肿瘤干细胞与肿瘤耐药

肿瘤细胞对化疗药物耐药是肿瘤治疗的主要障碍,肿瘤干细胞(CSC)是造成肿瘤耐药的最根本原因,故肿瘤治疗的关键应以CSC为治疗靶点。CSC概念的提出为癌症靶向治疗的研究带来了新的思路,提供了选择性杀伤CSC的靶向分子疗法,即新的药物应有选择的杀伤CSC而不损伤正常的干细胞,克服肿瘤耐药、防止治疗后的复发与转移,达到真正的治愈肿瘤。     

Bmi1调节肿瘤细胞生长及放化疗敏感性的研究进展

Bmi1是多梳(PcG)蛋白家族的重要成员,它在维持造血干细胞的自我更新、胸腺细胞的发育及Th2细胞的分化中发挥重要作用。研究表明,Bmi1可通过多种机制调节肿瘤细胞的增殖和分化,也参与肿瘤细胞放化疗敏感性的调节。由于Bmi1与肿瘤的发生、发展和复发,肿瘤干细胞(CSC)的自我更新及肿瘤的放化疗敏感性密切相关,Bmi1可能是一个重要的肿瘤治疗靶点。本文综述了Bmi1在肿瘤细胞中的生物学作用,以及其与CSC和放化疗敏感性关系的研究进展。     

间质干细胞、肿瘤干细胞和肿瘤

近来研究认为肿瘤来源于干细胞,提出了肿瘤中存在极少量肿瘤干细胞(CSC)的新学说.问质干细胞(MSC)作为间质细胞的来源,与肿瘤的关系尤为密切.本文就间质干细胞,肿瘤干细胞和肿瘤的发生,发展作一综述.     

肿瘤干细胞靶向治疗研究进展

<正>肿瘤干细胞(cancer stem cell,CSC)是存在于肿瘤组织中的一小部分具有干细胞性质的细胞群体,它具有自我更新的能力,是形成不同分化程度肿瘤细胞和肿瘤不断扩大的源泉。现有治疗肿瘤的方法主要是针对肿瘤组织内的大多数细胞,而不是肿瘤干细胞。即使99.99%的肿瘤细胞被杀死,但只要有0.01%的肿瘤干细胞存在,仍然会造成肿瘤的复     

肝癌干细胞的分子标记与靶向治疗

肿瘤干细胞假说认为只有很小一部分细胞具有引起肿瘤发生、维持肿瘤生长、保持肿瘤异质性的能力,这样的细胞叫肿瘤干细胞（cancer stem cell,CSC）。     

肿瘤干细胞的自我更新机制

多种肿瘤均起源于已恶性转化的单个细胞, 这种转化是由于基因突变的累积所致.肿瘤干细胞(cancer stem cells, CSC)是肿瘤的起始细胞这一观点已被广泛接受, 它既可诱导肿瘤的发生, 也可用于防治肿瘤.有多种人肿瘤的CSC已被分离鉴定, 如白血病以及一些实体瘤如乳腺癌、黑色素瘤、肺癌和脑肿瘤等.CSC与正常干细胞具有一些相同的特点, 但CSC并非完全起源于正常干细胞, 也可能来源于相应组织的定向祖细胞或间充质干细胞(mesenchymal stem cells, MSC), 甚至是干细胞与体细胞的融合细胞.     

肿瘤干细胞与肿瘤相关巨噬细胞的交互作用

肿瘤干细胞(cancer stem cell,CSC)被认为是一类具有自我更新和多向分化潜能的细胞亚群,与肿瘤的恶性生物学行为如侵袭、转移、化疗耐药等密切相关。CSC并不是固定不变的,而是处于不断转换且动态平衡的状态。肿瘤微环境中的巨噬细胞旁分泌多种细胞因子激活下游信号通路,诱导CSC转化和扩增,后者亦会产生相应的生物学效应促进肿瘤相关巨噬细胞极化为促肿瘤表型。文章对近年来CSC与肿瘤相关巨噬细胞交互作用的研究进行综述。     

肿瘤干细胞——肿瘤治疗的新靶点

肿瘤干细胞(cancer stem cell,CSC)是肿瘤组织中具有无限增殖潜能的极少量干细胞特征的细胞亚群,具有自我更新和多向分化能力.CSC是肿瘤增殖的源泉,目前常规放、化疗很难将其杀灭,使得CSC难以根除,肿瘤多次复发.由此看来,能否杀灭CSC是根治肿瘤的关键.通过阻止(或抑制)CSC信号通路,改变CSC生长的微环境,诱导其分化,开展针对CSC表面标志、CSC特定基因以及miRNA为基础的分子靶向治疗,将成为治疗肿瘤的新方法.     

