Cancer stem cell plasticity and tumor hierarchy

The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell(CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cel s harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.     

Mitochondria as therapeutic targets for cancer stem cells

Cancer stem cells(CSCs) are maintained by theirsomatic stem cells and are responsible for tumor initiation, chemoresistance, and metastasis. Evidence for the CSCs existence has been reported for a number of human cancers. The CSC mitochondria have been shown recently to be an important target for cancer treatment, but clinical significance of CSCs and their mitochondria properties remain unclear. Mitochondriatargeted agents are considerably more effective compared to other agents in triggering apoptosis of CSCs, as well as general cancer cells, via mitochondrial dysfunction. Mitochondrial metabolism is altered in cancer cells because of their reliance on glycolytic intermediates, which are normally destined for oxidative phosphorylation. Therefore, inhibiting cancer-specific modifications in mitochondrial metabolism, increasing reactive oxygen species production, or stimulating mitochondrial permeabilization transition could be promising new therapeutic strategies to activate cell death in CSCs as well, as in general cancer cells. This review analyzed mitochondrial function and its potential as a therapeutic target to induce cell death in CSCs. Furthermore, combined treatment with mitochondriatargeted drugs will be a promising strategy for the treatment of relapsed and refractory cancer.     

Nanomedicine targeting ferroptosis to overcome anticancer therapeutic resistance

A potential reason for the failure of tumor therapies is treatment resistance. Resistance to chemotherapy, radiotherapy, and immunotherapy continues to be a major obstacle in clinic, resulting in tumor recurrence and metastasis. The major mechanisms of therapy resistance are inhibitions of cell deaths, like apoptosis and necrosis, through drug inactivation and excretion, repair of DNA damage, tumor heterogeneity,or changes in tumor microenvironment, etc. Recent studies have shown that ferroptosi...     

Issues and opportunities of stem cell therapy in autoimmune diseases

The purpose of regenerative medicine is to restore or enhance the normal function of human cells, tissues, and organs. From a clinical point of view, the use of stem cells is more advantageous than differentiated cells because they can be collected more easily and in larger quantities, their proliferation capacity is more pronounced, they are more resistant in cell culture, their aging is delayed, they are able to form a number of cell lines, and they are able to promote vascularization of tissue carriers. The therapeutic use of stem cells for disease modification, immunomodulation, or regenerative purposes are undoubtedly encouraging, but most studies are still in their early stages, and the clinical results reported are not clear with regard to therapeutic efficacy and potential side effects. Uniform regulation of the clinical application of stem cells is also indispensable for this highly customizable, minimally invasive, individualized therapeutic method to become a successful and safe treatment alternative in many different autoimmune and autoinflammatory disorders.     

Hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment

The tumor microenvironment(TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous population of tumor cells and TME cells. This review will focus on two stromal cell types, the cancerassociated adipocyte(CAA) and the cancer-associated fibroblast(CAF). In the clinic, the presence of CAAs and CAFs in the TME translates to poor prognosis in multiple tumor types. CAAs and CAFs have an activated phenotype and produce growth factors, inflammatory factors, cytokines, chemokines, extracellular matrix components, and proteases in an accelerated and aberrant fashion. Through this activated state, CAAs and CAFs remodel the TME, thereby driving all aspects of tumor progression, including tumor growth and survival, chemoresistance, tumor vascularization, tumor invasion, and tumor cell metastasis. Similarities in the tumorpromoting functions of CAAs and CAFs suggest that a multipronged therapeutic approach may be necessary to achieve maximal impact on disease. While CAAs and CAFs are thought to arise from tissues adjacent to the tumor, multiple alternative origins for CAAs and CAFs have recently been identified. Recent studies from our lab and others suggest that the hematopoietic stem cell, through the myeloid lineage, may serve as a progenitor for CAAs and CAFs. We hypothesize that the multiple origins of CAAs and CAFs may contribute to the heterogeneity seen in the TME. Thus, a better understanding of the origin of CAAs and CAFs, how this origin impacts their functions in the TME, and thetemporal participation of uniquely originating TME cells may lead to novel or improved anti-tumor therapeutics.     

