Near-infrared fluorescence heptamethine carbocyanine dyes mediate imaging and targeted drug delivery for human brain tumor

Brain tumors and brain metastases are among the deadliest malignancies of all human cancers, largely due to the cellular blood–brain and blood–tumor barriers that limit the delivery of imaging and therapeutic agents from the systemic circulation to tumors. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. Here we identified and synthesized a group of near-infrared fluorescence (NIRF) heptamethine carbocyanine dyes and derivative NIRF dye-drug conjugates for effective imaging and therapeutic targeting of brain tumors of either primary or metastatic origin in mice, which is mechanistically mediated by tumor hypoxia and organic anion-transporting polypeptide genes. We also demonstrate that these dyes, when conjugated to chemotherapeutic agents such as gemcitabine, significantly restricted the growth of both intracranial glioma xenografts and prostate tumor brain metastases and prolonged survival in mice. These results show promise in the application of NIRF dyes as novel theranostic agents for the detection and treatment of brain tumors.     

脑肿瘤干细胞的研究现状

背景：在脑肿瘤中存在一种具有自我更新、无限增殖与多向分化能力的细胞,即脑肿瘤干细胞。脑肿瘤干细胞被认为是脑肿瘤发生、发展、转移与复发的根源。 目的：总结和探讨脑肿瘤干细胞的研究现状。 方法：以“脑肿瘤、脑肿瘤干细胞”为检索词,应该计算机检索Pubmed 数据库1977-01/2011-07的相关文章,并查阅与干细胞及脑肿瘤干细胞实验有关的书籍,对资料进行初审,选取符合要求的有关文章共32 篇。 结果与结论：在恶性脑肿瘤中存在脑肿瘤干细胞。脑肿瘤干细胞是恶性脑肿瘤发生、发展、转移及复发的根源,其表达特异性的CD133、Nestin蛋白和ABC转运体。目前已经获得了分离脑肿瘤干细胞的简便方法。CD133阳性的肿瘤干细胞所占的比例与脑肿瘤的恶性程度呈正相关,可作为预后诊断指标之一。      

Brain tumors in children: a review

Brain tumors are the second most common malignancy of children. In contrast to adults, childhood brain tumors are usually of glial origin; metastases and meningiomas are rare. Some tumors, i.e., medulloblastomas, are found almost exclusively in children. The posterior fossa is the most frequent site of occurrence. The prognosis for childhood neoplasms tends to be more favorable than in adults, and some lesions are curable. New techniques, including immunostaining, tumor markers, and cytogenetics, have improved diagnostic accuracy. A review of some of the most important brain tumors of children is presented along with an upgrade on recent developments in diagnoses and treatment.     

Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression

Brain angiogenesis inhibitors (BAI) are putative transmembrane proteins containing an extracellular domain with thrombospondin type-1 repeats which can exhibit anti-angiogenic activity. BAI1 mRNA is expressed mainly in the brain, while BAI2 and BAI3 mRNAs are more widely expressed. We hypothesized that the BAI family might have anti-tumoral properties and studied the expression of BAI1 protein in normal human brain and in glioblastoma multiforme. We generated an anti-BAI1 antibody and showed that BAI1 was widely expressed in normal brain but was absent in 28 glioma cell lines and in the majority of human glioblastoma investigated. BAI1 expression did not correlate with TP53 status and we did not confirm previous findings that p53 regulates BAI1 mRNA expression in glioma cells. The finding that expression of BAI proteins may be lost during tumor formation is of special interest as restoration of their function in tumors may be of therapeutic benefit.     

Brain Tumor Susceptibility: the Role of Genetic Factors and Uses of Mouse Models to Unravel Risk

Brain tumors are relatively rare but deadly cancers, and present challenges in the determination of risk factors in the population. These tumors are inherently difficult to cure because of their protected location in the brain, with surgery, radiation and chemotherapy options carrying potentially lasting morbidity for patients and incomplete cure of the tumor. The development of methods to prevent or detect brain tumors at an early stage is extremely important to reduce damage to the brain from the tumor and the therapy. Developing effective prevention or early detection methods requires a deep understanding of the risk factors for brain tumors. This review explores the difficulties in assessing risk factors in rare diseases such as brain tumors, and discusses how mouse models of cancer can aid in a better understanding of genetic risk factors for brain tumors.     

