Stem cells in breast tumours: Are they ready for the clinic?

The concept of stem-like cells in cancer has been gaining currency over the last decade or so since evidence for stem cell activity in human leukaemia and solid tumours, including breast cancer, was first published. The evidence established that sub-populations of cells identified by antibodies to cell surface markers behaved like developmental stem cells in their capacity to re-grow the human tumour for several generations in experimental immune-deficient hosts. The experiments established that cells with tumourigenic capacity expressed ‘cancer stem cell’ (CSC) markers and that activity could also be measured by self-renewal of tumour sphere colonies in culture. In breast and other cancers, there is good evidence that CSCs are relatively resistant to radio- and chemotherapy indicating that novel CSC-targeted therapies are needed. Several pathways are promising targets in breast CSCs. There are several ways of combating CSC activity including inducing their apoptosis, inhibiting stem cell self-renewal to either stop their division or to promote their differentiation, or targeting the CSC niche that supports them. The first challenge for developing novel CSC therapies is to ascertain which of these CSC properties is being targeted. The second challenge is to determine suitable CSC biomarkers to measure the efficacy of the novel CSC therapies. We propose using biomarkers as a means to identify and assess CSC activity in clinical trials. This is likely to be demanding but feasible in the near future. Thus, we asked if CSCs are ready for the clinic, however, the emerging question becomes: is the clinic ready for cancer stem cells?     

肿瘤干细胞的临床意义

肿瘤干细胞(cancer stem cell, CSC)是近年来在许多肿瘤组织中发现的一类特殊干细胞。肿瘤干细胞具有自我更新和分化的能力,可以通过不断分化肿瘤细胞使新的肿瘤产生;肿瘤干细胞具有很强的耐药性和放射抗拒,这可以用来解释肿瘤的复发和转移。肿瘤干细胞可用于对肿瘤的诊断和治疗：通过对肿瘤干细胞标志物的鉴定可实现对一些肿瘤的早期诊断;一些新的治疗手段则通过作用于肿瘤干细胞的信号转导途径、表面标记和其生存的微环境,以及诱导其分化,从而达到靶向治疗肿瘤的目的。深入研究肿瘤干细胞的耐药性以及确定更多的肿瘤干细胞标志物,可为肿瘤治疗提供新途径。     

In vitro models of cancer stem cells and clinical applications

Cancer cells, stem cells and cancer stem cells have for a long time played a significant role in the biomedical sciences. Though cancer therapy is more effective than it was a few years ago, the truth is that still none of the current non-surgical treatments can cure cancer effectively. The reason could be due to the subpopulation called “cancer stem cells” (CSCs), being defined as those cells within a tumour that have properties of stem cells: self-renewal and the ability for differentiation into multiple cell types that occur in tumours.The phenomenon of CSCs is based on their resistance to many of the current cancer therapies, which results in tumour relapse. Although further investigation regarding CSCs is still needed, there is already evidence that these cells may play an important role in the prognosis of cancer, progression and therapeutic strategy. Therefore, long-term patient survival may depend on the elimination of CSCs. Consequently, isolation of pure CSC populations or reprogramming of cancer cells into CSCs, from cancer cell lines or primary tumours, would be a useful tool to gain an in-depth knowledge about heterogeneity and plasticity of CSC phenotypes and therefore carcinogenesis. Herein, we will discuss current CSC models, methods used to characterize CSCs, candidate markers, characteristic signalling pathways and clinical applications of CSCs. Some examples of CSC-specific treatments that are currently in early clinical phases will also be presented in this review.     

Stem cell-like cancer cells in cancer cell lines

Both stem cells and cancer cells are thought to be capable of unlimited proliferation. Moreover, a small number of cancer cells express stem cell markers, including CD133 and ATP-binding cassette transporters, by which the cells can pump out specific fluorescence dyes, such as Hoechst33342, as well as anti-cancer drugs, suggesting that either cancer cells resemble stem cells or cancers contain stem cell-like cancer cells, called "cancer stem cells (CSCs)". Using the common characteristics of tissue-specific stem cells, it was demonstrated that many types of tumors and cancer cell lines contain CSCs, which self-renew, express stem cell markers, and are tumorigenic. It was also shown that CSCs are resistant to anti-cancer drugs and irradiation. Thus CSCs might be a crucial target for the therapy. Because tumors contain CSCs and recruited normal stem cells, both of which contribute to tumorigenesis, it is difficult to separate CSCs from tumors. By contrast, cancer cell lines do not have any contaminating normal stem cells that quickly loose mulitpotentiality and differentiate in normal culture condition, suggesting that cancer cell lines could be an attractive alternative source of cells for CSC research. In this review I summarize the recent progress in CSC research using cancer cell lines.     

