Regulated genes in mesenchymal stem cells and gastric cancer

AIM: To investigate the genes regulated in mesenchymal stem cells(MSCs) and diffuse-type gastric cancer(GC),gene expression was analyzed. METHODS: Gene expression of MSCs and diffuse-type GC cells were analyzed by microarray. Genes related to stem cells, cancer and the epithelial-mesenchymal transition(EMT) were extracted from human gene lists using Gene Ontology and reference information. Gene panels were generated, and messenger RNA gene expression in MSCs and diffuse-type GC cells was analyzed. Cluster analysis was performed using the NCSS software.RESULTS: The gene expression of regulator of G-protein signaling 1(RGS1) was up-regulated in diffuse-type GC cells compared with MSCs. A panel of stem-cell related genes and genes involved in cancer or the EMT were examined. Stem-cell related genes, such as growth arrest-specific 6, musashi RNA-binding protein 2 and hairy and enhancer of split 1(Drosophila), NOTCH family genes and Notch ligands, such as delta-like 1(Drosophila) and Jagged 2, were regulated.CONCLUSION: Expression of RGS1 is up-regulated, and genes related to stem cells and NOTCH signaling are altered in diffuse-type GC compared with MSCs.     

Glioblastoma cancer stem cells: heterogeneity,microenvironment and related therapeutic strategies

Glioblastoma Multiforme (GBM) is an incurable malignancy. GBM patients have a short life expectancy despite aggressive therapeutic approaches based on surgical resection followed by adjuvant radiotherapy and concomitant chemotherapy. Glioblastoma growth is characterized by a high motility of tumour cells, their resistance to both chemo/radio‐therapy, apoptosis inhibition leading to failure of conventional therapy. Cancer Stem Cells (CSCs), identified in GBM as well as in many other cancer types, express the membrane antigen prominin‐1 (namely CD133). These cells and normal Neural Stem Cells (NSC) share surface markers and properties, i.e. are able to self‐renew and differentiate into multiple cell types. Stem cell self‐renewal depends on microenvironmental cues, including Extracellular Matrix (ECM) composition and cell types. Therefore, the role of microenvironment needs to be evaluated to clarify its importance in tumour initiation and progression through CSCs. The specific microenvironment of CSCs was found to mimic in part the vascular niche of normal stem cells. The targeting of GMB CSCs may represent a powerful treatment approach. Lastly, in GBM patients cancer‐initiating cells contribute to the profound immune suppression that in turn correlated with CSCs STAT3 (CD133 + ). Further studies of microenvironment are needed to better understand the origin of GMB/GBM CSCs and its immunosuppressive properties. Copyright © 2010 John Wiley & Sons, Ltd.     

Role of platelets and breast cancer stem cells in metastasis

The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called tumor-educated platelets. Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes.     

Energy metabolism in cancer stem cells

Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.     

肺干细胞和肺癌干细胞研究进展

近年来成体干细胞研究进展迅速。肺干细胞和肺癌干细胞在表面标志、分离方法和功能研究等方面也取得了一定进展。在肺组织中,肺干细胞维持着肺上皮的更新和稳定,肺脏不同解剖结构存在不同的干细胞,主要的肺干细胞有气管—支气管干细胞、细支气管干细胞、细支气管肺泡干细胞和肺泡干细胞等,不同干细胞特异表面标志也不同。根据肿瘤干细胞理论,目前研究认为肺癌的发生与肺癌干细胞有关,肺癌干细胞来源于其对应肺干细胞的恶性转化。肺癌干细胞特异标志研究主要集中在侧群细胞、CD133和醛脱氢酶等。与其他成体干细胞相似,肺癌干细胞维持自我更新以及分化能力的信号通路主要有Wnt、Hedgehog和Notch通路等。肺癌干细胞与肺癌的发生、发展、转移、治疗反应及预后关系,也取得了一定的进展。该文对肺干细胞和肺癌干细胞研究进展作简要综述。     

Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a five-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells (PCSCs) contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are reviewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic targets are also discussed with a focus on selected specific inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specific drug delivery are highlighted, and their limitations considered.     

Beyond tumorigenesis： cancer stem cells in metastasis

The importance of cancer stem cells （CSCs） in tumor-initiation has been firmly established in leukemia and recently reported for a variety of solid tumors. However, the role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well-defined. Cancer metastasis requires the seeding and successful colonization of specialized CSCs at distant organs. The biology of normal stem cells and CSCs share remarkable similarities and may have important implications when applied to the study of cancer metastasis. Furthermore, overlapping sets of molecules and pathways have recently been identified to regulate both stem cell migration and cancer metastasis. These molecules constitute a complex network of cellular interactions that facilitate both the initiation of the pre-metastasis niche by the primary tumor and the formation of a nurturing organ microenvironment for migrating CSCs. In this review, we surveyed the recent advances in this dynamic field and propose a unified model of cancer progression in which CSCs assume a central role in both tumorigenesis and metastasis. Better understanding of CSCs as a fundamental component of the metastatic cascade will lead to novel therapeutic strategies against metastatic cancer.     

