Targeting breast cancer stem cells

The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self‐renewing CSC population that is also capable of differentiating into non‐self‐renewing cell populations that constitute the bulk of the tumor. Although, the CSC hypothesis does not directly address the cell of origin of cancer, it is postulated that tissue‐resident stem or progenitor cells are the most common targets of transformation. Clinically, CSCs are predicted to mediate tumor recurrence after chemo‐ and radiation‐therapy due to the relative inability of these modalities to effectively target CSCs. If this is the case, then CSC must be efficiently targeted to achieve a true cure. Similarities between normal and malignant stem cells, at the levels of cell‐surface proteins, molecular pathways, cell cycle quiescence, and microRNA signaling present challenges in developing CSC‐specific therapeutics. Approaches to targeting CSCs include the development of agents targeting known stem cell regulatory pathways as well as unbiased high‐throughput siRNA or small molecule screening. Based on studies of pathways present in normal stem cells, recent work has identified potential “Achilles heals” of CSC, whereas unbiased screening provides opportunities to identify new pathways utilized by CSC as well as develop potential therapeutic agents. Here, we review both approaches and their potential to effectively target breast CSC.     

Implications of understanding cancer stem cell (CSC) biology in head and neck squamous cell cancer

Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of this disease. Efforts are ongoing throughout the world to improve early detection and prevention of HNSCCs. Often, treatment fails to obtain total cancer cure and this is more likely with advanced stage disease. In recent years it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells (CSC) that 'escape' currently available therapies. CSCs form a minute portion of the total tumour burden but may play a disproportionately important role in determining outcomes. Molecular mechanisms which underlie the genesis of CSCs are yet not fully understood and their detection within the total tumour bulk remains a challenge. Specific markers like Aldehyde dehydrogenase 1 (ALDH1), CD44 and Bmi-1 have shown early promising results both in CSC detection and in guiding treatment protocols. CSCs have been shown to be relatively resistant to standard treatment modalities. It is hoped that developing robust in vitro and in vivo experimental models of CSCs might provide a means of devising more effective therapeutic strategies.     

胃癌干细胞的研究进展

随着恶性肿瘤基础研究的不断深入,肿瘤干细胞的存在被越来越多的基础和临床研究所证实。目前,包括血液系统肿瘤和实体瘤在内的多种肿瘤干细胞已被分离纯化和鉴定。胃癌作为目前在中国发病率和致死率最高的肿瘤之一,其具有肿瘤干细胞特性的胃癌细胞亚群已被分选出来,但多数研究对胃癌干细胞的特异性表面标志物尚不能达成共识,导致胃癌干细胞表面标志物未能明确。至今已有多项研究先后报道了不同表面标志物的胃癌干样细胞,它们中的大部分都可分化为其他具有不同表型的胃癌细胞,并可以在体外克隆成球及在免疫缺陷小鼠体内成瘤,符合肿瘤干细胞自我更新、多向分化、高效致瘤等特征。本文就近年胃癌干细胞及其分离鉴定方面的研究进展进行综述。     

结直肠癌肿瘤干细胞标志物的研究进展

近年来,肿瘤干细胞（CSC）学说得到越来越多的支持,识别CSC的关键就是寻找干细胞的表面特异性标志物.结直肠癌CSC的相关研究不断取得进展,文章综述了近几年发现的比较公认的干细胞标志物CD44、SOX9、ALDH1和OCT-4等的研究进展及其与结直肠癌的关系.     

Brain tumor stem cells: The cancer stem cell hypothesis writ large

Brain tumors, which are typically very heterogeneous at the cellular level, appear to have a stem cell foundation. Recently, investigations from multiple groups have found that human as well as experimental mouse brain tumors contain subpopulations of cells that functionally behave as tumor stem cells, driving tumor growth and generating tumor cell progeny that form the tumor bulk, but which then lose tumorigenic ability. In human glioblastomas, these tumor stem cells express neural precursor markers and are capable of differentiating into tumor cells that express more mature neural lineage markers. In addition, modeling brain tumors in mice suggests that neural precursor cells more readily give rise to full blown tumors, narrowing potential cells of origin to those rarer brain cells that have a proliferative potential. Applying stem cell concepts and methodologies is giving fresh insight into brain tumor biology, cell of origin and mechanisms of growth, and is offering new opportunities for development of more effective treatments. The field of brain tumor stem cells remains very young and there is much to be learned before these new insights are translated into new patient treatments.     

