Breast cancer stem cells: Obstacles to therapy

Only a fraction of the cells in a breast tumour are able to seed new tumour growth. These so-called breast cancer stem cells (bCSCs) are characterised by a number of discrete functional properties, some of which impact on therapeutic strategies aimed at eliminating these cells from tumours. Here we discuss how recent experimental evidence indicates that phenotypic plasticity is a central feature of tumour cell heterogeneity and drug resistance, traits that must be overcome in order to efficiently target bCSCs as a therapy for breast cancer. We propose that a better understanding of this fundamental property of breast cancer stem cells, over and above their identification in tumours, is a priority for improvement of patient survival.     

Pancreatic cancer stem cells: Emerging target for designing novel therapy

In the past few years, there have been significant advances in the research on cancer stem cells (CSCs). The emerging evidences have demonstrated that CSCs and epithelial–mesenchymal transition (EMT)-type cells, which share molecular characteristics with CSCs, play critical roles in drug resistance, invasion, and metastasis. Pancreatic cancer (PC) has a high mortality due to both intrinsic (de novo) and extrinsic (acquired) drug resistance, leading to increased invasive and metastatic potential of PC cells. Therefore, targeting pancreatic CSCs and EMT-type cells could be a novel therapeutic strategy for the treatment of PC. In this article, we will review the current state of our knowledge on the role of pancreatic CSCs and EMT-type cells, and summarize the novel therapeutic strategies that could target pancreatic CSCs and EMT-type cells, leading to the reversal of EMT phenotype, the induction of drug sensitivity, and the inhibition of invasion and metastasis of PC, which is expected to yield better treatment outcome.     

Overview: Cellular plasticity,cancer stem cells and metastasis

Recently, a number of hypotheses have converged into a unified theoretical framework which addresses the most vexing aspects of cancer: metastasis, relapse and therapeutic resistance. The central component of this framework is the new paradigm of cellular differentiation, once viewed as a unidirectional process, but now recognized as a plastic process in which cancer cells can dedifferentiate into more primitive, stem-like phenotypes. This plasticity is controlled by both intrinsic biochemical processes and bi-directional environmental cues involving cancer-associated non-cancerous cells. Such plastic phenotypic shifts may influence the discontinuous behavior of cancers, in which some cancers remain dormant for months or years after therapy, only to relapse and wreak havoc. This Special Issue of Cancer Letters assembles a collection of mini-reviews describing the current knowledge of cellular plasticity and its relationship to cancer “stemness” and progression, illuminating how progress in this field may yield major benefits in overcoming resistance and thwarting metastasis.     

Combinatorial treatment of mammospheres with trastuzumab and salinomycin efficiently targets HER2-positive cancer cells and cancer stem cells

A major obstacle in the successful treatment of cancer is the occurrence of chemoresistance. Cancer cells surviving chemotherapy and giving rise to a recurrence of the tumor are termed cancer stem cells and can be identified by elevated levels of certain stem cell markers. Eradication of this cell population is a priority objective in cancer therapy. Here, we report elevated levels of stem cell markers in MCF-7 mammospheres. Likewise, an upregulation of HER2 and its differential expression within individual cells of mammospheres was observed. Sorting for HER2^high and HER2^low cells revealed an upregulation of stem cell markers NANOG, OCT4 and SOX2 in the HER2^low cell fraction. Accordingly, HER2^low cells also showed reduced proliferation, ductal-like outgrowths and an increased number of colonies in matrigel. Xenografts from subcutaneously injected HER2^low sorted cells exihibited earlier onset but slower growth of tumors and an increase in stem cell markers compared to tumors developed from the HER2^high fraction. Treatment of mammospheres with salinomycin reduced the expression of SOX2 indicating a selective targeting of cancer stem cells. Trastuzumab however, did not reduce the expression of SOX2 in mammospheres. Furthermore, a combinatorial treatment of mammospheres with trastuzumab and salinomycin was superior to single treatment with each drug. Thus, targeting HER2 expressing tumors with anti-HER2 therapies will not necessarily eliminate cancer stem cells and may lead to a more aggressive cancer cell phenotype. Our study demonstrates efficient killing of both HER2 positive cells and cancer stem cells, hence opening a possibility for a new combinatorial treatment strategy.     

