Chronic myeloid leukemia as a stem cell-derived malignancy

Chronic myeloid leukemia (CML) is a myeloproliferative disease of the hematopoietic stem cells, characterized by the presence of the Philadelphia (Ph) chromosome. Although imatinib inhibits the BCR-ABL kinase activity, clinical experiences confirm that imatinib may not target CML stem cells in vivo. The identification of signaling pathways responsible for the self-renewal properties of leukemic stem cells in CML will help in the discovery of novel therapeutic targets. Here we review signaling pathways including Wnt/β-catenin, Hedgehog, Alox5, and Foxo which play crucial roles in the maintenance of stem cell functions in CML. It is thought that inhibition of key genes that are part of self-renewal associated signaling pathways may provide an effective way to reduce aberrant stem cell renewal in CML

Signaling pathways involved in chronic myeloid leukemia pathogenesis: the importance of targeting Musashi2-Numb signaling to eradicate leukemia stem cells

Objective(s): Chronic myeloid leukemia (CML) is a myeloid clonal proliferation disease defining by the presence of the Philadelphia chromosome that shows the movement of BCR-ABL1. In this study, the critical role of the Musashi2-Numb axis in determining cell fate and relationship of the axis to important signaling pathways such as Hedgehog and Notch that are essential for self-renewal pathways in CML stem cells will be reviewed meticulously.Materials and Methods: In this review, a PubMed search using the keywords of Leukemia, signaling pathways, Musashi2-Numb was performed, and then we summarized different research works.Results: Although tyrosine kinase inhibitors such as Imatinib significantly kill and remove the cell with BCR-ABL1 translocation, they are unable to target BCR-ABL1 leukemia stem cells. The main problem is stem cells resistance to Imatinib therapy. Therefore, the identification and control of downstream molecules/ signaling route of the BCR-ABL1 that are involved in the survival and self-renewal of leukemia stem cells can be an effective treatment strategy to eliminate leukemia stem cells, which supposed to be cured by Musashi2-Numb signaling pathway.Conclusion: The control of molecules /pathways downstream of the BCR-ABL1 and targeting Musashi2-Numb can be an effective therapeutic strategy for treatment of chronic leukemia stem cells. While Musashi2 is a poor prognostic marker in leukemia, in treatment and strategy, it has significant diagnostic value

The effects of ovarian cancer cell-derived exosomes on vascular endothelial growth factor expression in endothelial cells

Ovarian carcinoma is considered as a major clinical challenge worldwide. Exosomes, nano-sized intraluminal vesicles of multivesicular bodies, are secreted by most types of cells and play an important role in intercellular communication. Cancer cell-derived exosomes can develop cancer progression and metastasis by manipulating the local and distant biological environments. Angiogenesis is an important contributor to tumor progression. Vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic protein and induces proliferation, sprouting, and vessel formation by endothelial cells. In this study, exosomes derived from ovarian epithelial cancer cells OVACAR-3 (exo-OVCAR-3) were successfully isolated and characterized by scanning electron microscopy in terms of size and morphology. Cellular internalization of exosomes labeled with PKH fluorescent dye was monitored by a fluorescence microscope. Our results elucidated that exosomes treatment (100 µg/ml) had a promoting effect on VEGF expression and secretion in endothelial cells. Furthermore, we demonstrated that exo-OVCAR-3 caused an increase in the proliferation and migration rate of endothelial cells. It seems that inducing VEGF by exo-OVCAR-3 can influence the vascular behavior of endothelial cells in vitro

The Promising Role of Non-Coding RNAs as Biomarkers and Therapeutic Targets for Leukemia

Early-stage leukemia identification is crucial for effective disease management and leads to an improvement in the survival of leukemia patients. Approaches based on cutting-edge biomarkers with excellent accuracy in body liquids provide patients with the possibility of early diagnosis with high sensitivity and specificity. Non-coding RNAs have recently received a great deal of interest as possible biomarkers in leukemia due to their participation in crucial oncogenic processes such as proliferation, differentiation, invasion, apoptosis, and their availability in body fluids. Recent studies have revealed a strong correlation between leukemia and the deregulated non-coding RNAs. On this basis, these RNAs are also great therapeutic targets. Based on these advantages, we tried to review the role of non-coding RNAs in leukemia. Here, the significance of several non-coding RNA types in leukemia is highlighted, and their potential roles as diagnostic, prognostic, and therapeutic targets are covered

Evaluation of the expansion of umbilical cord blood derived from CD133+ cells on biocompatible microwells