Targeting cancer stem cells by curcumin and clinical applications

Curcumin is a well-known dietary polyphenol derived from the rhizomes of turmeric, an Indian spice. The anticancer effect of curcumin has been demonstrated in many cell and animal studies, and recent research has shown that curcumin can target cancer stem cells (CSCs). CSCs are proposed to be responsible for initiating and maintaining cancer, and contribute to recurrence and drug resistance. A number of studies have suggested that curcumin has the potential to target CSCs through regulation of CSC self-renewal pathways (Wnt/β-catenin, Notch, sonic hedgehog) and specific microRNAs involved in acquisition of epithelial–mesenchymal transition (EMT). The potential impact of curcumin, alone or in combination with other anticancer agents, on CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been well-established by numerous clinical studies. Importantly, the low bioavailability of curcumin has been dramatically improved through the use of structural analogues or special formulations. More clinical trials are underway to investigate the efficacy of this promising agent in cancer chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer treatments.     

肿瘤干细胞研究现状

复发和转移是限制肿瘤临床治疗疗效的瓶颈。近些年,产生和发展了肿瘤干细胞理论,试图解释这种现象。本文就肿瘤干细胞研究的理论基础、现状及前景做一综述。     

外阴鳞状细胞癌肿瘤干细胞的分选和鉴定

目的:分离外阴鳞状细胞癌A-431细胞系中CD44+的细胞亚群,鉴定其具有肿瘤干细胞特性。方法:采用流式细胞术分选出CD44免疫荧光抗体标记的CD44+细胞亚群,检测CD133、CD34蛋白在CD44+和CD44-中表达的差异,检测CD44+及CD44-细胞亚群的细胞周期。结果:A-431细胞系中CD44+细胞亚群约占4%,胚胎干细胞因子CD133、CD34在CD44+和CD44-的VSCC中表达存在显著性差异,主要在细胞膜上表达,CD44+的肿瘤细胞亚群97.69%处于G1期,CD44-的肿瘤细胞亚群61.12%处于S期。结论:在 A-431细胞系中 CD44 可以作为分选肿瘤干细胞的特异性表面标志物,CD133、CD34 在 CD44+的肿瘤细胞高表达,可能成为分选外阴鳞癌肿瘤干细胞的特异性表面标志物,CD44+肿瘤细胞具有典型的干细胞增殖特点。     

肿瘤干细胞研究现状

复发和转移是限制肿瘤临床治疗疗效的瓶颈。近些年,产生和发展了肿瘤干细胞理论,试图解释这种现象。本文就肿瘤干细胞研究的理论基础、现状及前景做一综述。     

Complexity of cancer stem cells

Heterogeneity of tumor tissue has been accounted for in recent years by a hierarchy‐based model in which cancer stem cells (CSCs) have the ability both to self‐renew and to give rise to differentiated tumor cells and are responsible for the overall organization of a tumor. Research into CSCs has progressed rapidly and concomitantly with recent advances in the biology of normal tissue stem cells, resulting in the identification of CSCs in a wide range of human tumors. Studies of mouse models of human cancer have provided further insight into the characteristics of CSCs as well as a basis for the development of novel therapies targeted to these cells. However, recent studies have revealed complexities, such as plasticity of stem cell properties and clonal diversity of CSCs, in certain tumor types that have led to revision of the original CSC model. In this review, we summarize the history of the discovery and characterization of CSCs, as well as address recent advances that have revealed the complexity of these cells and their therapeutic implications.     

Cancer stem cell enrichment marker CD98: A prognostic factor for survival in patients with human papillomavirus-positive oropharyngeal cancer

PurposeSeveral hypotheses have been proposed to explain the relatively good prognosis of patients with a human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) and one of these is a higher sensitivity to (chemo)radiation. Previous studies have suggested that treatment failure in OPSCC patients is caused by resistance of cancer stem cells (CSCs). The purpose of this study was to evaluate the association between the number of CSCs and prognosis in HPV-positive OPSCC patients.Experimental designAll OPSCC patients (n = 711) treated between 2000 and 2006 in two Dutch university hospitals were included. Presence of HPV in a tumour tissue specimen was tested by p16-immunostaining followed by HPV DNA GP5+/6+polymerase chain reaction (PCR). The presence and intensity of tumour CSC markers CD44 and CD98 were determined by immunohistochemistry and semiquantitative scoring was performed. Overall survival (OS) and progression-free survival (PFS) rates were compared between patients with low and high CD44/CD98 expression in relation to HPV status.ResultsHPV-positive tumours showed a lower percentage of cells with CD44 and CD98 expression than HPV-negative tumours (p < 0.001, χ²-test). Within the group of patients with HPV-positive OPSCC, a high percentage of CD98-positive tumour cells was associated with a significantly worse 5-year OS and PFS (OS: 36.4% and PFS: 27.3%) compared to patients with a low percentage of CD98-positive cells (OS: 71.9% and PFS: 70.5%, respectively) (p < 0.001).ConclusionsHPV-positive OPSCCs harbour fewer cells expressing the CSC enrichment markers CD44 and CD98. Furthermore, OS and PFS were significantly worse for patients with HPV-positive OPSCC with a high percentage of CD98-positive cells.     