Induction of rat brain tumor with xenotropic pseudotype murine sarcoma virus

The oncogenicity of xenotropic pseudotype Kirsten murine sarcoma virus (MSV) was investigated in Sprague-Dawley rats. When fetal or newborn rats were inoculated intracerebrally with xenotropic pseudotype MSV, brain tumors developed after about one month. Tumors were induced both in the cerebrum and the cerebellum. Histologically, the tumors were predominantly glioblastoma multiforme and hemangioendotheliomas. In cerebellar lesions, malignant transformation of vascular endothelial cells, polycystic areas and numerous giant cells were noted. Proliferation of Purkinje cells was also observed in some of the cerebellar tumors. Inoculation of the same virus by other routes, such as s.c., i.p. and i.m., also caused cerebral and cerebellar tumors. Brain tumors thus induced were transplantable subcutaneously into suckling rats.     

Brain tumors induced in hamsters by intracerebral inoculation of SR-RSV-infected embryonic brain cells.

Brain tumors were induced in Syrian hamsters by intracerebral inoculation of brain cells which were obtained from 12-day old syngeneic hamster and infected with Schmidt-Ruppin strain of Rous sarcoma virus (SR-RSV) in vitro. A total of 212 tumors were developed in all 25 recipients within 19 to 125 days after transplantation. On the basis of light and electron microscopic study, they were classified into four main groups: astrocytoma (45.8%), pleomorphic glioma (50.0%), sarcoma (3.8%), unclassified (0.4%). The morphological features of these tumors were described, and the advantages of this brain tumor model were discussed.     

BRAIN TUMORS INDUCED IN HAMSTERS BY INTRACEREBRAL INOCULATION OF SR-RSV-INFECTED EMBRYONIC BRAIN CELLS

Brain tumors were induced in Syrian hamsters by intracerebral inoculation of brain cells which were obtained from 12-day old syngeneic hamster and infected with Schmidt-Ruppin strain of Rous sarcoma virus (SR-RSV) in vitro. A total of 212 tumors were developed in all 25 recipients within 19 to 125 days alter transplantation. On the basis of light and electron microscopic study, they were classified into four main groups: astrocytoma (45.8%). pleomorphic glioma (50.0%), sarcoma (3.8%). unclassified (0.4%). The morphological features of these tumors were described, and the advantages of this brain tumor model were discussed.     

Papillary tumor of the pineal region and spindle cell oncocytoma of the pituitary: new tumor entities in the 2007 WHO Classification

We have reviewed the features of two recently described intracranial tumors, which have been formally recognized as distinct entities by the 2007 WHO Classification of Brain Tumours: Papillary tumor of the pineal region and spindle cell oncocytoma of the pituitary gland. Their salient clinicopathological features, differential diagnosis, histogenetic hypothesis and outcome are discussed.     

Potential of gene therapy for brain tumors

Brain tumors comprise a broad spectrum of biological and clinical entities making it unlikely for any single therapeutic approach to be universally applicable. In particular, malignant glioblastoma multiforme have defied all current therapeutic modalities. Gene therapy offers the potential to augment current neurosurgical, radiation and drug treatments with little increase in morbidity. Many therapeutic transgenes have shown efficacy in experimental models, including generation of toxic compounds, enzymatic activation of pro-drugs, expression of tumor suppressor or apoptotic proteins, inhibition of angiogenesis and enhancement of immune responses to tumor antigens. Vectors have been used as gene delivery vehicles and as cytotoxic agents in their own right by selective replication and lysis of tumor cells, thereby also generating vectors on-site. Brain tumors appear to offer some "Achilles' heels" in that they are usually contained within the brain and represent a unique dividing cell population there. However, the heterogeneous and invasive characteristics of these tumor cells, as well as sequestration of tumor antigens within a relatively immune privileged location present serious problems for effective therapy. This review will focus on current transgene/vector strategies, including novel therapeutic genes, combinational therapies and new delivery modalities, the latter of which appears to be the rate limiting factor for gene therapy of brain tumors in humans.     