胃癌干细胞与胃癌术后复发及其治疗

胃癌是最常见的恶性肿瘤之一,其发病率和病死率在我国恶性肿瘤的分布中均居第2位.腹膜种植转移是最常见的胃癌术后复发方式,是影响患者预后的主要原因.近年来发现肿瘤细胞起源于肿瘤干细胞（cancer stem cells,CSC）[1],肿瘤的复发及转移是由CSC引起的,CSC是肿瘤复发及转移的种子细胞.有效清除肿瘤切除术后残存的CSC是预防肿瘤术后复发的关键.本文对胃癌CSC在胃癌术后复发及其治疗中的作用作一综述.     

干细胞与肿瘤发生

干细胞具有自我更新能力 ,肿瘤细胞具有无限增殖能力 ,越来越多的证据显示肿瘤可看作是干细胞生长调控机制失调引起的异常组织器官 ,本文从三个方面概述了肿瘤与干细胞的关系 ,认为肿瘤与干细胞有相似的生长调控机制 ;突变最先发生于干细胞 ;肿瘤也有分化现象 ,其中一部分肿瘤细胞具有无限增殖能力 ,称为肿瘤干细胞。最后对干细胞理论在肿瘤治疗中的意义也作了一些阐述。     

Stemming Cancer: Functional Genomics of Cancer Stem Cells in Solid Tumors

Cancer stem cells (CSCs) were discovered about 15 years ago in hematopoietic cancers. Subsequently, cancer stem cells were discovered in various solid tumors. Based on parallels with normal stem cells, a developmental process of cancer stem cells follows paths of organized, hierarchical structure of cells with different degrees of maturity. While some investigators have reported particular markers as identification of cancer stem cells, these markers require further research. In this review, we focus on the functional genomics of cancer stem cells. Functional genomics provides useful information on the signaling pathways which are consecutively activated or inactivated amongst those cells. This information is of particular importance for cancer research and clinical treatment in many respects. (1) Understanding of self-renewal mechanisms crucial to tumor growth. (2) Allow the identification of new, more specific marker for CSCs, and (3) pathways that are suitable as future targets for anti-cancer drugs. This is of particular importance, because today’s chemotherapy targets the proliferating cancer cells sparing the relatively slow dividing cancer stem cells. The first step on this long road therefore is to analyze genome-wide expression-profiles within the same type of cancer and then between different types of cancer, encircling those target genes and pathways, which are specific to these cells.     

Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas

Evidence indicates that human ether à-go-go-related gene 1 (HERG1) voltage-gated potassium channels could represent new valuable membrane therapeutic targets and diagnostic/prognostic biomarkers in various cancers. This study is the first to investigate the expression pattern of HERG1 potassium channel subunit in both primary tumors and precancerous lesions to establish its clinical and biological role during the development and progression of head and neck squamous cell carcinomas. HERG1 protein expression was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 133 patients with laryngeal/hypopharyngeal squamous cell carcinomas and 75 patients with laryngeal dysplasia, and correlated with clinical data. Our findings demonstrate that HERG1 is frequently aberrantly expressed in a high percentage of primary tumors (87%), whereas expression was negligible in both stromal cells and normal-adjacent epithelia. HERG1 expression increased during head and neck squamous cell carcinoma progression and was significantly associated with lymph node metastasis (P=0.04), advanced disease stages (P<0.001), regional tumor recurrence (P=0.004), distant metastasis (P=0.03) and reduced disease-specific survival (P=0.012, log-rank test). HERG1-positive expression was also detected in 31 (41%) of 75 laryngeal dysplasias. Interestingly, HERG1 expression increased with the grade of dysplasia; however, HERG1 expression but not histology correlated significantly with increased laryngeal cancer risk (P=0.007). In addition, functional studies in head and neck squamous cell carcinoma-derived cell lines further revealed that HERG1 expression promotes anchorage-dependent and -independent cell growth and invasive capability, although independently of its ion-conducting function. Our data demonstrate that HERG1 expression is a biologically and clinically relevant feature in head and neck squamous cell carcinoma progression and also during malignant transformation, and a promising candidate as cancer risk marker and therapeutic target for head and neck squamous cell carcinoma prevention and treatment.     

