Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.

Cancer stem cells in solid tumours: accumulating evidence and unresolved questions

MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

Transitions between epithelial and mesenchymal states have crucial roles in embryonic development. Emerging data suggest a role for these processes in regulating cellular plasticity in normal adult tissues and in tumours, where they can generate multiple, distinct cellular subpopulations contributing to intratumoural heterogeneity. Some of these subpopulations may exhibit more differentiated features, whereas others have characteristics of stem cells. Owing to the importance of these tumour-associated phenotypes in metastasis and cancer-related mortality, targeting the products of such cellular plasticity is an attractive but challenging approach that is likely to lead to improved clinical management of cancer patients.

Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits

Tumors are cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like features (CSCs). Epithelial to mesenchymal transitions (EMT) are transdifferentiation programs that are required for tissue morphogenesis during embryonic development. The EMT process can be regulated by a diverse array of cytokines and growth factors, such as transforming growth factor (TGF)-β, whose activities are dysregulated during malignant tumor progression. Thus, EMT induction in cancer cells results in the acquisition of invasive and metastatic properties. Recent reports indicate that the emergence of CSCs occurs in part as a result of EMT, for example, through cues from tumor stromal components. Recent evidence now indicates that EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. In this review, we will provide potential mechanistic explanations for the association between EMT induction and the emergence of CSCs. We will also highlight recent studies implicating the function of TGF-β-regulated noncoding RNAs in driving EMT and promoting CSC self-renewal. Finally we will discuss how EMT and CSCs may contribute to drug resistance, as well as therapeutic strategies to overcome this clinically.

/pdf/emt-cancer-stem-cells-and-drug-resistance-an-emerging-axis-3ztp4dopjd.pdf

EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer

MicroRNAs (miRNAs) are critical regulators of gene expression. Amplification and overexpression of individual 'oncomiRs' or genetic loss of tumour suppressor miRNAs are associated with human cancer and are sufficient to drive tumorigenesis in mouse models. Furthermore, global miRNA depletion caused by genetic and epigenetic alterations in components of the miRNA biogenesis machinery is oncogenic. This, together with the recent identification of novel miRNA regulatory factors and pathways, highlights the importance of miRNA dysregulation in cancer.

MicroRNA biogenesis pathways in cancer

http://basicmed.med.ncku.edu.tw/admin/up_img/970307-3.pdf

let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells

Glutathion s transferase π indicates chemotherapy resistance in breast cancer

Stable RNA interference of ErbB-2 gene synergistic with epirubicin suppresses breast cancer growth in vitro and in vivo.

Hypothesis Toremifen is effective in reducing breast pain and does not increase the incidence of adverse events as a therapy for moderate to severe mastalgia. Design and Patients In a double-blind randomized controlled trial, patients with moderate to severe mastalgia received toremifen citrate, 30 mg daily, or a placebo tablet for 3 menstrual cycles and were followed up for breast pain score and adverse events. The serum levels of estradiol, progesterone, and prolactin were examined before treatment and correlated with the response rate to toremifen treatment. Results Seventy-two (69.2%) of 104 patients receiving toremifen and 29 (31.9%) of 91 receiving placebo responded to the treatment, with reduction in breast pain score of more than 50% ( P P P  = .09). Adverse events were observed in 44 (42.9%) of 104 patients receiving placebo and 46 (50.5%) of 91 patients receiving toremifen ( P  = .45). A positive correlation between baseline breast pain score and serum estradiol level was observed in patients with cyclical mastalgia ( r  = 0.35, P  = .003). Conclusions Toremifen effectively relieves moderate and severe cyclical mastalgia and tends to exert a positive therapeutic effect on noncyclical mastalgia. In addition, toremifen therapy does not increase the incidence of intolerable adverse event. Therefore, it is a feasible therapy for mastalgia, especially cyclical mastalgia.

https://jamanetwork.com/journals/jamasurgery/articlepdf/397862/soa4220.pdf

A Double-blind Randomized Controlled Trial of Toremifen Therapy for Mastalgia

Breast cancer, presented by multiple breast cancer subtypes that coexist within a diagnosed tumor in clinical, has ranked as the most common malignancy in women in recent years. Evidence suggested that limited effective drugs caused the unsatisfactory therapeutic efficacy of breast cancer. Flavokavain C exhibited anticancer activity on colon cancer cells HCT116. It is yet unknown if it can be used to treat breast cancer. This study aims to believe the mechanisms by which Flavokavain C suppresses cell proliferation and the pathways that impact on this effect in breast cancer. 3-(4,5-Dimethythiazol)-2,5-diphenyltetrazolium bromide assay was chosen to evaluate cell cytotoxicity. Colony formation and cell proliferation assays using 5-ethynyl-2'-deoxyuridine staining were performed. Cell cycle progression and apoptosis were examined via flow cytometry and Western blotting, respectively. Five methods (comet assay, immunofluorescence, Western blotting, agarose gel electrophoresis and molecular docking) were used to quantify DNA damage and its cellular response. Compared to cisplatin, Flavokavain C possessed a comparable or more substantial inhibitory effect on breast cancer cell viability while having lower cytotoxicity on human mammary cells. Breast cancer cells treated with Flavokavain C had their colony formation suppressed, DNA replication blocked, the G2/M phase cell cycle arrested, and apoptosis. Furthermore, the results indicated that Flavokavain C would directly interact with DNA and induce DNA cleavage, demonstrating that DNA is an attractive substrate for Flavokavain C. These results suggested that Flavokavain C had strong anticancer activity against multiple subtypes of breast cancer cells.

Xiaoqu Hu

Papers

let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells

Glutathion s transferase π indicates chemotherapy resistance in breast cancer

Stable RNA interference of ErbB-2 gene synergistic with epirubicin suppresses breast cancer growth in vitro and in vivo.

A Double-blind Randomized Controlled Trial of Toremifen Therapy for Mastalgia

Flavokavain C Suppresses Breast Cancer Cell Viability and Induces Cell Apoptosis by Triggering DNA Damage.