Hit 'em where they live: targeting the cancer stem cell niche

Cancer stem cells (CSCs) are thought to be critical for initiation and propagation of many types of cancer. Because these cells are resistant to conventional therapies, they have been very difficult to eliminate. A study in this issue of Cancer Cell suggests that brain tumor CSCs live in a "vascular niche" that promotes their long-term growth and self-renewal. Disrupting this niche impairs CSC self-renewal and thereby significantly inhibits the growth of tumors. Targeting the unique microenvironment of CSCs may be the key to effective cancer therapy.     

Perivascular stem cell niche in head and neck cancer

Cancers may contain a small sub-population of uniquely tumorigenic cells that exhibit self-renewal and multipotency, i.e. cancer stem cells (CSCs). These cells reside in invasive fronts in close proximity to blood vessels in many tumors, including head and neck squamous cell carcinomas (HNSCCs). Recent evidence suggests that CSC resist chemotherapy and “drive” local recurrence and metastatic spread. Notably, endothelial cell-initiated signaling is critical for the survival and self-renewal of CSC and may play a role in resistance to therapy. Therefore, patients with head and neck cancer might benefit from therapies that target the CSC directly or their supportive perivascular niche.     

Cellules souches du cancer du sein : prendre le cancer à la racine

In cancer stem cell (CSC) hypothesis, tumors are organized in a hierarchical model with CSC at the top of the hierarchy. CSCs display both stem cell properties (self-renewal and differentiation) and specific tumoral properties (tumorigenicity, metastatic capacity, resistance to conventional therapies). Recent works on breast cancer allow CSCs isolation and help deciphering CSC biology and targeting with specific therapies. In clinical trials, CSC biology has to be taken into account and the criteria to judge therapeutic efficiency have to change.     

Targeting cancer stem cell-specific markers and/or associated signaling pathways for overcoming cancer drug resistance

Cancer stem cells (CSCs) are a small subpopulation of tumor cells with capabilities of self-renewal, dedifferentiation, tumorigenicity, and inherent chemo-and-radio therapy resistance. Tumor resistance is believed to be caused by CSCs that are intrinsically challenging to common treatments. A number of CSC markers including CD44, CD133, receptor tyrosine kinase, aldehyde dehydrogenases, epithelial cell adhesion molecule/epithelial specific antigen, and ATP-binding cassette subfamily G member 2 have been proved as the useful targets for defining CSC population in solid tumors. Furthermore, targeting CSC markers through new therapeutic strategies will ultimately improve treatments and overcome cancer drug resistance. Therefore, the identification of novel strategies to increase sensitivity of CSC markers has major clinical implications. This review will focus on the innovative treatment methods such as nano-, immuno-, gene-, and chemotherapy approaches for targeting CSC-specific markers and/or their associated signaling pathways.     

Breast cancer stem cells: tools and models to rely on

There is increasing evidence for the "cancer stem cell (CSC) hypothesis", which holds that cancers are driven by a cellular component that has stem cell properties, including self-renewal, tumorigenicity and multi-lineage differentiation capacity. Researchers and oncologists see in this model an explanation as to why cancer may be so difficult to cure, as well as a promising ground for novel therapeutic strategies. Given the specific stem cell features of self-renewal and differentiation, which drive tumorigenesis and contribute to cellular heterogeneity, each marker and assay designed to isolate and characterize CSCs has to be functionally validated. In this review, we survey tools and markers available or promising to identify breast CSCs. We review the main models used to study breast CSCs and how they challenge the CSC hypothesis.     

