Targeting glioma stem cells: a novel framework for brain tumors

The past decade has seen a dramatic increase in stem cell research that focuses on glioma stem cells (GSC) and their mechanisms of action, revealing multiple potential targets for primary malignant brain tumors. Herein, we present a novel framework for considering GSC targets based on direct and indirect strategies. Direct strategies target GSC molecular pathways to overcome their resistance to radiation and chemotherapy, block their function or induce their differentiation. Indirect strategies target the microenvironment of the GSC, namely the perivascular, hypoxic and immune niches. Progress made on GSC targets is reviewed in detail and specific pathways are identified in context of the proposed framework. The potential barriers for translation to the clinical setting are also discussed. Overall, targeting GSC provides an unprecedented opportunity for revolutionary approaches to treat high-grade gliomas that continue to have a poor patient prognosis.     

Cancer stem cells and brain tumors

Besides the role of normal stem cells in organogenesis, cancer stem cells are thought to be crucial for tumorigenesis. Most current research on human tumors is focused on molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and, more recently, in solid tumors suggests that the tumor cell population is heterogeneous. In recent years, several groups have described the existence of a cancer stem cell population in different brain tumors. These neural cancer stem cells (NCSC) can be isolated by cell sorting of dissociated suspensions of tumor cells for the neural stem cell marker CD133. These CD133+ cells -which also express nestin, an intermediate filament that is another neural stem cell marker- represent a small fraction of the entire brain tumor population. The stem-like cancer cells appear to be solely responsible for propagating the disease in laboratory models. A promising new approach to treating glioblastoma proposes targeting cancer stem cells. Here, we summarize progress in delineating NCSC and the implications of the discovery of this cell population in human brain tumors.     

Targeting T cells against brain tumors with a bispecific ligand-antibody conjugate

High-affinity receptors expressed on the surface of some tumors can be exploited by chemically conjugating the ligand for the receptor and an antibody against immune effector cells, thus redirecting their cytolytic potential against the tumor. Ovarian carcinomas and some brain tumors express the high-affinity folate receptor (FR). In this report, a transgenic mouse model that generates endogenously arising choroid plexus tumors was used to show that folate/anti- T-cell receptor antibody conjugates can direct infiltration of T cells into solid brain tumor masses. An engineered single-chain Fv form of the anti-T-cell receptor antibody KJ16 was conjugated with folate, to produce a bispecific agent that was substantially smaller than most previously characterized bispecific antibodies. Folate conjugation to the antibody increased T-cell infiltration into the tumors by 10- to 20-fold, and significantly prolonged survival of the mice. Int. J. Cancer 76:761–766, 1998.© 1998 Wiley-Liss, Inc.     

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.     

Targeting of melanoma brain metastases using engineered neural stem/progenitor cells

Brain metastases are an increasingly frequent and serious clinical problem for cancer patients, especially those with advanced melanoma. Given the extensive tropism of neural stem/progenitor cells (NSPCs) for pathological areas in the central nervous system, we expanded investigations to determine whether NSPCs could also target multiple sites of brain metastases in a syngeneic experimental melanoma model. Using cytosine deaminase-expressing NSPCs (CD-NSPCs) and systemic 5-fluorocytosine (5-FC) pro-drug administration, we explored their potential as a cell-based targeted drug delivery system to disseminated brain metastases. Our results indicate a strong tropism of NSPCs for intracerebral melanoma metastases. Furthermore, in our therapeutic paradigm, animals with established melanoma brain metastasis received intracranial implantation of CD-NSPCs followed by systemic 5-FC treatment, resulting in a significant (71%) reduction in tumor burden. These data provide proof of principle for the use of NSPCs for targeted delivery of therapeutic gene products to melanoma brain metastases.     

Targeting apoptosis pathways in cancer stem cells

There is a significant void in cancer biology with regard to the elucidation of the mechanisms that underlie tumor formation and progression. Recently, the existence of a hierarchy within cancer cell populations has been demonstrated experimentally for several tumor types. The identification of a tumor cell subset that is capable of self-renewal and, concurrently, generation into more differentiated progeny has engendered new perspectives toward selective targeting of tumors.     