Induction of Epstein-Barr virus lytic replication by recombinant adenoviruses expressing the zebra gene with EBV specific promoters

The latent Epstein-Barr virus (EBV) is found in the cells of many tumors. For example, EBV is detectable in almost all cases, and in almost all tumor cells, of non-keratinizing nasopharyngeal carcinoma.Activating the latent virus, which will result in its lytic replication and the death of tumor cells, is a potential approach for the treatment of EBV-associated cancers. In this study, three recombinant adenoviruses were constructed to express the Zebra gene, an EBV gene responsible for switching from the latent state to lytic replication. EBV-specific promoters were used in order to limit Zebra expression in EBV-positive cells, and reduce the potential side effects. The EBV promoters used were Cp, Zp and a dual promoter combining both promoters, CpZp. The Zebra protein was detected in HEK293 cells as well as the EBV-positive D98-HR1 cells infected with recombinant viruses. An EBV lytic replication early antigen, EA-D, was also detected in infected D98-HR1, implying the initiation of lytic replication. In the cell viability assay, Zebra-expressing adenoviruses had little effect on EBV-negative HeLa cells, while significantly reducing the cell viability and proliferation of D98-HR1 cells. The results indicate that EBV virus promoters can be used in adenovirus vectors to express the Zebra gene and induce EBV lytic replication in D98-HR1 cells.     

Open Sesame: treasure in store-operated calcium entry pathway for cancer therapy

Store-operated Ca2+ entry(SOCE) controls intracellular Ca2+ homeostasis and regulates a wide range of cellular events including proliferation,migration and invasion.The discovery of STIM proteins as Ca2+ sensors and Orai proteins as Ca2+ channel pore forming units provided molecular tools to understand the physiological function of SOCE.Many studies have revealed the pathophysiological roles of Orai and STIM in tumor cells.This review focuses on recent advances in SOCE and its contribution to tumorigenesis.Altered Orai and/or STIM functions may serve as biomarkers for cancer prognosis,and targeting the SOCE pathway may provide a novel means for cancer treatment.     

Exploitation of Gene Expression and Cancer Biomarkers in Paving the Path to Era of Personalized Medicine

Cancer therapy agents have been used extensively as cytotoxic drugs against tissue or organ of a specific type of cancer. With the better understanding of molecular mechanisms underlying carcinogenesis and cellular events during cancer progression and metastasis, it is now possible to use targeted therapy for these molecular events. Targeted therapy is able to identify cancer patients with dissimilar genetic defects at cellular level for the same cancer type and consequently requires individualized approach for treatment. Cancer therapy begins to shift steadily from the traditional approach of ‘‘one regimen for all patients" to a more individualized approach, through which each patient will be treated specifically according to their specific genetic defects. Personalized medicine accordingly requires identification of indicators or markers that guide in the decision making of such therapy to the chosen patients for more effective therapy. Cancer biomarkers are frequently used in clinical practice for diagnosis and prognosis, as well as identification of responsive patients and prediction of treatment response of cancer patient. The rapid breakthrough and development of microarray and sequencing technologies is probably the main tool for paving the way toward ‘‘individualized biomarker-driven cancer therapy" or ‘‘personalized medicine". In this review, we aim to provide an updated knowledge and overview of the current landscape of cancer biomarkers and their role in personalized medicine, emphasizing the impact of genomics on the implementation of new potential targeted therapies and development of novel cancer biomarkers in improving the outcome of cancer therapy.     

Origin of cells and network information

All cells are derived from one cell, and the origin of different cell types is a subject of curiosity. Cells construct life through appropriately timed networks at each stage of development. Communication among cells and intracellular signaling are essential for cell differentiation and for life processes. Cellular molecular networks establish cell diversity and life. The investigation of the regulation of each gene in the genome within the cellular network is therefore of interest. Stem cells produce various cells that are suitable for specific purposes. The dynamics of the information in the cellular network changes as the status of cells is altered. The components of each cell are subject to investigation.     

