeting

Radiotherapy represents a first-line treatment for many inoperable lung tumors. New technologies offer novel opportunities for the treatment of lung cancer with the administration of higher doses of radiation in smaller volumes. Because both therapeutic and toxic treatment effects are dose-dependent, it is important to identify a minimal dose protocol for each individual patient that maintains efficacy while decreasing toxicity. Cancer stem cells sustain tumor growth, promote metastatic dissemination, and may give rise to secondary resistance. The identification of effective protocols targeting these cells may improve disease-free survival of treated patients. In this work, we evaluated the existence of individual profiles of sensitivity to radiotherapy in patient-derived cancer stem cells (CSCs) using both in vitro and in vivo models. Both CSCs in vitro and mice implanted with CSCs were treated with radiotherapy at different dose intensities and rates. CSC response to different radiation doses greatly varied among patients. In vitro radiation sensitivity of CSCs corresponded to the therapeutic outcome in the corresponding mouse tumor model. On the other side, the dose administration rate did not affect the response. These findings suggest that in vitro evaluation of CSCs may potentially predict patients’ response, thus guiding clinical decision.

• Ministero dello Sviluppo Economico

Loco-regional recurrences and distant metastases represent the main cause of head and neck squamous cell carcinoma (HNSCC) mortality. The overexpression of chemokine receptor 4 (CXCR4) in HNSCC primary tumors associates with higher risk of developing loco-regional recurrences and distant metastases, thus making CXCR4 an ideal entry pathway for targeted drug delivery. In this context, our group has generated the self-assembling protein nanocarrier T22-GFP-H6, displaying multiple T22 peptidic ligands that specifically target CXCR4. This study aimed to validate T22-GFP-H6 as a suitable nanocarrier to selectively deliver cytotoxic agents to CXCR4⁺ tumors in a HNSCC model. Here we demonstrate that T22-GFP-H6 selectively internalizes in CXCR4⁺ HNSCC cells, achieving a high accumulation in CXCR4⁺ tumors in vivo, while showing negligible nanocarrier distribution in non-tumor bearing organs. Moreover, this T22-empowered nanocarrier can incorporate bacterial toxin domains to generate therapeutic nanotoxins that induce cell death in CXCR4-overexpressing tumors in the absence of histological alterations in normal organs. Altogether, these results show the potential use of this T22-empowered nanocarrier platform to incorporate polypeptidic domains of choice to selectively eliminate CXCR4⁺ cells in HNSCC. Remarkably, to our knowledge, this is the first study testing targeted protein-only nanoparticles in this cancer type, which may represent a novel treatment approach for HNSCC patients.

• CXCR4 receptor
• Cancer therapy
• Cell targeting
• HNSCC
• Nanotoxins
• Protein nanoparticles
• Recombinant proteins
• Targeted drug delivery

• cell proliferation
• chemoresistance
• genes
• metastasis
• osteosarcoma stem cells

The recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated.

The levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed.

In this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells.

These findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC.

The online version contains supplementary material available at 10.1186/s12967-021-03059-y.

• CSCs
• FOXA1
• Invasion
• Migration
• NPC
• Nanog
• miR-4721

Bladder cancer (BCa) is the most prevalent malignancy of the urinary system. Circular RNAs (circRNAs), a novel subtype of non-coding RNAs, play a crucial role in physiological and developmental processes. CircRNAs mainly function as regulators of splicing process and transcription, microRNA sponges, and protein brackets. Recent advances in understanding the pathogenesis of BCa have led to the identification of an abundance of dysregulated circRNAs associated with BCa. These aberrantly expressed circRNAs eventually lead to abnormalities in biological, genetic, and epigenetic information. In this review, we introduce the potential of circRNAs as biomarkers for BCa diagnosis and prognosis. Notably, diverse mechanisms have been proposed for circRNAs driving carcinogenesis, including increasing cell proliferation, promoting invasive and migratory capacity, enhancing endothelial–mesenchymal transition, sustaining stemness, and enabling resistance to chemotherapy. Importantly, a full understanding of circRNA mechanisms is needed to mine promising therapeutic approaches for targeting BCa. In this paper, we present the latest advances in circRNAs and systemically summarize the characteristics and mechanisms of circRNAs in BCa, providing potential perspectives for BCa treatment.