Cancer stem cells and brain tumors: uprooting the bad seeds

The cancer stem cell (CSC) hypothesis is predicated on the idea that not all cells have equal proliferative potential and that, in brain tumors, the cells with the greatest ability to proliferate and contribute to tumorigenesis have phenotypic and functional properties similar to normal neural stem cells (NSCs). Over the past few years, multiple investigators have shown that CSCs isolated from human brain tumors (glioma and medulloblastoma) undergo self-renewal and multilineage cell differentiation, similar to normal NSCs. In addition, CSCs from these tumors, when implanted into rodent brains, generate tumors histologically identical to the parental tumors, suggesting that progenitor/stem cells can fully recapitulate the neoplastic phenotype in vivo. While these seminal studies clearly highlight the central role of stem cells in brain tumors, they also evoke important questions regarding the importance of these unique cells to tumor initiation, maintenance and treatment.     

Cancer stem cells and brain tumors: uprooting the bad seeds

The cancer stem cell (CSC) hypothesis is predicated on the idea that not all cells have equal proliferative potential and that, in brain tumors, the cells with the greatest ability to proliferate and contribute to tumorigenesis have phenotypic and functional properties similar to normal neural stem cells (NSCs). Over the past few years, multiple investigators have shown that CSCs isolated from human brain tumors (glioma and medulloblastoma) undergo self-renewal and multilineage cell differentiation, similar to normal NSCs. In addition, CSCs from these tumors, when implanted into rodent brains, generate tumors histologically identical to the parental tumors, suggesting that progenitor/stem cells can fully recapitulate the neoplastic phenotype in vivo. While these seminal studies clearly highlight the central role of stem cells in brain tumors, they also evoke important questions regarding the importance of these unique cells to tumor initiation, maintenance and treatment.     

Hedgehog--Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer

The Hedgehog-Gli signaling pathway is involved in the regulation of the proliferation of precursors in different organs of the normal vertebrate embryo. These cells express Gli1 and may be the target of cancer-causing agents. Many tumor types derived from organs that contain Gli1+ precursors appear to consistently express Gli1, indicating their origin and/or the presence of an active pathway. Inappropriate pathway activation in a variety of precursor cells in model organisms leads to tumor formation while inhibition of the pathway in human tumor cells leads to a decrease in their proliferation. In the brain we have documented the expression of Gli1 in germinative zones, and a variety of brain tumors express GLI1, including medulloblastomas of the cerebellum and a number of gliomas of the cerebral cortex. The requirement for SHH-Gli signaling in the growth of the mouse brain, together with the ability of inappropriate pathway activation in the cerebellum to cause medulloblastomas, and the inhibition of the growth of a number of brain tumors with cyclopamine, a SHH signaling inhibitor, underscores the critical role of the SHH-GLI pathway in brain growth and tumor formation. Moreover, they highlight the components of this pathway as prime targets for drug development, with special emphasis on the GLI proteins. Such reagents would allow a rational therapeutic approach to highly intractable diseases.     

Radiotherapy of primary brain stem tumors

This paper presents results of treatment for 80 patients with primary brain stem tumors who were seen at McGill University Hospitals from 1960–1975. A large proportion of the patients were under 15 years old. The majority of pretreatment diagnoses were based on neuroradiologic procedures. The correlation of these procedures in histologically verified cases is high. Glioblastoma comprised 38.7 % of the histologically proven cases. Radiotherapy was the main modality of the treatment. Of the patients who received over 5000 rod, 44/63 (39.8°10) survived at 3 years, 34.5 % at 5 years and 28.4 % at 10 years. This result is similar to that in Bouchard's series which analyzed the cases from the same source prior to this series. The initial response to treatment was beneficial in the majority of patients and this early response appears to be a dependable prognostic parameter.     

Cancer stem cells in solid tumors

In this review, we discuss recent issues about cancer stem cells, especially in solid tumors. Cancer stem cells show the ability to self-renew; and they possess multi-potential differentiation and tumorigenic potential. Cancer stem cells are reported to show resistance to anticancer drugs and radiotherapy, and therefore, they are involved in progression, recurrence, and metastasis in cancer. The existence of cancer stem cells in leukemia has long been known, since early times. In recent years cancer stem cells have been identified in solid tumors of breast, prostate, lung, brain, colon, and pancreas, owing to the development of identification techniques using cell surface markers. Although many features remain to be addressed, it is expected that cancer stem cells could be a main target for cancer therapy in the near future.     