UCH-L1 promotes cancer metastasis in prostate cancer cells through EMT induction

Ubiquitin C-terminal hydrolse-L1 (UCH-L1) is a deubiquitinating enzyme (DUB) that cleaves the ubiquitin (ub) moiety from ub precursors or protein substrates. The correlation between UCH-L1 and cancer has been reported in various tissues, but the role of UCH-L1 in prostate cancer has not been thoroughly researched. Here we found that UCH-L1 is specifically highly expressed in the metastatic DU145 prostate cancer cell line, but not in the benign or weakly metastatic prostate cancer cells. To determine the role of UCH-L1 in prostate cancer metastasis, we constructed UCH-L1-knockdown DU145 and UCH-L1 or the active site mutant form of UCH-L1 (UCH-L1 C90S) expressing RWPE1 stable cells. Notably, the expression of UCH-L1 in RWPE1 cells promotes epithelial-to-mesenchymal transition (EMT), and this is an important process for cancer cell invasion and metastasis. On the contrary, knockdown of UCH-L1 in DU145 cells induces MET, the reverse program of EMT. Furthermore, the change of EMT status caused by altering the UCH-L1 level affects the migration and invasiveness of prostate cancer cells. Our results indicate that UCH-L1 promotes prostate cancer metastasis through EMT induction and UCH-L1 could be a novel diagnostic and therapeutic target for prostate cancer treatment.     

Lung cancer stem cells: Progress and prospects

Epithelial stem cells are critical for tissue generation during development and for repair following injury. In both gestational and postnatal stages, the highly branched and compartmentalized organization of the lung is maintained by multiple, resident stem/progenitor cell populations that are responsible for the homeostatic maintenance and injury repair of pulmonary epithelium. Though lung epithelial injury in the absence of oncogenic mutation is more commonly expressed as chronic lung disease, lung cancer is the most common form of death worldwide and poses a highly significant risk to human health. Cancer is defined by the cell of origin, responsible for initiating the disease. The Cancer Stem Cell Hypothesis proposes that cancer stem cells, identified by stem-like properties of self-renewal and generation of differentiated progeny, are responsible for propagating growth and spread of the disease. In lung cancer, it is hypothesized that cancer stem cells derive from several possible cell sources. The stem cell-like resistance to injury and proliferative potentials of bronchioalveolar stem cells (BASCs) and alveolar epithelial type II cells (AEC2), as well as cells that express the cancer stem cell marker glycoprotein prominin-1 (CD133) or markers for side populations make them potential reservoirs of lung cancer stem cells. The abnormal activation of pathways that normally regulate embryonic lung development, as well as adult tissue maintenance and injury repair, including the Wnt, Hedgehog (Hh) and Notch pathways, has also been identified in lung tumor cells. It is postulated that therapies for lung cancer that specifically target stem cell signaling pathways utilized by lung cancer stem cells could be beneficial in combating this disease.     

Adipose-derived stem cells promote tumor initiation and accelerate tumor growth by interleukin-6 production

Adipose-derived stem cells (ADSCs) are multipotent cells that have attracted much recent attention. Here, we show that ADSCs enhance sphere formation and in vivo tumor initiation of breast and colon cancer cells. In co-culture, ADSCs induced several stem cell markers in cancer cells. ADSCs also accelerated tumor growth. Interaction of ADSCs and cancer cells stimulated secretion of interlukin-6 in ADSCs, which in turn acted in a paracrine manner on cancer cells to enhance their malignant properties. Interleukin-6 regulated stem cell-related genes and activated JAK2/STAT3 in cancer cells. We suggest that ADSCs may enhance tumor initiation and promotion.     

Cancer stem cells,the epithelial to mesenchymal transition (EMT) and radioresistance: Potential role of hypoxia

Numerous studies have demonstrated the presence of cancer stem cells (CSCs) within solid tumors. Although the precursor of these cells is not clearly established, recent studies suggest that the phenotype of CSCs may be quite plastic and associated with the epithelial-to-mesenchymal transition (EMT). In patients, the presence of EMT and CSCs has been implicated in increased resistance to radiotherapy. Hypoxia, a negative prognostic factor for treatment success, is a potent driver of a multitude of molecular signalling pathways that allow cells to survive and thrive in the hostile tumor microenvironment and can induce EMT. Hypoxia also provides tumor cells with cues for maintenance of a stem-like state and may help to drive the linkage between EMT and CSCs. Understanding the biology of CSCs, the EMT phenotype and their implications in therapeutic relapse may provide crucial new approaches in the development of improved therapeutic strategies.     

乳腺癌干细胞及其临床应用

乳腺癌干细胞(BCSC)是乳腺癌细胞中一类具有自我更新能力和多向分化潜能的细胞.这类细胞具有高度的致瘤性和侵袭转移性,在乳腺癌的转移和复发以及放化疗抵抗中都起着重要作用.针对BCSC进行靶向治疗对提高乳腺癌疗效具有重要意义.     