舌癌耐药细胞株的建立及癌干细胞特性的实验观察

目的建立舌癌耐药细胞株,并观察耐药细胞株癌干细胞的相关生物学特性。方法以低浓度阿霉素持续增量诱导法建立TCA-8113舌癌耐药细胞株,并对亲代与舌癌耐药细胞株进行癌细胞基本特性、癌干细胞相关细胞学特性的检测,分别以计数法检测癌细胞生长曲线、倍增时间以及用MTT法测定耐药倍数,并进行单个细胞成克隆实验、平板克隆形成实验和悬浮球形成实验。结果TCA-8113舌癌耐药细胞为“铺路石”状上皮样生长方式,但其中异形细胞略多,耐药倍数为22倍;生长曲线提示其增殖速度明显低于亲本TCA-8113舌癌细胞,且倍增时间增加,但在细胞周期中各期细胞比例未见明显改变;TCA-8113舌癌耐药细胞克隆形成率、单个细胞培养成株率均明显低于其亲本TCA-8113舌癌细胞（P〈0．05）。结论低浓度阿霉素持续增量法可诱导形成舌癌耐药细胞株,但舌癌耐药细胞株的癌干细胞特征并不明显。     

前列腺癌干细胞与去势抵抗性前列腺癌放射性耐受的研究进展

前列腺癌经过去势治疗后有进展为去势抵抗性前列腺癌的可能。去势抵抗性前列腺癌对临床医生最大的挑战为其治疗抵抗特性。针对放疗耐受,相关研究认为与前列腺癌干细胞及前列腺癌干细胞相关miRNA相关。下文从去势抵抗性前列腺癌进展机制、前列腺癌干细胞及前列腺癌干细胞相关miRNA等方面介绍去势抵抗性前列腺癌放射性耐受的研究进展。     

Human DNAJ in cancer and stem cells

The heat shock protein 40 kDa (HSP40/DNAJ) co-chaperones constitute the largest and most diverse sub-group of the heat shock protein (HSP) family. DNAJ are widely accepted as regulators of HSP70 function, but also have roles as co-chaperones for the HSP90 chaperone machine, and a growing number of biological functions that may be independent of either of these chaperones. The DNAJ proteins are differentially expressed in human tissues and demonstrate the capacity to function to both promote and suppress cancer development by acting as chaperones for tumour suppressors or oncoproteins. We review the current literature on the function and expression of DNAJ in cancer, stem cells and cancer stem cells. Combining data from gene expression, proteomics and studies in other systems, we propose that DNAJ will be key regulators of cancer, stem cell and possibly cancer stem cell function. The diversity of DNAJ and their assorted roles in a range of biological functions means that selected DNAJ, provided there is limited redundancy and that a specific link to malignancy can be established, may yet provide an attractive target for specific and selective drug design for the development of anti-cancer treatments.     

Ovarian cancer stem cell markers: Prognostic and therapeutic implications

Cancer stem cells are rare chemotherapy resistant cells within a tumor which can serve to populate the bulk of a tumor with more differentiated daughter cells and potentially contribute to recurrent disease. Ovarian cancer is a disease for which at the time of initial treatment we can obtain complete clinical remission in the majority of patients. Unfortunately, most will relapse and succumb to their disease. This clinical course is in line with the cancer stem cell model. In the past 5 years a significant amount of work has been done to identify cells with characteristics of ovarian cancer stem cells. This review will focus specifically on the markers used to define human ovarian cancer stem cells, the prognostic implications of the expression of these cancer stem cell markers in patient’s primary tumors, and the potential of these cancer stem cell markers to serve as therapeutic targets.     

A novel approach to the identification and enrichment of cancer stem cells from a cultured human glioma cell line

Enrichment of cancer stem cells for studies of carcinogenesis remains a difficult issue. We hypothesized that the unique features of cancer stem cells (CSCs) may allow formation of their colonies in vitro with distinct morphology. We therefore investigated the possibility to use morphological diversity of colonies to identify and enrich CSCs from cultured malignant human glioma cells. We found that a small proportion of the cells from a human glioma cell line U251 formed tight and round-shaped colonies in culture. Most cells in such colonies were capable of self-renewal, generating tumor spheres and differentiating into lineages with markers for neurons, astrocytes and oligodendrocytes. In addition, several neural stem cell-related genes were highly expressed by tumor cells in those tight colonies. Our results thus demonstrate a novel approach to the identification and enrichment of CSCs based on unique morphology of their colonies formed in vitro.     

肿瘤治疗的新靶标:肿瘤干细胞

近年来研究显示,在一些肿瘤中存在一些能够自我更新和分化增殖的干细胞即肿瘤干细胞。本文重点介绍了关于肿瘤干细胞的理论,研究现状,研究方法以及问题,推测肿瘤干细胞的深入研究将会对今后肿瘤防治产生巨大影响。     

Understanding the cancer stem cell

The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents.