Oligodendroglioma with neurocytic differentiation versus atypical extraventricular neurocytoma: a case report of unusual pathologic findings of a spinal cord tumor

Differentiating oligodendroglioma from extraventricular neurocytoma by conventional light microscopy alone can present a diagnostic challenge. We report pathologic findings of an unusual spinal cord tumor from a 33-year-old male patient which showed hybrid features of oligodendroglioma and extraventricular neurocytoma. Magnetic resonance imaging (MRI) showed an enhancing intramedullary mass in the cervicothoracic region (C7 through T6). Histologic examination revealed a clear cell neoplasm containing ganglion-like cells and calcifications, prompting the differential diagnosis of oligodendroglioma and extraventricular neurocytoma. The immunohistochemical analysis disclosed neural differentiation of the neoplastic cells with strong synaptophysin and neurofilament staining consistent with extraventricular neurocytoma, as well as strong S-100 and glial fibrillary acidic protein (GFAP) expression. Molecular studies with fluorescent in situ hybridization (FISH) revealed chromosome 1p/(partial) 19q deletions, a finding commonly observed in oligodendroglioma. The proliferation index (using antibody MIB1) of the tumor was approximately 30%. The morphologic findings and these results strengthen the hypothesis that these tumors may share a common progenitor cell, which has also been observed by others. Because there are differences in patient management and long-term prognosis, it is important to attempt to distinguish between oligodendroglioma and neurocytoma. This unusual case and similar rare reported cases support the need to reclassify tumors showing pathologic features common to both neurocytoma and oligodendroglioma as a unique entity, while the effort continues to identify the cell of origin.     

Definition of genetic events directing the development of distinct types of brain tumors from postnatal neural stem/progenitor cells

Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2α, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors.     

Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor

The transplantation of neural stem cells (NSCs) offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF) is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumor-upregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors.     

Cancer stem cells in nervous system tumors

Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and more recently in solid tumors such as breast cancer suggests that the tumor cell population is heterogeneous with respect to proliferation and differentiation. Recently, several groups have described the existence of a cancer stem cell population in human brain tumors of different phenotypes from both children and adults. The finding of brain tumor stem cells (BTSCs) has been made by applying the principles for cell culture and analysis of normal neural stem cells (NSCs) to brain tumor cell populations and by identification of cell surface markers that allow for isolation of distinct tumor cell populations that can then be studied in vitro and in vivo. A population of brain tumor cells can be enriched for BTSCs by cell sorting of dissociated suspensions of tumor cells for the NSC marker CD133. These CD133+ cells, which also expressed the NSC marker nestin, but not differentiated neural lineage markers, represent a minority fraction of the entire brain tumor cell population, and exclusively generate clonal tumor spheres in suspension culture and exhibit increased self-renewal capacity. BTSCs can be induced to differentiate in vitro into tumor cells that phenotypically resembled the tumor from the patient. Here, we discuss the evidence for and implications of the discovery of a cancer stem cell in human brain tumors. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC. Specific genetic and molecular analyses of the BTSC will further our understanding of the mechanisms of brain tumor growth, reinforcing parallels between normal neurogenesis and brain tumorigenesis.     

The roles of chemokine CXCL12 in embryonic and brain tumor angiogenesis

The formation of blood vessels in embryos and tumors are different processes but under the control of common molecular mechanisms. Chemokine CXCL12 involved in both embryonic and tumor angiogenesis. In this review, we summarize recent advances in understanding the roles of CXCL12 in brain tumor angiogenesis/vasculogenesis. CXCL12 and its cognate receptors are abnormally induced in brain tumors, in particular in tumor cells and endothelium. Pathologically enhanced CXCL12 signaling may promote the formation of new vessels through recruiting circulating endothelial progenitor cells or directly enhancing the migration/growth of endothelial cells. Therefore, CXCL12 signaling represents an important mechanism that regulates brain tumor angiogenesis/vasculogenesis and may provide potential targets for anti-angiogenic therapy in malignant gliomas.     