Molecular mechanism of therapeutic approaches for human gastric cancer stem cells

Gastric cancer(GC)is a primary cause of cancer-related mortality worldwide,and even after therapeutic gastrectomy,survival rates remain poor.The presence of gastric cancer stem cells(GCSCs)is thought to be the major reason for resistance to anticancer treatment(chemotherapy or radiotherapy),and for the development of tumor recurrence,epithelial–mesenchymal transition,and metastases.Additionally,GCSCs have the capacity for self-renewal,differentiation,and tumor initiation.They also synthesize antiapoptotic factors,demonstrate higher performance of drug efflux pumps,and display cell plasticity abilities.Moreover,the tumor microenvironment(TME;tumor niche)that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor.However,the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential.In this review,we provide up-todate information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development.This information will support improved diagnosis,novel therapeutic approaches,and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy.To date,most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents.However,when used in combination with adjuvant therapy,treatment can improve.By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC,the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy,radiotherapy,or other adjuvant treatment.     

Convergence of normal stem cell and cancer stem cell developmental stage: Implication for differential therapies

Increased evidence shows that normal stem cells may contribute to cancer development and progression by acting as cancer-initiating cells through their interactions with abnormal environmental elements.We postulate that normal stem cells and cancer stem cells (CSC) possess similar mechanisms of self-renewal and differentiation.CSC can be the key to the elaboration of anti-cancer-based therapy.In this article,we focus on a controversial new theme relating to CSC.Tumorigenesis may have a critical stage characterized as a "therapeutic window",which can be identified by asso-ciation of molecular,biochemical and biological events.Identifying such a stage can allow the production of more effective therapies (e.g.manipulated stem cells) to treat several cancers.More importantly,confirming the existence of a similar therapeutic window during the conversion of normal stem cells to malignant CSC may lead to targeted therapy specifically against CSC.This conversion information may be derived from investigating the biological behaviour of both normal stem cells and cancerous stem cells.Currently,there is little knowledge about the cellular and molecular mechanisms that govern the initiation and maintenance of CSC.Studies on co-evolution and interdependence of cancer with normal tissues may lead to a useful treatment paradigm of cancer.The crosstalk between normal stem cells and cancer formation may converge developmental stages of different types of stem cells (e.g.normal stem cells,CSC and embryonic stem cells).The differential studies of the convergence may result in novel therapies for treating cancers.     

Stem cell therapy in inflammatory bowel disease: A promising therapeutic strategy?

Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and with immunoregulatory cells(regulatory T-lymphocytes and dendritic T-cells) opens up new expectations for their use in these diseases. The goal for stem cell-based therapy is to provide a permanent cure. To achieve this, it will be necessary to obtain a cellular product, original or genetically modified, that has a high migration capacity and homes into the intestine, has high survival after transplantation, regulates the immune reaction while not being visible to the patient’s immune system, and repairs the injured tissue.     

Cell transformation as aberrant differentiation：Environmentally dependent spontaneous transformation of NIH 3T3 cells

NIH 3T3 cells, a mouse fibroblast cell line used as routine target cells for transfection experiments, undergo spontaneous transformation in our experiments after they form a confluent sheet in medium containing fetal bovine serum (FBS) or lower coneentration of calf serum (CS). The transformation takes the form of foci of multiplying cells among the surrounding cells which have stopped cell division. However, no focus of transformed cells could be seen in medium containing high concentration (10％) of CS. Further experiments indicated that the frequency of transformation is highly dependent on the concentration of serum and the transformation in CS is changeable when the cells are passaged in FBS. 3~H-thymidine autoradiography has been proved to be a sensitive measurement indicator for focus formation. Our results suggest that the high frequency of transformation and its dependence on confluency as well as on medium composition are characteristics of cell differentiation rather than mutation. The role of the NIH 3T3 cell line as a cancer-initiated cell population and its accelerated transformation by ras oncogene might be considered as a form of tumor promotion is discussed.     