• biomarker
• bladder cancer
• circular RNA
• diagnosis
• prognosis
• treatment

• cancer stem cells
• colorectal carcinoma
• feedback loop
• miRNAs
• regulatory network
• signaling pathways

• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Disease Progression
• Epithelial-Mesenchymal Transition/genetics
• Epithelial-Mesenchymal Transition/physiology
• Feedback, Physiological
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Models, Biological
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Signal Transduction

Radiotherapy is often used as a neo-adjuvant treatment in locally advanced rectal cancer. While treatment generally induces an improvement in the outcome, some patients show resistance to treatment for reasons that still have to be elucidated. In this work, we report an in vitro and in vivo model based on patient-derived cancer stem cells. This model is able to predict individual responses to radiotherapy. The results indicate that cells found to be radiation-sensitive in vitro generated radiation-sensitive tumor xenografts upon subcutaneous implantation. Analogously, cancer stem cells (CSCs) that did not respond to in vitro radiation treatment generated radiation-resistant tumor xenografts. Moreover, radioresistant CSCs were generally isolated via biopsies of patients with poor responses to neo-adjuvant radiotherapy. This suggests that a cell-based in vitro test may itself be sufficient to predict outcomes in donor patients.

Neo-adjuvant radiotherapy is frequently employed in the therapeutic management of locally advanced rectal cancer (LARC). Radiotherapy can both reduce local recurrence and improve the success of surgical procedures by reducing tumor mass size. However, some patients show a poor response to treatment, which results in primary resistance or relapse after apparent curative surgery. In this work, we report in vitro and in vivo models based on patient-derived cancer stem cells (CSCs); these models are able to predict individual responses to radiotherapy in LARC. CSCs isolated from colorectal cancer biopsies were subjected to in vitro irradiation with the same clinical protocol used for LARC patients. Animal models, generated by CSC xenotransplantation, were also obtained and treated with the same radiotherapy protocol. The results indicate that CSCs isolated from rectal cancer needle biopsies possess an intrinsic grade of sensitivity to treatment, which is also maintained in the animal model. Notably, the specific CSCs’ in vitro and in vivo sensitivity values correspond to patients’ responses to radiotherapy. This evidence suggests that an in vitro radiotherapy response predictivity assay could support clinical decisions for the management of LARC patients, thus avoiding radiation toxicity to resistant patients and reducing the treatment costs.

• cancer stem cells
• in vitro radiotherapy
• locally advanced rectal cancer (LARC)
• neo-adjuvant radiotherapy
• preclinical model of radiotherapy

Pancreatic cancer (PC) is difficult to defeat due to mechanism (s) driving metastasis and drug resistance. Cancer stemness is a major challenging phenomenon associated with PC metastasis and limiting therapy efficacy. In this study, we evaluated the pre-clinical and clinical significance of eradicating pancreatic cancer stem cells (PCSC) and its components using a pan-EGFR inhibitor afatinib in combination with gemcitabine. Afatinib in combination with gemcitabine, significantly reduced Kras^G12D/+; Pdx-1 Cre (KC) (P<0.01) and Kras^G12D/+; p53^R172H/+; Pdx-1 Cre (KPC) (P<0.05) derived mouse tumoroids and KPC-derived murine syngeneic cell line growth compared to gemcitabine/afatinib alone treatment. The drug combination also reduced PC xenograft tumor burden (P<0.05) and the incidence of metastasis by affecting key stemness markers, as confirmed by co-localization studies. Moreover, the drug combination significantly decreases the growth of various PC patient-derived organoids (P<0.001). We found that SOX9 is significantly overexpressed in high-grade PC tumors (P<0.05) and in chemotherapy-treated patients compared to chemo-naïve patients (P<0.05). These results were further validated using publicly available datasets. Moreover, afatinib alone or in combination with gemcitabine decreased stemness and tumorspheres by reducing phosphorylation of EGFR family proteins, ERK, FAK, and CSC markers. Mechanistically, afatinib treatment decreased CSC markers by downregulating SOX9 via FOXA2. Indeed, EGFR and FOXA2 depletion reduced SOX9 expression in PCSCs. Taken together, pan EGFR inhibition by afatinib impedes PCSCs growth and metastasis via the EGFR/ERK/FOXA2/SOX9 axis. This novel mechanism of panEGFR inhibitor and its ability to eradicate CSC may serve as a tailor-made approach to enhance chemotherapeutic benefits in other cancer types.