Grade II oligodendroglioma localized to the corpus callosum

The presence of a primary central nervous system (CNS) neoplasm within the corpus callosum generally portends a grave prognosis. Common pathologies encountered include glioblastomas and primary CNS lymphomas. In contrast, World Health Organization grade II oligodendroglial tumors demonstrating loss of heterozygosity at 1p and 19q are generally less aggressive, often responding favorably to chemotherapy. The authors present a case of a primary brain tumor isolated to the corpus callosum diagnosed as a grade II oligodendroglioma. A 52-year-old woman presented with new-onset generalized seizure. Magnetic resonance imaging (MRI) revealed a non-contrast-enhancing lesion with associated edema and regional mass effect. The patient underwent a craniotomy and subtotal resection of the lesion using an endoscopic port. Pathological examination revealed a grade II oligodendroglioma. Molecular analysis identified 1p and 19q deletion as well as MGMT promoter methylation. The patient subsequently underwent adjuvant radiation therapy with an excellent response. We present, to our knowledge, the first report of a grade II oligodendroglioma isolated within the corpus callosum with the characteristic molecular features of this tumor type. Histopathologic diagnosis is essential to appropriately guide therapy of callosal tumors.     

Therapeutic anti-angiogenesis for malignant brain tumors.

Malignant brain tumors, especially malignant gliomas, have a poor prognosis, a fact which has remained unchanged over the last decades despite the employment of multimodal therapeutic approaches. Malignant gliomas are among the most vascularized tumors known and the amount of vascularization has been correlated to their prognosis. Since tumor growth is dependent on concomitant vascularization, recent experimental studies have focused on the use of anti-angiogenic molecules as a novel strategy in brain tumor therapy. Angiogenesis inhibitors target at proliferating endothelial cells and suppress the formation of a sufficient vascular bed. Inhibitors such as TNP-470, suramin and angiostatin have shown their therapeutic potential in experimental studies. In a clinical setting, they could be applied for the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence. This article discusses presently available anti-angiogenic agents, emphasizing on substances already in clinical trials.     

Anti-angiogenic Treatment Strategies for Malignant Brain Tumors

The use of angiogenesis inhibitors may offer novel strategies in brain tumor therapy. In contrast to traditional cancer treatments that attack tumor cells directly, angiogenesis inhibitors target at the formation of tumor-feeding blood vessels that provide continuous supply of nutrients and oxygen.With respect to brain tumor therapy, inhibitors of angiogenesis display unique features that are unknown to conventional chemotherapeutic agents. The most important features are independence of the blood–brain barrier, cell type specificity, and reduced resistance. Malignant brain tumors, especially malignant gliomas, are among the most vascularized tumors known. Despite multimodal therapeutic approaches, the prognosis remains dismal. Thus, angiogenesis inhibitors may be highly effective drugs against these tumors. In a clinical setting, they could be applied in the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence.This article provides an overview of current anti-angiogenic treatment strategies with emphasis on substances already in clinical trials or candidate substances for clinical trials. The cellular and molecular basis of these substances is reviewed.     

Tumorigenesis in the brain: location, location, location

Emerging evidence from numerous laboratories supports the notion that brain tumors arise from cells with stem cell/neuroglial progenitor cell properties ("cancer stem cells"). Two recent studies suggest that histologically similar tumors from different brain regions are molecularly distinct because they arise from distinct populations of site-restricted progenitor cells. These new findings imply an interaction between the cell of origin, the tumor microenvironment, and specific cancer-causing genetic changes in the evolution of central nervous system tumors.     

Leukemia-like onset of bone marrow metastasis from anaplastic oligodendroglioma after 17 years of dormancy: an autopsy case report

Extraneural metastases from primary brain tumors are extremely rare. We present an autopsy case that displayed a very late and unique pattern of metastasis from an anaplastic oligodendroglioma. The patient was a 74-year-old woman who was disease free for 17 years after resection of the primary oligodendroglioma. She was subsequently admitted to a hospital for heart failure where her bone marrow was found to be completely infiltrated with tumor cells, eventually resulting in disseminated intravascular coagulation. The onset was like leukemia, but the “blast-like” cells were different from leukemic cells, and the diagnosis was difficult until autopsy. After her death, a review of her past medical history and comprehensive analysis of her primary brain tumor and aspiration biopsy/autopsy bone marrow samples with glial immunohistochemical markers, fluorescence in situ hybridization examination, and immunohistochemical/sequencing analyses of mutant IDH1 revealed the accurate diagnosis. The metastatic tumor in her bone marrow was finally diagnosed as bone metastasis from the primary anaplastic oligodendroglioma. Although metastatic oligodendroglioma is very rare, it should be noted that this condition displays a propensity for bone and bone marrow and can present with features similar to those of leukemia after a long latency period.     