Background: Hematopoietic stem cell transplantation (HSCT) is a therapeutic approach for treatment of hematological malignancies and incompatibility of Bone marrow. Umbilical cord blood (UCB) has known as an alternative for hematopoietic stem/progenitor cells (HPSC) in allogeneic transplantation. The low volume of collected samples is the main hindrance in application of HPSC derived from umbilical cord blood. So, ex vivo expansion of HPSCs is the useful approach to overcome this restriction. The goal of using this system is to produce appropriate amount of hematopoietic stem cells, which have the ability of transplantation and long term haematopoiesis. Material & Methods: In current study CD133+ cells were isolated from cord blood (CB). Isolated cells were seeded on microwells. Then expanded cells proliferation rate and ability in colony formation were assessed and finally were compared with 2 Dimensional (2D) culture systems. Results: Our findings demonstrated that CD133+ cells derived from UCB which were cultivated on microwells had significantly higher rate of proliferation in compared with routine cell culture systems. Conclusion: In Current study, it was shown that CD133+ cells’ proliferations which were seeded on PDMS microwells coated with collagen significantly increased. We hope that 3 dimensional (3D) microenvironment which mimics the 3D structure of bone marrow can solve the problem of using UCB as an alternative source of bone marrow

Exosomal microRNAs as potential circulating biomarkers in gastrointestinal tract cancers: a systematic review protocol

Background: Metastasis is the most frequent type of recurrence in gastrointestinal (GI) cancers, and there is an emerging potential for new diagnostic and therapeutic approaches, especially in the cases of metastatic GI carcinomas. The expression profiles of circulating exosomal microRNAs are of particular interest as novel non-invasive diagnostic and prognostic biomarkers for improved detection of GI cancers in body fluids, especially in the serum of patients with recurrent cancers. The aim of this study is to systematically review primary studies and identify the miRNA profiles of serum exosomes of GI cancers. Methods and design: This systematic review will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidance. Relevant studies will be identified through a comprehensive search of the following main electronic databases: PubMed, Web of Science, Embase, Scopus, and Google Scholar, with no language restrictions (up to July 2017). Full copies of articles will be identified by a defined search strategy and will be considered for inclusion against pre-defined criteria. The quality assessment of the included studies will be performed by the Newcastle-Ottawa Scale (NOS). Data will be analyzed using Stata software V.12. Publication bias will be assessed by funnel plots, Beggs’ and Eggers’ tests. The levels of evidence for primary outcomes will be evaluated using the GRADE criteria. Discussion: The analysis of circulating exosomal miRNA profiles provides attractive screening and non-invasive diagnostic tools for the majority of solid tumors including GI cancers. There is limited information regarding the relationship between serum exosomal miRNA profiles and the pathological condition of patients with different GI cancers. Since there is no specific biomarker for GI cancers, we aim to suggest a number of circulating exosomal miRNA candidates as potential multifaceted GI cancer biomarkers for clinical utility. Systematic review registration: PROSPERO CRD42017057129Medicine, Faculty ofNon UBCCellular and Physiological Sciences, Department ofReviewedFacult

Milk thistle nano-micelle formulation promotes cell cycle arrest and apoptosis in hepatocellular carcinoma cells through modulating miR-155-3p /SOCS2 /PHLDA1 signaling axis

Abstract Background Hepatocellular Carcinoma (HCC) is a prevalent form of liver cancer that causes significant mortality in numerous individuals worldwide. This study compared the effects of milk thistle (MT) and nano-milk thistle (N-MT) on the expression of the genes that participate in apoptosis and cell cycle pathways in Huh-7 and HepG2 cells. Methods IC50 values of MT and N-MT were determined using the MTT assay. Huh-7 and HepG2 cell lines (containing mutant and wild-type TP53 gene, respectively) were incubated with MT and N-MT for 24h and 48h and the impact of MT and N-MT on the proliferation of these cell lines was evaluated through a comparative analysis. Cell cycle and apoptosis were assessed by flow cytometry after 24h and 48h treatment in the cell lines mentioned. Real-time PCR was used to analyze miR-155-3p, PHLDA1, SOCS2, TP53, P21, BAX, and BCL-2 expression in the cell lines that were being treated. Results N-MT reduces cancer cell growth in a time and concentration-dependent manner, which is more toxic compared to MT. Huh-7 was observed to have IC50 values of 2.35 and 1.7 μg/ml at 24h and 48h, and HepG2 was observed to have IC50 values of 3.4 and 2.6 μg/ml at 24 and 48h, respectively. N-MT arrested Huh-7 and HepG2 cells in the Sub-G1 phase and induced apoptosis. N-MT led to a marked reduction in the expression of miR-155-3p and BCL-2 after 24h and 48h treatments. Conversely, PHLDA1, SOCS2, BAX, and P21 were upregulated in the treated cells compared to untreated cells, which suggests that milk thistle has the potential to regulate these genes. N-MT reduced the expression of TP53 in Huh-7 cells after mentioned time points, while there was a significant increase in the expression of the TP53 gene in HepG2 cells. No gene expression changes were observed in MT-treated cells after 24h and 48h. Conclusion N-MT can regulate cancer cell death by arresting cell cycle and inducing apoptosis. This occurs through the alteration of apoptotic genes expression. A reduction in the expression of miR-155-3p and increase in the expression of SOCS2 and PHLDA1 after N-MT treatment showed the correlation between miR-155-3p and PHLDA1/SOCS2 found in bioinformatics analysis. While N-MT increased TP53 expression in HepG2, reduced it in Huh-7. The findings indicate that N-MT can function intelligently in cancer cells and can be a helpful complement to cancer treatment