• antitumor agents
• bioinorganic chemistry
• cyclooxygenase-2
• necroptosis
• nickel

• Anti-Inflammatory Agents, Non-Steroidal/pharmacology
• Breast Neoplasms/drug therapy
• Breast Neoplasms/pathology
• Coordination Complexes/chemistry
• Coordination Complexes/pharmacology
• Female
• Humans
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Nickel/chemistry

• EP/S005544/1 Engineering and Physical Sciences Research Council
• Engineering and Physical Sciences Research Council

The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.

• cancer stem cells
• hepatocellular carcinoma
• liver cancer

The leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial protein that has been associated with the occurrence and development of malignant tumors. Previous studies have shown that LETM1 expression is increased in several types of human cancer and is associated with a poor clinical outcome. However, the role of LETM1 in prostate cancer (PCa) has not yet been determined. In this study, we investigated the clinicopathological significance of LETM1 expression and its role in PCa progression.

We assessed the expression of LETM1 and genes related to cancer stemness, epithelial-mesenchymal transition (EMT), cell cycle, and PI3K/Akt signaling in 133 paraffin-embedded PCa tissue samples and cancer cells by using immunohistochemistry, immunofluorescence, and Western blotting.

LETM1 expression was significantly increased in PCa, and it was positively correlated with Gleason score, pathologic tumor (pT) stage, clinical stage, and high microvessel density. Survival analysis showed that patients with PCa with a high level of LETM1 expression exhibited a low overall survival. Cox regression analysis indicated that LETM1 is an independent poor prognostic PCa factor. Additionally, the expression of LETM1 was correlated with cancer cell stemness-associated genes, EMT-related genes, cell cycle regulatory genes, and PI3K/Akt signaling gene expression in PCa. Furthermore, knocking down LETM1 expression down-regulated the expression of stemness-related proteins, while inhibiting tumor spheroid formation, EMT-like changes, cell proliferation, migration, and invasion in PCa cells. Importantly, the PI3K inhibitor LY294002 strongly inhibited the expression of LETM1, pPI3K-p85, and pAkt (Thr308, Ser473) in PCa cells.

These results indicate that LETM1 expression is associated with cancer cell stemness, promotes EMT-like changes and cell proliferation and is a potential prognostic biomarker for PCa.

• epithelial-mesenchymal transition
• leucine zipper-EF-hand containing transmembrane protein 1
• prognosis
• prostate cancer

• Youth Innovation Promotion Association of the Chinese Academy of Sciences
• National Natural Science Foundation of China

Resistance to trastuzumab remains a major obstacle in HER2‐overexpressing breast cancer treatment. miR‐200c is important for many functions in cancer stem cells (CSCs), including tumour recurrence, metastasis and resistance. We hypothesized that miR‐200c contributes to trastuzumab resistance and stemness maintenance in HER2‐overexpressing breast cancer. In this study, we used HER2‐positive SKBR3, HER2‐negative MCF‐7, and their CD44⁺CD24⁻ phenotype mammospheres SKBR3‐S and MCF‐7‐S to verify. Our results demonstrated that miR‐200c was weakly expressed in breast cancer cell lines and cell line stem cells. Overexpression of miR‐200c resulted in a significant reduction in the number of tumour spheres formed and the population of CD44⁺CD24⁻ phenotype mammospheres in SKBR3‐S. Combining miR‐200c with trastuzumab can significantly reduce proliferation and increase apoptosis of SKBR3 and SKBR3‐S. Overexpression of miR‐200c also eliminated its downstream target genes. These genes were highly expressed and positively related in breast cancer patients. Overexpression of miR‐200c also improved the malignant progression of SKBR3‐S and SKBR3 in vivo. miR‐200c plays an important role in the maintenance of the CSC‐like phenotype and increases drug sensitivity to trastuzumab in HER2+ cells and stem cells.