类固醇激素在乳腺癌中的作用及对肿瘤干细胞的影响

类固醇激素尤其雌激素和孕激素在乳腺癌的发病、进展和治疗中起着重要作用。与此同时,大量的研究证实肿瘤干细胞在乳腺癌发生、进展和转移过程中也起着关键作用。在乳腺癌临床治疗中,尽管肿瘤细胞经过常规抗内分泌治疗后受到了明显的抑制,但仅需少量的乳腺肿瘤干细胞(Breast cancer stem cells,BCSCs)存在,仍可维持肿瘤的再生长。以往大量的研究多集中在激素对正常乳腺发育及其与乳腺癌的相关性方面,最近,更多的研究观察激素对乳腺肿瘤干细胞活性影响,这为乳腺癌治疗和肿瘤干细胞研究开辟了新的方向。本文全面讨论类固醇激素(雌激素和孕激素)在乳腺癌中的作用及其对乳腺肿瘤干细胞的活性调节。     

促进乳腺癌增殖转移和肿瘤干细胞特征的研究

目的 研究Gankyrin在乳腺肿瘤中的表达及其促进肿瘤进展的分子机制。方法 利用数据库研究Gankyrin在乳腺癌中的表达情况,并分析其表达与患者生存的关系。在BT549和MDA-MB-231乳腺癌细胞系过表达和敲减Gankyrin基因后,利用CCK-8、Transwell和流式细胞实验分析细胞增殖、转移和肿瘤干细胞的比例。结果 通过数据库分析显示Gankyrin在乳腺癌组织表达较高(P＜0.01),其高表达与患者的不良预后有关(P＜0.01)。与正常乳腺组织相比,乳腺癌组织中Gankyrin启动子甲基化水平较低(P＜0.01)。通过在乳腺癌细胞中过表达和敲减Gankyrin基因后,表明Gankyrin具有促进乳腺肿瘤细胞增殖和转移的能力,可以维持乳腺癌细胞的肿瘤干细胞特征(P＜0.01)。结论 Gankyrin在乳腺癌高表达与患者的不良预后相关,其可能作为乳腺癌肿瘤标记物。     

实体瘤肿瘤干细胞的研究进展

干细胞与肿瘤细胞存在许多相似之处,可能是肿瘤细胞的起源细胞。在血液系统恶性肿瘤和实体瘤中均分离和鉴定出具有干细胞特征的细胞群,称之为肿瘤干细胞。它们在恶性肿瘤的发生和发展中发挥重要的作用。肿瘤可能是一种干细胞疾病,这对认识肿瘤的发病机理和有效的临床治疗具有重要的指导作用。     

Circulating tumor cells exhibit a biologically aggressive cancer phenotype accompanied by selective resistance to chemotherapy

With prostate cancer (PCa), circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) portend a poor clinical prognosis. Their unknown biology precludes rational therapeutic design. We demonstrate that CTC and DTC cell lines, established from mice bearing human PCa orthotopic implants, exhibit increased cellular invasion in vitro, increased metastasis in mice, and express increased epithelial to mesenchymal transition biomarkers. Further, they are selectively resistant to growth inhibition by mitoxantrone-like agents. These findings demonstrate that CTC formation is accompanied by phenotypic progression without obligate reversion. Their increased metastatic potential, selective therapeutic resistance, and differential expression of potential therapeutic targets provide a rational basis to test further interventions.     

Ovarian cancer stem cells: Working towards the root of stemness

Despite medical advances made over the past decade, ovarian cancer remains one of the more lethal gynecologic cancers in the United States. While current therapeutic strategies are relatively effective, there is a high incidence of recurrent chemoresistant disease. This has been attributed, in part, to a regenerative tumor cell sub-population that has acquired stem cell properties which allows these cells to escape standard chemotherapeutics and drive recurrent disease. To date, a number of laboratories have identified these cancer stem cell (CSC) sub-populations in ovarian cancer cell lines, tumors or ascites and the collective findings suggest ovarian CSCs are likely to be as heterogeneous as the disease itself. Moreover, the multiple ovarian histophenotypes and possible sites of disease origin together with the potential for differential hierarchal contributions of multiple CSCs populations represent significant challenges to the identification, functional characterization and therapeutic targeting of ovarian CSC. This review will highlight the markers and methodology currently used to identify and isolate these cells. We will discuss some of the underlying ovarian CSC biology, the signaling pathways implicated in their survival, replication and differentiation and potential therapeutic targeting strategies.     

间质干细胞与肿瘤转移

间质干细胞(MSC)能够向炎症和肿瘤部位趋化,参与肿瘤微环境的组成,对肿瘤的生长和转移起重要作用.对间质干细胞在肿瘤生长与转移中的作用及机制研究将为肿瘤发生及肿瘤靶向治疗提供新的思路.     

肿瘤干细胞及肿瘤靶向治疗的研究进展

研究发现引起肿瘤复发或转移的根源是肿瘤中一少部分具有无限增殖能力的肿瘤干细胞,其在体内长期存在并不断自我更新,使肿瘤快速增殖且侵袭、转移能力增加,药物敏感性减弱,成为临床治疗的难题。因此,深入了解肿瘤干细胞进而寻找抑制肿瘤干细胞的方法对临床靶向治疗肿瘤具有重要意义。本文从肿瘤干细胞的发现过程、生物学特性、鉴别及培养方法等方面进行了阐述,根据其特点总结针对肿瘤干细胞治疗肿瘤的方法,并重点综述抗生素治疗肿瘤干细胞的研究进展。