VEGF-specific siRNAs modified with 2′-deoxy effectively suppress VEGF expression and inhibit growth of nasopharyngeal carcinoma xenograft in a mouse model

Vascular endothelial growth factor (VEGF) is up-regulated in the vast majority of human tumors. The up-regulation of VEGF not only plays important roles in tumor angiogenesis, but also provides a target for tumor treatment with small interfering RNA (siRNA) that targets VEGF; however, it is unclear whether a quite high up-regulation of VEGF will affect the efficiency of RNA interference strategies targeting VEGF. A high level expression of VEGF was found in CNE cells from a nasopharyngeal carcinoma cell line. In this study, we investigate whether VEGF-specific siRNAs can effectively suppress VEGF expression in CNE cells, and study the methods for the use of VEGF-specific siRNAs as potential therapeutic agents. CNE cells with high VEGF expression induced by hypoxia were transfected with VEGF-specific siRNAs. The expression of VEGF was effectively suppressed by VEGF-specific siRNAs, measured by ELISA, Western blot analysis and RT-PCR. Furthermore, experiments in nude mice bearing nasopharyngeal carcinoma xenograft were initiated 5 d after injection of CNE cells. VEGF-specific siRNAs were modified with 2′-deoxy, then injected into the tumors, and a liposome-mediated siRNA transfection system and ultrasound exposure were used to help delivery of the siRNAs. Tumor growth was reduced significantly after 3 weeks' treatment. These studies suggest that VEGF-specific siRNAs still can effectively suppress VEGF expression even in tumor cell lines with a relatively high level of VEGF expression, such as CNE, and VEGF-specific siRNAs modified with 2′-deoxy can be used as potential agents for tumor therapy.     

Advances in cellular technology in the hematology field: What have we learned so far?

Despite the advances in the hematology field, blood transfusion-related iatrogenesis is still a major issue to be considered during such procedures due to blood antigenic incompatibility. This places pluripotent stem cells as a possible ally in the production of more suitable blood products. The present review article aims to provide a comprehensive summary of the state-of-theart concerning the differentiation of both embryonic stem cells and induced pluripotent stem cells to hematopoietic cell lines. Here, we review the most recently published protocols to achieve the production of blood cells for future application in hemotherapy, cancer therapy and basic research.     

Human mesenchymal stem cells with adenovirus-mediated TRAIL gene transduction have antitumor effects on esophageal cancer cell line Eca-109

The apoptotic ligand TNF-related apoptosis-inducing ligand （TRAIL） is believed to be a promising candidate for cancer gene therapy, yet gene therapy strategies to tackle this disease systemically are often impaired by inefficient delivery of the vector to the tumor tissue. Mesenchymal stem cells （MSCs） have been shown to home to tumor sites and could potentially act as a shield and vehicle for an anti tumor gene therapy vector. Here, we used an adenoviral vector expressing TRAIL to transduce MSCs and studied the apoptosis-inducing activity of these TRAIL-carrying MSCs on esophageal cancer cell Eca-109. Our results showed that, in vitro, TRAIL-expressing MSCs were able to inhibit proliferation and induce apoptosis in Eca-109 cells by an MTT assay, co-culture experiments and flow cytometry analysis. In vivo, TRAIL-expressing MSCs also displayed an ability to inhibit tumor growth in an Eca-109 xenograft mouse model. Together, our findings indicated that the gene therapy strategy of MSCs-based TRAIL gene delivery has a wide potential value for improving the treatment of esophageal cancer.     