• CD44+CD24− phenotype
• HER2
• breast cancer
• miR-200c
• stem cell
• trastuzumab

• Y-box binding protein-1
• biomarker
• lung cancer
• mesothelioma
• targeted therapy

• CD44
• Cancer niche
• Cancer stem cells (CSCs)
• Drug resistance
• EMT
• Exosomes
• Hyaluronan

• FRK
• lung cancer
• metabolic reprogramming
• poor prognosis
• stemness

• Anti-CRC SCs strategies
• CRC biology and biomarkers
• CRC circulating stem cells
• CRC metastatic stem cells
• CRC stem cells
• Human colorectal carcinoma (CRC)
• Stemness

• Animals
• Biomarkers
• Cell Self Renewal
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• DNA Copy Number Variations
• Disease Models, Animal
• Epithelial-Mesenchymal Transition/genetics
• Fluorescent Antibody Technique
• Heterografts
• Humans
• Immunohistochemistry
• Loss of Heterozygosity
• Mice
• Neoplasm Grading
• Neoplasm Staging
• Neoplastic Cells, Circulating/metabolism
• Neoplastic Cells, Circulating/pathology
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology

• cancer stem cells
• doxorubicin
• drug resistance
• resveratrol

Circular RNAs (circRNAs) are a class of RNA molecules with closed loops and high stability. CircRNAs are abundantly expressed in eukaryotic organisms and exhibit both location- and step-specificity. In recent years, circRNAs are attracting considerable research attention attributed to their possible contributions to gene regulation through a variety of actions, including sponging microRNAs, interacting with RNA-binding proteins, regulating transcription and splicing, and protein translation. Growing evidence has revealed that circRNAs play critical roles in the development and progression of diseases, especially in cancers. Without doubt, expanding our understanding of circRNAs will enrich knowledge of cancer and provide new opportunities for cancer therapy. In this review, we provide an overview of the characteristics, functions and functional mechanisms of circRNAs. In particular, we summarize current knowledge regarding the functions of circRNAs in the hallmarks, stemness, resistance of cancer, as well as the possibility of circRNAs as biomarkers in cancer.

• Biomarker
• Cancer
• CircRNAs
• Function
• Hallmarks
• Resistance
• Stemness

Objectives: Recently, embryonic microenvironment is being known for its non-permissive property for tumor growth. However, the regulatory mechanism to maintain the balance between differentiation and tumorigenicity of cancer cell in microenvironment is not well understood.

Materials and Methods: qRT-PCR was performed to detect the levels of gene expression in HT29, LoVo and Caco-2 colorectal cancer cells, and Western blot was used to measure the protein levels. Cell migration and apoptosis were measured by Transwell and flow cytometry assays. Cancer cell markers were detected using immunohistochemical staining. In vivo tumor formation assay was conducted by subcutaneous injection of embryonic microenvironment-treated cancer cells.

Results: Colorectal cancer cell lines were treated with human embryonic stem cell conditioned culture and then collected for in vivo tumor formation assay and in vitro assays assessing the aggressive properties. We found exposure of cancer cells in human ES cultures resulted in inhibition of growth, migration of tumor cells. Moreover, we found that manipulation of Notch pathway in the ES cells microenvironment could influence the stemness of tumor. We specifically discovered that some factor in the embryonic microenvironment could suppress Notch1 pathway in the cancer cells, leading to a reduction in tumorigenesis and invasiveness.

Conclusions: This study may provide another evidence to understand the crosstalk between tumor cells and embryonic environment and may offer new therapeutic strategies to inhibit colorectal cancer progression.

• Notch pathway
• colorectal cancer
• embryonic stem cell microenvironment
• tumorigenicity

Esophageal cancer (EC) is the sixth leading cause of cancer-related death worldwide. The lack of early diagnostic biomarkers and effective prognostic indicators for metastasis and recurrence has resulted in the poor prognosis of EC. In addition, the underlying molecular mechanisms of EC development have yet to be elucidated. Accumulating evidence has demonstrated that lncRNAs play a vital role in the pathological progression of EC. LncRNAs may regulate gene expression through the recruitment of histone-modifying complexes to the chromatin and through interactions with RNAs or proteins. Recent evidence has demonstrated that the dysregulation of lncRNAs plays important roles in the proliferation, metastasis, invasion, angiogenesis, apoptosis, chemoradiotherapy resistance, and stemness of EC, which suggests potential clinical implications. In this review, we highlight the emerging roles and regulatory mechanisms of lncRNAs in the context of EC and discuss their potential clinical applications as diagnostic and prognostic biomarkers.