胃癌干细胞与微环境的研究进展

胃癌目前是仅次于肺癌的第二大致死性肿瘤,目前胃癌的发病机制还不是很清楚。近年来随着对肿瘤干细胞（CSC）和肿瘤生物学的研究,目前已经在多种实体瘤中发现CSC,但是由于胃癌干细胞缺乏特异性的标志物,因此还有很多空白待探究。虽然已发现一些胃癌干细胞表面标志物如CD44、CD133等,但缺乏特异性,仍需进一步探究更具特异性的胃癌干细胞标志物。CSC生存的环境在肿瘤的进程中也起重要的作用。文章对胃癌干细胞和微环境进行研究将有助于胃癌的诊断和治疗。     

胃癌干细胞研究进展

肿瘤干细胞(CSC)是一群具有自我更新能力和多向分化潜能的肿瘤细胞,许多研究已证实在多种实体瘤中存在CSC.虽然CSC在肿瘤细胞总数中只占很小比例,但在肿瘤的起源、发展、转移及复发等方面均有重要的作用.胃癌CSC的研究尚处于探索阶段,仍未发现胃癌CSC特异性标记物,但对其存在和来源均开展了一系列的研究.     

小细胞肺癌干细胞信号通路的研究进展

小细胞肺癌是具有高度侵袭性的肺肿瘤,其主要临床特征是化疗有效率高但易在短时间内复发转移,这一特点可能与肿瘤干细胞的存在有关。肿瘤干细胞被认为是恶性肿瘤发生发展、耐药、复发及转移的根源。目前多认为肿瘤干细胞与正常干细胞有着相同的信号通路,如Hedgehog、Notch、Wnt等通路。本文就这几条信号通路在小细胞肺癌干细胞中所起的作用以及针对这几条信号通路治疗药物的研究进展和可能的信号通路交互作用等方面进行综述。     

Implications of cancer stem cells in the treatment of cancer

Identification of cancer stem cells (CSCs) in both hematological and solid malignancies suggests that CSCs may be a common phenomenon for most malignancies. Similarly to normal stem cells, CSCs can self-renew and differentiate into progeny cancer cells. Almost all current therapy against cancer targets differentiated cancer cells. CSCs are more resistant to therapy secondary to quiescence, increased expression of antiapoptotic proteins and drug efflux transporters. In this article, we review the current status of CSC research and propose the targeting of CSC cell-surface molecules, signal transduction pathways, the stem cell niche, stem cell differentiation and drug resistance.     

Nanomedicine strategies for sustained,controlled, and targeted treatment of cancer stem cells of the digestive system

Cancer stem cells (CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability. They have been identified in a variety of tumors, including tumors of the digestive system. CSCs exhibit some unique characteristics, which are responsible for cancer metastasis and recurrence. Consequently, the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy. Several potential approaches to target CSCs of the digestive system have been explored, including targeting CSC surface markers and signaling pathways, inducing the differentiation of CSCs, altering the tumor microenvironment or niche, and inhibiting ATP-driven efflux transporters. However, conventional therapies may not successfully eradicate CSCs owing to various problems, including poor solubility, stability, rapid clearance, poor cellular uptake, and unacceptable cytotoxicity. Nanomedicine strategies, which include drug, gene, targeted, and combinational delivery, could solve these problems and significantly improve the therapeutic index. This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system.     

Cancer stem cells: in the line of fire

Most tumours appear to contain a sub-population(s) of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The CSC model proposes that CSCs are at the apex of a hierarchically organized cell population, somewhat akin to normal tissue organization. Selection pressures may also facilitate the stochastic clonal expansion of sub-sets of cancer cells that may co-exist with CSCs and their progeny, moreover the trait of stemness may be more fluid than hitherto expected, and cells may switch between the stem and non-stem cell state. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In this review we discuss the basis of such resistance that highlights the roles of ABC transporters, aldehyde dehydrogenase (ALDH) activity, intracellular signalling pathways, the DNA damage response, hypoxia and proliferative quiescence as being significant determinants. In the light of such observations, we outline strategies for the successful eradication of CSCs, including targeting the self-renewal controlling pathways (Wnt, Notch and Hedgehog), ALDH activity and ABC transporters, blocking epithelial mesenchymal transition (EMT), differentiation therapy and niche targeting.     