Diffusion magnetic resonance imaging: an early surrogate marker of therapeutic efficacy in brain tumors

BACKGROUND: A surrogate marker for treatment response that can be observed earlier than comparison of sequential magnetic resonance imaging (MRI) scans, which depends on relatively slow changes in tumor volume, may improve survival of brain tumor patients by providing more time for secondary therapeutic interventions. Previous studies in animals with the use of diffusion MRI revealed rapid changes in tumor water diffusion values after successful therapeutic intervention. METHODS: The present study examined the sensitivity of diffusion MRI measurements in orthotopic rat brain tumors derived from implanted rat 9L glioma cells. The effectiveness of therapy for individual brain cancer patients was evaluated by measuring changes in tumor volume on neuroimaging studies conducted 6--8 weeks after the conclusion of a treatment cycle. RESULTS: Diffusion MRI could detect water diffusion changes in orthotopic 9L gliomas after doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) that resulted in as little as 0.2 log cell kill, a measure of tumor cell death. Mean apparent diffusion coefficients in tumors were found to be correlated with and highly sensitive to changes in tumor cellularity (r =.78; two-sided P =.041). The feasibility of serial diffusion MRI in the clinical management of primary brain tumor patients was also demonstrated. Increased diffusion values could be detected in human brain tumors shortly after treatment initiation. The magnitude of the diffusion changes corresponded with clinical outcome. CONCLUSIONS: These results suggest that diffusion MRI will provide an early surrogate marker for quantification of treatment response in patients with brain tumors.     

少突胶质细胞瘤的诊疗进展

过去的十年间,少突胶质细胞瘤在诊断和治疗方面发生了很大的变化,本文旨在论述少突胶质细胞瘤的诊疗规范及预后,其中主要论述最新的研究进展。我们通过Medline对"少突胶质细胞瘤"进行检索,查阅了近期国内外相关文献。由于例如磁共振和正电子发射型计算机断层成像(positronemissiontomography,PET)等技术的应用,使得少突胶质细胞瘤的诊断越来越早。功能定位及在手术中的应用使得肿瘤切除更加安全,更加彻底,尤其是位于功能区的肿瘤。尽管术后放射治疗能延长患者的生存时间,但由于少突胶质细胞瘤(WHOII级)对化疗敏感,故放疗可推迟到肿瘤复发时再施行。少突胶质细胞瘤是脑肿瘤中第一个应用遗传分子学特征指导治疗的肿瘤,其中最重要的发现为1p和19q染色体杂合子缺失(lossofheterozygosity,LOH)的少突胶质细胞瘤对化疗敏感。尽管手术治疗仍是少突胶质细胞瘤的主要方法,但由于其对化疗的敏感性,使得化疗成为术后主要的治疗方法。少突胶质细胞瘤的分子学特征的研究及应用在不久的将来将成为指导少突胶质细胞瘤治疗的标准方法。     

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.     

Pre-B-cell leukemia homeobox interacting protein 1 is overexpressed in astrocytoma and promotes tumor cell growth and migration

Background

Glial brain tumors cause considerable mortality and morbidity in children and adults. Innovative targets for therapy are needed to improve survival and reduce long-term sequelae. The aim of this study was to find a candidate tumor-promoting protein, abundantly expressed in tumor cells but not in normal brain tissues, as a potential target for therapy.

Methods

In silico proteomics and genomics, immunohistochemistry, and immunofluorescence microscopy validation were performed. RNA interference was used to ascertain the functional role of the overexpressed candidate target protein.