• Application
• Biomarker
• Esophageal cancer
• Long non-coding RNA
• Mechanism

• 5-fluorouracil
• TNF-β
• alginate culture
• cancer stem cells
• colorectal cancer
• resveratrol

• Antimetabolites, Antineoplastic/pharmacology
• Apoptosis/drug effects
• Biomarkers, Tumor/metabolism
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition/drug effects
• Fluorouracil/pharmacology
• HCT116 Cells
• Humans
• Lymphotoxin-alpha/pharmacology
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Phenotype
• Resveratrol
• Signal Transduction/drug effects
• Stilbenes/pharmacology
• Tumor Microenvironment

• Aging
• Cancer stem cells
• Geroprotection
• Regenerative medicine
• Side population
• Stem cell markers
• Stem cells
• VSELs
• Very small embryonic-like stem cells

Bone morphogenetic proteins (BMPs) play important roles in embryonic and postnatal development by regulating cell differentiation, proliferation, motility, and survival, thus maintaining homeostasis during organ and tissue development. BMPs can lead to tumorigenesis and regulate cancer progression in different stages. Therefore, we summarized studies on BMP expression, the clinical significance of BMP dysfunction in various cancer types, and the molecular regulation of various BMP-related signaling pathways. We emphasized on the paradoxical effects of BMPs on various aspects of carcinogenesis, including epithelial–mesenchymal transition (EMT), cancer stem cells (CSCs), and angiogenesis. We also reviewed the molecular mechanisms by which BMPs regulate tumor generation and progression as well as potential therapeutic targets against BMPs that might be valuable in preventing tumor growth and invasion.

• BMP signaling pathway
• cancer stem cell
• epithelial–mesenchymal transition
• tumorigenesis

Cancer stem cells (CSCs) are defined as a rare subpopulation of undifferentiated cells with biological characteristics that include the capacity for self-renewal, differentiation into various lineages, and tumor initiation. To explore the mechanism of CSCs in esophageal squamous cell carcinoma (ESCC), we focused on Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), a target gene of the Wnt signaling pathway, which has been identified as a marker of intestinal stem cells and shown to be overexpressed in several human malignancies. Lgr5 expression was significantly correlated with lymph node metastasis, increased depth of invasion, increased tumor size, advanced differentiation, higher AJCC stage and poorer survival. Silencing of Lgr5 expression in the ESCC cell line KYSE450 by small interfering RNA (siRNA) strongly inhibited cell proliferation, migration and invasion ability, the expression of CSCs-related genes and Wnt/β-catenin signaling. In addition, Lgr5 was highly expressed in ESCC spheroid body cells, which were identified by high expression of CSCs-related genes, and high tumorigenicity in vivo. Taken together, these results demonstrate that Lgr5 activation of Wnt/β-catenin signaling is a potential mechanism to promote the progression of ESCC and ESCC stem cell renewal, and Lgr5 may be used as a molecular target for the development of treatments for ESCC.

• Lgr5
• cancer stem cells
• esophageal squamous cell carcinoma
• small interfering RNA
• spheroid body cells

• Anticancer agents
• Cellular pharmacology
• Guidelines

• Antineoplastic Agents/pharmacology
• Data Accuracy
• Drug Discovery
• Drug Evaluation, Preclinical/methods
• Drug Evaluation, Preclinical/standards
• Europe
• Humans
• Neoplasms/drug therapy

Lymphovascular emboli is a prognostic factor in stage II CRC, but the significance of intravascular emboli (IVE) in stage III is unclear. Data from consecutive stage III CRC patients receiving radical surgery between January 2009 and November 2014 were retrospectively collected. The expression of CD133 was tested by immumohistochemical (IHC) staining. The potential prognosis risk factors were tested using univariate and multivariate survival analyses. IVE was significantly associated with CD133 expression (P < 0.001), gross tumor morphology (P = 0.001), histologic type (p < 0.001), lymph node status (pN) (p < 0.001), sub-class of stage III (p = 0.001), and serum CA199 level (p = 0.022). IVE, CD133 expression and lymph node status (pN) were independent risk factors for overall survival (OS) (p < 0.001, p = 0.003, and p = 0.008, respectively) and disease-free survival (DFS) (p < 0.001, p = 0.004, and p = 0.007, respectively) in stage III CRC. IVE might be an independent risk factor for the prognosis of stage III CRC patients after radical surgery. IVE might express a cancer stem cell (CSC) phenotype.

• CD133
• clinicopathological characteristics
• intravascular emboli
• prognosis
• stage III colorectal cancer

• biomarkers
• cancer stem cells
• disruptive innovation
• heterogeneity
• innovation systems
• stem cell markers
• therapeutics
• tumour initiating cells