Identification of cancer stem cells in vincristine preconditioned SGC7901 gastric cancer cell line

Cancer stem cells (CSCs), or tumor initiating cells, are a subpopulation of cancer cells with self-renewal and differentiation properties. However, there has been no direct observation of the properties of gastric CSCs in vitro. Here we describe a vincristine (VCR)-preconditioning approach to obtain cancer stem-like cells (CSLCs) from the gastric cancer cell line SGC7901. The CSLCs displayed mesenchymal characteristics, including the up-regulated mesenchymal markers Snail, Twist, and vimentin, and the down-regulated epithelial marker E-cadherin. Using a Matrigel-based differentiation assay, CSLCs formed 2D tube-like and 3D complex lumen-like structures, which resembled differentiated gastric crypts. The characteristic of cellular differentiation was also found by transmission electron microscopy and up-regulation of gastrointestinal genes CDX2 and SOX2. We further showed that CSLCs could self-renew through significant asymmetric division compared with parent cells by tracing PKH-26, BrdU, and EDU label-retaining cells. In addition, these CSLCs also increased expression of CD44, CD90, and CXCR4 at the mRNA level, which was identified as novel targets. Furthermore, drug sensitivity assays and xenograft experiments demonstrated that the cells developed multi-drug resistance (MDR) and significant tumorigenicity in vivo. In summary, gastric CSCs were identified from VCR-preconditioned SGC7901 cell line, characterized by high tumorigenicity and the capacity for self-renewal and differentiation.     

Contribution of cancer stem cells to tumor vasculogenic mimicry

Vasculogenic mimicry (VM), a newly-defined pattern of tumor blood supply, provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis. The biological features of the tumor cells that form VM remain unknown. Cancer stem cells (CSCs) are believed to be tumor-initiating cells, capable of self-renewal and multipotent differentiation, which resemble normal stem cells in phenotype and function. Recently CSCs have been shown to contribute to VM formation as well as angiogenesis. These findings challenge the previous understanding of the cellular basis of VM formation. In this review, we present evidence for participation of CSCs in VM formation. We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche. Based on the importance of VM in tumor progression, it constitutes a novel therapeutic target for cancer.     

Role and mechanism of neural stem cells of the subventricular zone in glioblastoma

Glioblastoma multiforme (GBM), the most frequently occurring malignant brain tumor in adults, remains mostly untreatable. Because of the heterogeneity of invasive gliomas and drug resistance associated with the tumor microenvironment, the prognosis is poor, and the survival rate of patients is low. Communication between GBMs and non-glioma cells in the tumor microenvironment plays a vital role in tumor growth and recurrence. Emerging data have suggested that neural stem cells (NSCs) in the subventricular zone (SVZ) are the cells-of-origin of gliomas, and SVZ NSC involvement is associated with the progression and recurrence of GBM. This review highlights the interaction between SVZ NSCs and gliomas, summarizes current findings on the crosstalk between gliomas and other non-glioma cells, and describes the links between SVZ NSCs and gliomas. We also discuss the role and mechanism of SVZ NSCs in glioblastoma, as well as the interventions targeting the SVZ and their therapeutic implications in glioblastoma. Taken together, understanding the biological mechanism of glioma-NSC interactions can lead to new therapeutic strategies for GBM.     

Glioblastoma stem cells:Molecular characteristics and therapeutic implications

Glioblastoma Multiforme(GBM)is a grade IV astrocytoma,with a median survival of 14.6 mo.Within GBM,stem-like cells,namely glioblastoma stem cells(GSCs),have the ability to self-renew,differentiate into distinct lineages within the tumor and initiate tumor xenografts in immunocompromised animal models.More importantly,GSCs utilize cell-autonomous and tumor microenvironment-mediated mechanisms to overcome current therapeutic approaches.They are,therefore,very important therapeutic targets.Although the functional criteria defining GSCs are well defined,their molecular characteristics,the mechanisms whereby they establish the cellular hierarchy within tumors,and their contribution to tumor heterogeneity are not well understood.This review is aimed at summarizing current findings about GSCs and their therapeutic importance from a molecular and cellular point of view.A better characterization of GSCs is crucial for designing effective GSCtargeted therapies.     

肝癌干细胞分子标志物和干性维持机制研究进展

原发性肝癌是一种发生在肝脏的侵袭性肿瘤,具有极易发生转移和复发的特点.原发性肝癌主要包括肝细胞癌、肝内胆管癌、混合肝细胞胆管癌和纤维板层型肝细胞癌等.目前,手术切除、放射性和化学治疗仍是肝癌治疗的主要手段,但其特异性差、临床效果有限,肝癌患者5年总生存率仅为18％.肝癌干细胞是存在于肝癌组织中特定的细胞亚群,具有自我更...     

Ovarian cancer stem cell: A potential therapeutic target for overcoming multidrug resistance

The cancer stem cell (CSC) model encompasses an advantageous paradigm that in recent decades provides a better elucidation for many important biological aspects of cancer initiation, progression, metastasis, and, more important, development of multidrug resistance (MDR). Such several other hematological malignancies and solid tumors and the identification and isolation of ovarian cancer stem cells (OV-CSCs) show that ovarian cancer also follows this hierarchical model. Gaining a better insight into CSC-mediated resistance holds promise for improving current ovarian cancer therapies and prolonging the survival of recurrent ovarian cancer patients in the future. Therefore, in this review, we will discuss some important mechanisms by which CSCs can escape chemotherapy, and then review the recent and growing body of evidence that supports the contribution of CSCs to MDR in ovarian cancer.     

