Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.

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Targeting cancer stem cell pathways for cancer therapy

Polyphenolic phytochemicals are ubiquitous in plants, in which they function in various protective roles A 'recommended' human diet contains significant quantities of polyphenolics, as they have long been assumed to be 'antioxidants' that scavenge excessive, damaging, free radicals arising from normal metabolic processes There is recent evidence that polyphenolics also have 'indirect' antioxidant effects through induction of endogenous protective enzymes There is also increasing evidence for many potential benefits through polyphenolic-mediated regulation of cellular processes such as inflammation Inductive or signalling effects may occur at concentrations much lower than required for effective radical scavenging Over the last 2-3 years, there have been many exciting new developments in the elucidation of the in vivo mechanisms of the health benefits of polyphenolics We summarise the current knowledge of the intake, bio-availability and metabolism of polyphenolics, their antioxidant effects, regulatory effects on signalling pathways, neuro-protective effects and regulatory effects on energy metabolism and gut health

Polyphenolic phytochemicals--just antioxidants or much more?

Multitargeted therapy of cancer by silymarin.

To understand the genetic drivers of immune recognition and evasion in colorectal cancer (CRC), we analyzed 1,211 CRC primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas CRC cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of CRC, had a high rate of significantly mutated genes in important immune modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). WNT/β-catenin signaling genes were significantly mutated in all CRC subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of CRC demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration, and furthermore, that CRC tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.

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Genetic Mechanisms of Immune Evasion in Colorectal Cancer

Background:A recent association between breast implants and the development of anaplastic large-cell lymphoma (ALCL) has been observed. The purpose of this study was to identify whether bacterial biofilm is present in breast implant–associated ALCL and, if so, to compare the bacterial microbiome to

Bacterial Biofilm Infection Detected in Breast Implant-Associated Anaplastic Large-Cell Lymphoma.

Matrine induced gastric cancer MKN45 cells apoptosis via increasing pro-apoptotic molecules of Bcl-2 family.

Up-regulation of microRNA-1290 impairs cytokinesis and affects the reprogramming of colon cancer cells.

CagA of Helicobacter pylori is a bacterium-derived oncogenic protein closely associated with the development of gastric cancers. MicroRNAs (miRNAs) are a class of widespread non-coding RNAs, many of which are involved in cell growth, cell differentiation and tumorigenesis. The relationship between CagA protein and miRNAs is unclear. Using mammalian miRNA profile microarrays, we found that miRNA-584 and miRNA-1290 expression was up-regulated in CagA-transformed cells, miRNA-1290 was up-regulated in an Erk1/2-dependent manner, and miRNA-584 was activated by NF-κB. miRNA-584 sustained Erk1/2 activities through inhibition of PPP2a activities, and miRNA-1290 activated NF-κB by knockdown of NKRF. Foxa1 was revealed to be an important target of miRNA-584 and miRNA-1290. Knockdown of Foxa1 promoted the epithelial-mesenchymal transition significantly. Overexpression of miRNA-584 and miRNA-1290 induced intestinal metaplasia of gastric epithelial cells in knock-in mice. These results indicate that miRNA-584 and miRNA-1290 interfere with cell differentiation and remodel the tissues. Thus, the miRNA pathway is a new pathogenic mechanism of CagA.

/pdf/micrornas-up-regulated-by-caga-of-helicobacter-pylori-induce-46otgwmh4s.pdf

MicroRNAs Up-Regulated by CagA of Helicobacter pylori Induce Intestinal Metaplasia of Gastric Epithelial Cells

CagA of Helicobacter pylori is a protein that has been closely associated with gastric cancer and that can intervene with signal pathways in cells. Its precise relationship with the occurrence of gastric cancer, however, remains unclear. The purpose of this study is to investigate whether CagA can promote transformation of normal gastric epithelial cells and to consider via what mechanisms CagA may exert its effects. Transformed colonies were merged in soft-agarose medium after immortalized gastric epithelial cells were transfected with recombinant pLHCX retrovirus with cagA and/or dimethylhydrazine. The number of transformed colonies in the group containing cagA/pLHCX retrovirus, combined with a subthreshold dose of dimethylhydrazine, was more than that for cagA/pLHCX retrovirus or dimethylhydrazine at a subthreshold dose alone. For cagA-transfected cells, only IQGAP-2, R-Ras and B-Raf of the Ras/mitogen-activated protein kinase signal pathway were markedly increased, and the activity of extracellular signal-regulated kinase 1/2 (Erk1/2) kinase was significantly higher than that in dimethylhydrazine-transformed cells or control cells. However, no evidence of alteration of any other molecules of the Ras superfamily was observed in cagA-transfected cells. These findings suggest that CagA can transform gastric epithelial cells through activation of the Erk1/2 pathway; this mechanism may, however, be independent of Ras activation.

Transformed immortalized gastric epithelial cells by virulence factor CagA of Helicobacter pylori through Erk mitogen-activated protein kinase pathway.

It has been shown by epidemiological and animal studies that microcystin is an important exogenous factor involved in the carcinogenesis of colorectal cancer (CRC). However, details of the mechanism remain unclear. Transformation of colorectal cells is an important initial step in carcinogenesis. Whether microcystin is capable of transforming immortalized colorectal crypt cells, and what the mechanism might be, was investigated. In the present study, we demonstrated that immortalized colorectal crypt cells could be transformed by microcystin. Transformed colorectal crypt cells showed an anchorage-independent growth phenotype, and the proliferation activities of microcystin-transformed cells were also greater than that of immortalized colorectal crypt cells. The Akt and the p38, JNK of mitogen-activated protein kinase (MAPK) pathways in microcystin-transformed cells were found to be constitutively activated. In microcystin-transformed cells, PI3K, MAPKAPK2, Akt, cyclin D1 and cyclin D3 in the Akt pathway; IQGAP-2, RabGTPase, Rap1GAP, RasGAP, R-Ras, Krev-1 and TC21 of the Ras GTP/GDP protein family; and A-Raf, B-Raf and PAK in the Ras/MAPK pathway were all markedly upregulated. However, in positive control cells, dimethylhydrazine-transformed cells, only the Akt pathway was activated by PI3K, and no evidence of alteration of any molecules of the Ras superfamily was observed. Inhibition of Akt, p38 and JNK activation led to a reduced proliferation of microcystin-transformed cells. This implies that the constitutive activation of Akt and the p38, JNK of MAPK pathways in microcystin-transformed cells may be the mechanism by which this important external factor acts in the carcinogenesis of CRC.

Yongliang Zhu

Papers

Matrine induced gastric cancer MKN45 cells apoptosis via increasing pro-apoptotic molecules of Bcl-2 family.

Up-regulation of microRNA-1290 impairs cytokinesis and affects the reprogramming of colon cancer cells.

MicroRNAs Up-Regulated by CagA of Helicobacter pylori Induce Intestinal Metaplasia of Gastric Epithelial Cells

Transformed immortalized gastric epithelial cells by virulence factor CagA of Helicobacter pylori through Erk mitogen-activated protein kinase pathway.

Transformation of immortalized colorectal crypt cells by microcystin involving constitutive activation of Akt and MAPK cascade.