Priming cancer cells for drug resistance: role of the fibroblast niche

Conventional and targeted chemotherapies remain integral strategies to treat solid tumors. Despite the large number of anti-cancer drugs available, chemotherapy does not completely eradicate disease. Disease recurrence and the growth of drug resistant tumors remain significant problems in anti-cancer treatment. To develop more effective treatment strategies, it is important to understand the underlying cellular and molecular mechanisms of drug resistance. It is generally accepted that cancer cells do not function alone, but evolve through interactions with the surrounding tumor microenvironment. As key cellular components of the tumor microenvironment, fibroblasts regulate the growth and progression of many solid tumors. Emerging studies demonstrate that fibroblasts secrete a multitude of factors that enable cancer cells to become drug resistant. This review will explore how fibroblast secretion of soluble factors act on cancer cells to enhance cancer cell survival and cancer stem cell renewal, contributing to the development of drug resistant cancer.     

VEGF-specific siRNAs modified with 2′-deoxy effectively suppress VEGF expression and inhibit growth of nasopharyngeal carcinoma xenograft in a mouse model

Vascular endothelial growth factor (VEGF) is up-regulated in the vast majority of human tumors. The up-regulation of VEGF not only plays important roles in tumor angiogenesis, but also provides a target for tumor treatment with small interfering RNA (siRNA) that targets VEGF; however, it is unclear whether a quite high up-regulation of VEGF will affect the efficiency of RNA interference strategies targeting VEGF. A high level expression of VEGF was found in CNE cells from a nasopharyngeal car-cinoma cell line. In this study, we investigate whether VEGF-specific siRNAs can effectively suppress VEGF expression in CNE cells, and study the methods for the use of VEGF-specific siRNAs as potential therapeutic agents. CNE cells with high VEGF expression induced by hypoxia were transfected with VEGF-specific siRNAs. The expression of VEGF was effectively suppressed by VEGF-specific siRNAs, measured by ELISA, Western blot analysis and RT-PCR. Furthermore, experiments in nude mice bear-ing nasopharyngeal carcinoma xenograft were initiated 5 d after injection of CNE cells. VEGF-specific siRNAs were modified with 2′-deoxy, then injected into the tumors, and a liposome-mediated siRNA transfection system and ultrasound exposure were used to help delivery of the siRNAs. Tumor growth was reduced significantly after 3 weeks’ treatment. These studies suggest that VEGF-specific siRNAs still can effectively suppress VEGF expression even in tumor cell lines with a relatively high level of VEGF expression, such as CNE, and VEGF-specific siRNAs modified with 2′-deoxy can be used as po-tential agents for tumor therapy.     

The role of autophagy in sensitizing malignant glioma cells to radiation therapy

Malignant gliomas represent the majority of primary brain tumors. The current standard treatments for malignant gliomas include surgical resection, radiation therapy, and chemotherapy. Radiotherapy, a standard adjuvant therapy, confers some survival advantages, but resistance of the glioma cells to the efficacy of radiation limits the success of the treatment. The mechanisms underlying glioma cell radioresistance have remained elusive. Autophagy is a protein degradation system characterized by a prominent formation of double-membrane vesicles in the cytoplasm. Recent studies suggest that autophagy may be important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. Also, autophagy is a novel response of glioma cells to ionizing radiation. Autophagic cell death is considered programmed cell death type II, whereas apoptosis is programmed cell death type I. These two types of cell death are predominantly distinctive, but many studies demonstrate a cross-talk between them. Whether autophagy in cancer cells causes death or protects cells is controversial. The regulatory pathways of autophagy share several molecules. PI3K/Akt/mTOR, DNA-PK, tumor suppressor genes, mitochondrial damage, and lysosome may play important roles in radiation-induced autophagy in glioma cells. Recently, a highly tumorigenic glioma tumor subpopulation, termed cancer stem cell or tumor-initiating cell, has been shown to promote therapeutic resistance. This review summarizes the main mediators associated with radiation-induced autophagy in malignant glioma cells and discusses the implications of the cancer stem cell hypothesis for the development of future therapies for brain tumors.