Dueling models in head and neck tumor formation

The two leading models that have been used to explain tumor progression in head and neck squamous cell carcinoma (HNSCC) are the stochastic clonal evolution model, in which many tumor cells are individually capable of recapitulating the entire tumor mass, and the cancer stem hierarchy model, in which only rare totipotential tumor stem cells can recapitulate the tumor. In this issue, Cameron et al use cell surface marker and clonal cell analyses in combination with a xenotransplant approach to provide data that support the stochastic clonal evolution model in HNSCC. This interpretation is subject, however, to limitations inherent in the experimental approach employed. Understanding the basis of tumor progression in HNSCC as well as other cancers should be further explored because of important implications for effective treatments.     

Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds

Nanoparticle-mediated delivery of chemotherapies has demonstrated enhanced anti-cancer efficacy, mainly through the mechanisms of both passive and active targeting. Herein, we report other than these well-elucidated mechanisms, rationally designed nanoparticles can efficiently deliver drugs to cancer stem cells (CSCs), which in turn contributes significantly to the improved anti-cancer efficacy. We demonstrate that doxorubicin-tethered gold nanoparticles via a poly(ethylene glycol) spacer and an acid-labile hydrazone bond mediate potent doxorubicin delivery to breast CSCs, which reduces their mammosphere formation capacity and their cancer initiation activity, eliciting marked enhancement in tumor growth inhibition in murine models. The drug delivery mediated by the nanoparticles also markedly attenuates tumor growth during off-therapy stage by reducing breast CSCs in tumors, while the therapy with doxorubicin alone conversely evokes an enrichment of breast CSCs. Our findings suggest that with well-designed drug delivery system, the conventional chemotherapeutic agents are promising for cancer stem cell therapy.     

Selective inhibition of breast cancer stem cells by gold nanorods mediated plasmonic hyperthermia

Cancer stem cells (CSCs) have been identified in a variety of cancers and emerged as a new target for cancer therapy. CSCs are resistant to many current cancer treatments, including chemotherapy and radiation therapy. Therefore, eradication of this cell population is a primary objective in cancer therapy. Here, we report gold nanorods (AuNRs) mediated photothermal treatment can selectively eliminate CSCs in MCF-7 breast cancer cells. It significantly reduced the aldehyde dehydrogenase positive (ALDH⁺) cells subpopulation and the mammosphere formation ability of treated cells. Also, the gene expression of stem cell markers was decreased. Cellular uptake assay revealed that polyelectrolyte conjugated AuNRs could be internalized by CSCs much more and faster than non cancer stem cells (NCSCs), which might be the main reason for the selective elimination of CSCs. We further loaded salinomycin (SA), a CSCs inhibitor with polyelectrolyte conjugated AuNRs to get a synergistic CSCs inhibition. Enhanced inhibition of CSCs was obtained by NIR light triggered drug release and hyperthermia. This CSCs-targeted thermo-chemotherapy platform provides a new combinatorial strategy for efficient inhibition of CSCs, which is promising to improve cancer treatment and may overcome the chemoresistance and recurrence of cancer.     