Results

In silico proteomics and genomics revealed pre-B-cell leukemia homeobox (PBX) interacting protein 1 (PBXIP1) overexpression in adult and childhood high-grade glioma and ependymoma compared with normal brain. PBXIP1 is a PBX-family interacting microtubule-binding protein with a putative role in migration and proliferation of cancer cells. Immunohistochemical studies in glial tumors validated PBXIP1 expression in astrocytoma and ependymoma but not in oligodendroglioma. RNAi-mediated PBXIP1-knockdown in glioblastoma cell lines strongly reduced proliferation and migration and induced morphological changes, indicating that PBXIP1 knockdown decreases glioma cell viability and motility through rearrangements of the actin cytoskeleton. Furthermore, expression of PBXIP1 was observed in radial glia and astrocytic progenitor cells in human fetal tissues, suggesting that PBXIP1 is an astroglial progenitor cell marker during human embryonic development.

Conclusion

PBXIP1 is a novel protein overexpressed in astrocytoma and ependymoma, involved in tumor cell proliferation and migration, that warrants further exploration as a novel therapeutic target in these tumors.     

Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma

In a subset of gliomas, the platelet-derived growth factor (PDGF) signaling pathway is perturbed. This is usually an early event occurring in low-grade tumors. In high-grade gliomas, the subsequent loss of the INK4a-ARF locus is one of the most common mutations. Here, we dissected the separate roles of Ink4a and Arf in PDGFB-induced oligodendroglioma development in mice. We found that there were differential functions of the two tumor suppressor genes. In tumors induced from astrocytes, both Ink4a-loss and Arf-loss caused a significantly increased incidence compared to wild-type mice. In tumors induced from glial progenitor cells there was a slight increase in tumor incidence in Ink4a-/- mice and Ink4a-Arf-/- mice compared to wild-type mice. In both progenitor cells and astrocytes, Arf-loss caused a pronounced increase in tumor malignancy compared to Ink4a-loss. Hence, Ink4a-loss contributed to tumor initiation from astrocytes and Arf-loss caused tumor progression from both glial progenitor cells and astrocytes. Results from in vitro studies on primary brain cell cultures suggested that the PDGFB-induced activation of the mitogen-activated protein kinase pathway via extracellular signal-regulated kinase was involved in the initiation of low-grade oligodendrogliomas and that the additional loss of Arf may contribute to tumor progression through increased levels of cyclin D1 and a phosphoinositide 3-kinase-dependent activation of p70 ribosomal S6 kinase causing a strong proliferative response of tumor cells.     

Antitumor activity of a human cytotoxic T-cell line (TALL-104) in brain tumor xenografts

Malignant glioma in adults and primitive neuroectodermal tumors/medulloblastomas in children are the most common malignant primary brain tumors that either respond poorly to current treatment or tend to recur. Adoptive therapy with TALL-104 cells-an IL-2-dependent, major histocompatibility complex nonrestricted, cytotoxic T-cell line-has demonstrated significant antitumor activity against a broad range of implanted or spontaneously arising tumors. This study investigates distribution of systemically and locally administered TALL-104 cells and their efficacy in effecting survival of a rat model of human brain tumor. In vitro, TALL-104 cells showed significant cytotoxic activity when added to human glioblastoma cell lines U-87 MG, U-251 MG, and A1690; the medulloblastoma cell lines DAOY, D283 Med, and D341 Med; and the epidermoid cancer cell line A431. In brain tumor-bearing rats, the amount of fluorescent dye-labeled TALL-104 cells in brain increased after they were given by intracarotid injection as compared with i.v. cell administration. However, TALL-104 cells rapidly decreased to low levels within 1 h after intracarotid injection. This finding suggests that TALL-104 cells given systemically may not invade brain or tumor tissues, but rather may remain in the vascular system, making this approach less efficient for brain tumor treatment. In a model of athymic rats engrafted with human A431 carcinoma brain tumor, repetitive local administration of TALL-104 cells directly into the tumor bed resulted in a significant increase in survival time compared with control animals. Therefore, local therapy with TALL-104 cells may be a novel and highly effective treatment approach for malignant brain tumors.     

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。