Cancer stem cells in solid tumors

According to the cancer progression model, several events are required for the progression from normal epithelium to carcinoma. Due to their extended life span, stem cells would represent the most likely target for the accumulation of these genetic events but this has not been formally proven for most of solid cancers. Even more importantly, cancer stem cells seem to harbor mechanisms protecting them from standard cytotoxic therapy. While cancer stem cells have been demonstrated to be responsible for therapy resistance in glioblastoma and pancreatic cancer, further evidence now points to similar mechanisms in colon cancer stem cells. Therefore, it appears reasonable to conclude that there is sufficient evidence now for the existence of cancer stem cells in several epithelial tumors and that these cancer stem cells pose a significant threat via their resistance to standard therapies. Accumulating evidence suggests, however, that novel approaches targeting cancer stem cells are capable of overcoming these resistance mechanisms. To further foster our understanding of in vivo cancer stem cell biology, novel imaging modalities in conjunction with clinically most relevant cancer stem cell models need to be developed and utilized. These studies will then pave the way to better elucidate the underlying regulatory mechanisms of cancer stem cells and develop platforms for targeted theragnostics, which may eventually help improving the prognosis of our patients suffering from these deadly diseases.     

神经干细胞和脑肿瘤干细胞研究进展

神经干细胞(NSC)是中枢神经系统(CNS)内具有自我更新和多向分化潜能的干细胞,主要存在于脑室下区域(SVZ),NSC通过自我更新和分化维持正常CNS的形态和功能。可塑性(plastici- ty)是NSC的重要特征,由NSC所处的微环境(microenvironment)决定。脑肿瘤干细胞(BTSC)是脑肿瘤中与NSC相似的细胞,是脑肿瘤发生和生长的细胞来源。BTSC可能起源于NSC,是NSC可塑性的表现,导致NSC向BTSC分化的机制可能是微环境作用的结果。     

神经干细胞和脑肿瘤干细胞研究进展

神经干细胞（NSC）是中枢神经系统（CNS）内具有自我更新和多向分化潜能的干细胞，主要存在于脑室下区域（SVZ），NSC通过自我更新和分化维持正常CNS的形态和功能。可塑性（plasticity）是NSC的重要特征，由NSC所处的微环境（microenvironment）决定。脑肿瘤干细胞（BTSC）是脑肿瘤中与NSC相似的细胞，是脑肿瘤发生和生长的细胞来源。BTSC可能起源于NSC，是NSC可塑性的表现，导致NSC向BTSC分化的机制可能是微环境作用的结果。     

Targeting therapy-resistant cancer stem cells by hyperthermia

Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells (CSCs), is considered to be of particular significance for tumour initiation, progression and metastasis. CSCs are considered in particular to be therapy-resistant and may drive disease recurrence, which positions CSCs in the focus of anti-cancer research, but successful CSC-targeting therapies are limited. Here, we argue that hyperthermia – a therapeutic approach based on local heating of a tumour – is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising radiation and chemotherapy are least effective. Second, hyperthermia can modify factors that are essential for tumour survival and growth, such as the microenvironment, immune responses, vascularisation and oxygen supply. Third, hyperthermia targets multiple DNA repair pathways, which are generally upregulated in CSCs and protect them from DNA-damaging agents. Addition of hyperthermia to the therapeutic armamentarium of oncologists may thus be a promising strategy to eliminate therapy-escaping and -resistant CSCs.     

靶向肿瘤干细胞治疗肿瘤

具有独特的分子表达、表面标志物、干性相关信号通路和代谢模式等方面特征的肿瘤干细胞(cancer stem cell,CSC)因其具有高致瘤、高转移、高治疗抵抗能力,可能是多种类型恶性肿瘤生长、转移、治疗抵抗的关键因素,也是肿瘤发生和复发的重要根源.正常干细胞在产生了第一个致癌突变之后将逐步发展成为癌前干细胞和CSC,随...