The potential role of exosomes derived from ovarian cancer cells for diagnostic and therapeutic approaches

Most patients with ovarian cancer (OC) are diagnosed at the advanced stages due to the absence of appropriate early diagnostic markers. Thus, OC is a gynecological disease with a low-survival rate. Exosomes are extracellular vesicles that are widely being considered as mediators for the noninvasive diagnosis of OC. Exosomes are expected to aid in the effective diagnosis of OC because they carry components, such as RNAs, proteins, and lipids, the compositions of which vary depending on the pathological characteristics of the patient. In this review, we document the methods that have been developed to detect exosomes and their components in OC. We also assess the potential biomarkers contained in exosomes that could be clinically useful, such as proteins, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and phospholipids. Moreover, we described the role played by exosomes in the tumor microenvironment and in OC angiogenesis, migration, and tumor growth. Various types of cells in the tumor microenvironment, including macrophages, fibroblasts, and mesenchymal stem cells (MSCs), interact directly with exosomes and promote or inhibit the progression of OC. Therefore, we summarize the studies that have suggested a therapeutic approach to OC using exosomes. Collectively, understanding the mechanism of exosome-based OC progression would broaden our knowledge regarding the diagnosis and therapy of OC.     

Active RHOA favors retention of human hematopoietic stem/progenitor cells in their niche

Background

Hematopoietic stem/progenitor cells (HSPCs) maintain the hematopoietic system by balancing their self-renewal and differentiation events. Hematopoietic stem cells also migrate to various sites and interact with their specific microenvironment to maintain the integrity of the system. Rho GTPases have been found to control the migration of hematopoietic cells and other cell types. Although the role of RAC1, RAC2 and CDC42 has been studied, the role of RHOA in human hematopoietic stem cells is unclear.

Results

By utilizing constitutively active and dominant negative RHOA, we show that RHOA negatively regulates both in vitro and in vivo migration and dominant negative RHOA significantly increased the migration potential of human HSC/HPCs. Active RHOA expression favors the retention of hematopoietic stem/progenitor cells in the niche rather than migration and was found to lock the cells in the G0 cell cycle phase thereby affecting their long-term self-renewal potential.

Conclusion

The current study demonstrates that down-regulation of RHOA might be used to facilitate the migration and homing of hematopoietic stem cells without affecting their long-term repopulating ability. This might be of interest especially for increasing the homing of ex vivo expanded HSPC.     

Abnormal lipid synthesis as a therapeutic target for cancer stem cells

Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.     

Developments in cell culture systems for human pluripotent stem cells

Human pluripotent stem cells (hPSCs) are important resources for cell-based therapies and pharmaceutical applications. In order to realize the potential of hPSCs, it is critical to develop suitable technologies required for specific applications. Most hPSC technologies depend on cell culture, and are critically influenced by culture medium composition, extracellular matrices, handling methods, and culture platforms. This review summarizes the major technological advances in hPSC culture, and highlights the opportunities and challenges in future therapeutic applications.     

Aiming to immune elimination of ovarian cancer stem cells

Ovarian cancer accounts for only 3% of all cancers in women, but it causes more deaths than any other gynecologic cancer. Treatment with chemotherapy and cytoreductive surgery shows a good response to the therapy. However, in a large proportion of the patients the tumor grows back within a few years. Cancer stem cells, that are less responsive to these treatments, are blamed for this recurrence of disease. Immune therapy either cellular or humoral is a novel concept to treat cancer. It is based on the notice that immune cells invade the tumor. However, the tumor invest heavily to escape from immune elimination by recruiting several immune suppressive mechanisms. These processes are normally in place to limit excessive immune activation and prevent autoimmune phenomena. Here, we discuss current knowledge about the immune (suppressive) status in ovarian cancer. Moreover, we discuss the immunological targets of ovarian cancer stem cells.     

精原干细胞自我更新和分化的调控

精原干细胞（spermatogonial stem cells,SSCs）是体内自然状态下惟一能将遗传信息传至子代的成体干细胞,它们能通过维持自我更新和分化的稳定从而保证雄性生命过程中精子发生的持续进行。了解SSCs自我更新和分化的调节机制有助于阐明精子发生机理,并为探究其他组织中成体干细胞增殖分化的调节机制提供依据。然而目前对于SSCs自我更新和分化的调控机制所知甚少。SSCs的更新与分化遵循特定模式,受以睾丸支持细胞为主要成分的微环境及各种内分泌因素如胶质细胞源神经营养因子（GDNF）、维生素、Ets转录因子ERM/Etv5等的调控。本文评述了SSCs更新与分化的模式以及上述因素对其更新、分化的调控,探讨了其中可能涉及的信号通路,以期为本领域及其他成体干细胞相关研究提供借鉴。     

Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer

Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer.