We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis.
In some organs, adult stem cells are uniquely poised to serve as cancer cells of origin. It is unclear, however, whether tumorigenesis is influenced by the activation state of the adult stem cell. Hair follicle stem cells (HFSCs) act as cancer cells of origin for cutaneous squamous cell carcinoma and undergo defined cycles of quiescence and activation. The data presented here show that HFSCs are unable to initiate tumours during the quiescent phase of the hair cycle, indicating that the mechanisms that keep HFSCs dormant are dominant over the gain of oncogenes (such as Ras) or the loss of tumour suppressors (such as p53). Furthermore, Pten activity is necessary for quiescence-based tumour suppression, as its deletion alleviates tumour suppression without affecting proliferation. These data demonstrate that stem cell quiescence is a form of tumour suppression in HFSCs, and that Pten plays a role in maintaining quiescence in the presence of tumorigenic stimuli.
The cancer stem cell (CSC) model depicts that tumors are hierarchically organized and maintained by CSCs lying at the apex. CSCs have been “identified” in a variety of tumors through the tumor-forming assay, in which tumor cells distinguished by a certain cell surface marker (known as a CSC marker) were separately transplanted into immunodeficient mice. In such assays, tumor cells positive but not negative for the CSC marker (hereby defined as CSC(+) and CSC(-) cells, respectively) have the ability of tumor-forming and generating both progenies. However, here we show that CSC(+) and CSC(-) cells exhibit similar proliferation in the native states. Using a cell tracing method, we demonstrate that CSC(-) cells exhibit similar tumorigenesis and proliferation as CSC(+) cells when they were co-transplanted into immunodeficient mice. Through serial single-cell derived subline construction, we further demonstrated that CSC(+) and CSC(-) cells from CSC marker expressing tumors could invariably generate both progenies, and their characteristics are maintained among different generations irrespective of the origins (CSC(+)-derived or CSC(-)-derived). These findings demonstrate that tumorigenic cells cannot be distinguished by common CSC markers alone and we propose that cautions should be taken when using these markers independently to identify cancer stem cells due to the phenotypic plasticity of tumor cells.
The asymmetric total synthesis of cyclic depsipeptide BE-43547A₂ was achieved in 15 linear steps on a 350 mg scale in one batch. Our synthesis is featured with highly diastereoselective construction of α-hydroxy-β-ketoamide via α-hydroxylation with a d.r. up to 86:1. BE-43547A₂ can significantly reduce the percentage of pancreatic cancer stem cells in Panc-1 cells, and dramatically ablate the tumorsphere forming capability of Panc-1 cells. The tumor-initiating assay in-vivo, a gold standard for cancer stem cell assays, confirmed BE-43547A₂ could abolish the tumorigenesis of Panc-1 cells. The anti-PCSC activity of BE-43547A₂ will make this depsipeptide scaffold a start for discovering new PCSC-targeting drug.
Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/Apc(min/+) mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apc(min/+) mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.
Lung cancer is the leading cause of cancer-related death worldwide; tobacco smoke (TS) constitutes the main causes of lung cancer. Acquisition of cancer stem cells (CSCs)-like properties is the essential progression for the initiation of lung cancer. However, the mechanisms for tobacco smoke-induced lung carcinogenesis remain elusive. In the present study, we demonstrated that long-term exposure of human bronchial epithelial (HBE) cells to TS resulted in malignant transformation and acquisition of CSC-like properties. Moreover, Wnt/β-catenin pathway was involved in acquisition of the CSC-like phenotype during neoplastic transformation of HBE cells induced by TS. Downregulation of β-catenin reduced the tumorsphere and decreased the protein expression of lung CSCs markers in TS-transformated HBE sphere-forming cells. Furthermore, Diallyl trisulfide (DATS) inhibited the CSCs activity of TS-transformed HBE cells, as well as Wnt/β-catenin suppression. Activation of Wnt/β-catenin diminished the inhibitory effects of DATS on TS-induced stemness of HBE cells. Together, the present investigation elucidates the modulation of Wnt/β-catenin in chronic TS exposure-triggered pulmonary acquisition of CSCs properties and DATS intervention, which may provide new insights into the interventional strategies against lung CSCs.
Small nucleolar RNAs (snoRNAs) play an important role in carcinogenesis. In this study, we identified a C/D box snoRNA, snord105b, and further investigated the function and mechanism of the snord105b in gastric cancer (GC).
The fourth member of the leucine-rich repeat-containing GPCR family (LGR4, frequently referred to as GPR48) and its cognate ligands, R-spondins (RSPOs) play crucial roles in the development of multiple organs as well as the survival of adult stem cells by activation of canonical Wnt signaling. Wnt/β-catenin signaling acts to regulate breast cancer; however, the molecular mechanisms determining its spatiotemporal regulation are largely unknown. In this study, we identified LGR4 as a master controller of Wnt/β-catenin signaling-mediated breast cancer tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. LGR4 expression in breast tumors correlated with poor prognosis. Either Lgr4 haploinsufficiency or mammary-specific deletion inhibited mouse mammary tumor virus (MMTV)-PyMT- and MMTV-Wnt1-driven mammary tumorigenesis and metastasis. Moreover, LGR4 down-regulation decreased in vitro migration and in vivo xenograft tumor growth and lung metastasis. Furthermore, Lgr4 deletion in MMTV-Wnt1 tumor cells or knockdown in human breast cancer cells decreased the number of functional CSCs by ∼90%. Canonical Wnt signaling was impaired in LGR4-deficient breast cancer cells, and LGR4 knockdown resulted in increased E-cadherin and decreased expression of N-cadherin and snail transcription factor -2 (SNAI2) (also called SLUG), implicating LGR4 in regulation of epithelial-mesenchymal transition. Our findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast CSCs.-Yue, Z., Yuan, Z., Zeng, L., Wang, Y., Lai, L., Li, J., Sun, P., Xue, X., Qi, J., Yang, Z., Zheng, Y., Fang, Y., Li, D., Siwko, S., Li, Y., Luo, J., Liu, M. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells.
Carcinogenesis is a complex process involving in genotoxic and non-genotoxic pathways. Carcinogenic potential of AgNPs has been predicted by genotoxic effects using several in vitro and in vivo models. However, there is no little information on non-genotoxic effects of AgNPs for carcinogenesis. In vitro cell transformation assay (CTA) can provide specific and sensitive evidence to predict the tumorigenic potential of a chemical, which cannot be supplied by genotoxicity testing. Therefore, we carried out CTA in Balb/c 3T3 A31-1-1 cells to evaluate the carcinogenic potential of silver nanoparticle (AgNPs). Colony forming efficiency (CFE) assay, and crystal violet (CV) assay were carried out to find cytotoxicity of AgNPs. Cytokinesis-block micronucleus assay (CBMN) and CTA in Balb/c 3T3 A31-1-1 cells were performed to predict in vitro carcinogenic potential of AgNPs. In CBMN assay, AgNPs (10.6 ug/mL) induced a significant increase of the micronucleus formation indicating that AgNPs had genotoxicity and could be an initiator for carcinogenesis. In CTA assay to assess carcinogenic potential of AgNPs, cells exposed to AgNPs for 72 h significantly induced morphological neoplastic transformation at all treated doses (0.17, 0.66, 2.65, 5.3, and 10.6 ug/mL) and Tf (transformation frequency) showed a significant increase in a dose-dependent manner. These results indicated that short-term exposure (72 h) to AgNPs had in vitro carcinogenetic potency in Balb/c 3T3 A31-1-1 cells.