The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells

Human CD133 (human prominin-1), a five transmembrane domain glycoprotein, was originally identified as a cell surface antigen present on CD34+ hematopoietic stem cells. Although the biological function of CD133 is not well understood, antibodies to CD133 epitopes have been widely used to purify hematopoietic stem and progenitor cells. The cancer stem cell (CSC) hypothesis postulates that a rare population of tumor cells possessing increased capacities for self-renewal and tumor initiation is responsible for maintaining the growth of neoplastic tissue. The expression of the CD133 epitopes, AC133 and AC141, has been shown to define a subpopulation of brain tumor cells with significantly increased capacity for tumor initiation in xenograft models. Following the discovery of the AC133/AC141+ population of brain tumor stem cells, the AC133 and AC141 epitopes have been extensively used as markers for purifying CSCs in other solid tumors. There are, however, several issues associated with the use of the AC133 and AC141 CD133 epitopes as markers for CSCs. The antibodies routinely used for purification of AC133 and AC141-positive cells target poorly characterized glycosylated epitopes of uncertain specificity. Discordant expression of the AC133 and AC141 epitopes has been observed, and the epitopes can be absent despite the presence of CD133 protein. In addition, CD133 expression has recently been shown to be modulated by oxygen levels. These factors, in combination with the uncertain biological role of CD133, suggest that the use of CD133 expression as a marker for CSCs should be critically evaluated in each new experimental system and highlight the need for additional CSC surface markers that are directly involved in maintaining CSC properties.     

Morphology, DNA ploidy and HPV in lung cancer and head and neck cancer

Lung cancer and head and neck cancer have similar genotoxic risk factors. While the vast majority of lung cancers are caused by cigarette smoking alone, smoking together with heavy drinking are the major etiological agents of head and neck cancer. In addition, human papilloma virus (HPV) has been identified as an important causative factor of tonsillar carcinomas. In contrast, chromosomal instability and aneuploidy identifiable by DNA measurement are predominately associated with cancer progression. This selective review summarizes our studies that aimed to gain a better understanding of the biology and pathology of lung cancer and head and neck cancer. In particular, it was attempted (a) to develop a microscopy-based tumor classification system that provides insight into the genetics of cancer cells and in particular their DNA ploidy, (b) to apply this classification system to lung cancer and head and neck cancer and to correlate it with clinicopathological parameters and molecular biomarkers, and (c) to analyze molecular characteristics and in particular the presence of human papilloma virus in lung cancer and head and neck cancer. Therefore, we developed a core classification based on the semi-quantitative assessment of the size and type of tumor cell nuclei and mitoses. It was found that (1) nuclear and mitosis size correlated with the DNA content of the tumor cells, (2) tripolar mitoses were indicative of cancer with near-triploid DNA content, (3) morphological and DNA parameters indicating variability of the cancer genome were associated with poor prognosis of lung cancer patients, (4) HPV-positive head and neck squamous cell carcinomas were characterized by smaller tumor nuclei and reduced DNA amount compared to HPV-negative carcinomas, and (5) HPV is associated with lung cancer in certain geographical regions of the world.     

Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature

Development of metastasis is a leading cause of cancer-induced death. Acquisition of an invasive tumor cell phenotype suggests loss of cell adhesion and basement membrane breakdown during a process termed epithelial-to-mesenchymal transition (EMT). Recently, cancer stem cells (CSC) were discovered to mediate solid tumor initiation and progression. Prostate CSCs are a subpopulation of CD44⁺ cells within the tumor that give rise to differentiated tumor cells and also self-renew. Using both primary and established prostate cancer cell lines, we tested the assumption that CSCs are more invasive. The ability of unsorted cells and CD44-positve and -negative subpopulations to undergo Matrigel invasion and EMT was evaluated, and the gene expression profiles of these cells were analyzed by microarray and a subset confirmed using QRT-PCR. Our data reveal that a subpopulation of CD44⁺ CSC-like cells invade Matrigel through an EMT, while in contrast, CD44⁻ cells are non-invasive. Furthermore, the genomic profile of the invasive cells closely resembles that of CD44⁺CD24⁻ prostate CSCs and shows evidence for increased Hedgehog signaling. Finally, invasive cells from DU145 and primary prostate cancer cells are more tumorigenic in NOD/SCID mice compared with non-invasive cells. Our data strongly suggest that basement membrane invasion, an early and necessary step in metastasis development, is mediated by these potential cancer stem cells. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.