Tumour stem cell-targeted treatment: elimination or differentiation.

A wide range of studies suggest that most cancers are clonal and may represent the progeny of a single cell, a cancer stem cell (CSC) endowed with the capacity to maintain tumour growth. The concept of a cancer stem cell emerged decades ago, and the haematopoietic system is where it has mostly gained ground. More recently, CSC have been described in breast cancer and brain tumours. Growing evidence suggests that pathways regulating normal stem cell self-renewal and differentiation are also present in cancer cells and CSC. Malignant tumours can be viewed as an abnormal organ in which a small population of tumourigenic cancer stem cells have escaped the normal limits of self-renewal giving rise to abnormally differentiated cancer cells that contribute to tumour progression and growth. This new model has important implications for the study and treatment of cancer. Understanding the molecular circuitry which contributes to the maintenance of stem cells may provide an insight into the molecular mechanisms of cancer and thus new approaches for elimination or differentiation therapy. Therapies targeting CSC should focus on pathways such as Wnt, Shh and Notch which are required for the maintenance of cancer stem cells, but also on the ABC transporter family and other specific properties of cancer stem cells.     

Cancer stem cell and cancer stemloids: from biology to therapy

It has become a cliché that cancer therapy fails because it does not target rare cancer stem cells (CSCs). Here we are discuss that this is not how therapy fails and not any cancer cell with stem-like properties is CSC. Paradoxically, CSCs must be resting to explain their resistance to therapy yet must be cycling to explain their persistence in cell culture. To solve contradictions, this article introduces the term cancer stemloids (or stem cell-like cells) to describe proliferating self-renewing cells. The stem cell hierarchy (stem--proliferating--terminal cells) exists exactly to separate self-renewal (immortality) from proliferation. Cancer stemloids break the stem cell hierarchy and eventually may replace other cells. While CSC is shielded from any selective pressure and therefore unable to drive tumor progression, cancer stemloids undergo clonal selection, accumulate mutations, thus determining tumor progression and therapeutic failures. Unlike CSC, cancer stemloids are a crucial target for cancer therapy, exactly because they proliferate. Furthermore, two normally mutually-exclusive properties (proliferation and stemness) provide a means to design therapy to kill cancer stemloids selectively without killing normal stem and non-stem cells. In contrast, true CSCs are not only a difficult, but also an insufficient and perhaps even an unnecessary therapeutic target, especially in advanced malignancies.     

Cancer stem cells: characteristics and their potential role for new therapeutic strategies

With the cancer stem cell (CSC) hypothesis many questions regarding cancer development and drug resistance can be answered more coherently than with the traditional model based on clonal evolution. CSCs are a small subset of cancer cells within the tumour that show stem cell characteristics like self-renewal, the capability to develop into multiple lineages and the potential to proliferate extensively, and are characterised by a typical profile of different markers like CD44 and CD133. In the CSC model, the role of embryonic pathways like Wnt, Hedgehog and Notch is of special interest. This review presents current scientific knowledge on this topic and discusses the potential role of CSC in the resistance against chemotherapy or radiation and presents challenging options for therapeutic interventions.     

First among equals: the cancer cell hierarchy

Primary cancer cells exhibit heterogeneity in their proliferative ability. The cancer stem cell (CSC) model accounts for this heterogeneity by proposing that each cancer consists of a small population of CSCs that are capable of unlimited growth and self-renewal and a much larger population of cells, descendants of the CSCs, that have lost self-renewal capacity. The CSC model has important implications for cancer therapy. Eradication of CSCs, the cells responsible for maintenance of the neoplasm, would be necessary and sufficient to achieve cure. By extension, both the frequency of stem cells in a tumor and their propensity to undergo self-renewal (P_sr) would have a direct impact on the curability of that tumor. The P_sr is a critical biological characteristic of CSCs—small differences in P_sr have enormous impact on the probability of success in cancer therapy. Differentiation therapy, defined as treatment that reduces the P_sr of CSCs, is one approach to targeting CSCs.     

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.