Noninvasive imaging of the functional effects of anti-VEGF therapy on tumor cell extravasation and regional blood volume in an experimental brain metastasis model

Brain metastasis has become an increasing cause of morbidity and mortality in cancer patients as the treatment of systemic disease has improved. Brain metastases frequently are highly vascularized, a process driven primarily by VEGF. VEGF mediates numerous changes within the vasculature including endothelial cell retraction and increased permeability, vasodilation, and new vessel formation. Here we describe a xenograft brain metastasis model that mimics the critical steps of metastasis including tumor cell dissemination and vascular adhesion, tumor growth and tumor associated angiogenesis. Magnetic resonance (MR) imaging was used to evaluate two aspects of the functional response of brain metastasis to the anti-VEGF receptor therapeutic, AZD2171 (Cediranib, RECENTIN™). MR tracking of individual cells demonstrated that cediranib did not impede tumor cell extravasation into the brain parenchyma despite evidence that anti-VEGF treatment decreases the permeability of the blood brain barrier. In a second assay, blood volume imaging using ultrasmall superparamagnetic iron oxide revealed that treatment of well-developed brain metastasis with cediranib for 7 days led to a heterogeneous response with respect to individual tumors. Overall, there was a significant average decrease in the tumor vascular bed volume. The majority of large tumors demonstrated substantially reduced central blood volumes relative to normal brain while retaining a rim of elevated blood volume at the tumor brain interface. Small tumors or occasional large tumors displayed a static response. Models and assays such as those described here will be important for designing mechanism-based approaches to the use of anti-angiogenesis therapies for the treatment of brain metastasis.     

脑肿瘤细胞Ki－67抗原表达及单个核细胞浸润的免疫组织化学研究

５１例脑肿瘤的免疫组化研究发现：肿瘤中浸润的ＣＤ４５ＲＯ阳性、ＣＤ４（ＯＰＤ４＋）和ＣＤ８Ｔ细胞密度与肿瘤体积呈负相关，与单核巨噬细胞密度呈正相关。Ｋｉ－６７阳性肿瘤细胞密度随肿瘤恶性程度增加而升高，并与肿瘤体积呈正相关，与ＣＤ４Ｔ细胞密度呈负相关。ＣＤ４／ＣＤ８＝０．８５３，明显低于正常比例，两者密度呈正相关。提示Ｋｉ－６７表达水平能较客观的反应肿瘤增殖速度和恶性程度，脑肿瘤与宿主的细胞免疫系统之间有一个相互抑制消长的过程。     

Brain tumor in the first year of life: a single institute study.

Brain tumors in infants present special diagnostic and therapeutic challenges. To figure out the clinical features, pathological classification of the tumors and the treatment outcome of infantile brain tumors, 458 children (age<16) with brain tumors were reviewed retrospectively. Among them 21 cases (4.6%) were diagnosed during the first 12 months of life. Two tumors were definitely of congenital origin. The majority of infants with brain tumors presented with increased intracranial pressure. Fourteen tumors were located at the supratentorial area. Sixteen cases had neuroepithelial tumors; astrocytoma (optic pathway), supratentorial primitive neuroectodermal tumor (PNET) and medulloblastoma were found in three cases each. There were two treatment-related mortalities. Compared with the outcomes in older children, the treatment outcome was poorer in medulloblastoma and the optic pathway glioma which showed a higher growth potential. Because of the limited application of postoperative adjuvant therapy, radical surgical removal played a more important role in this age group. The prognosis of patients in whom the tumors could not be totally removed, largely depended on the pathological malignancy of the tumors. Though the treatment outcome was not always dismal, immaturity of the brain, higher growth potential, perioperative risks, limitations in adjuvant therapy, and pessimistic attitude on the part of parents made management more challenging.     

脑电地形图在脑肿瘤诊断中的价值

本文通过我院采用脑电地形图(BEAM)检查的脑肿瘤与同步检查的脑电图(EEG)和脑CT、磁共振(MRI)或手术证实的26例的比较分析,表明BEAM在脑肿瘤的诊断中有较高的价值。本组资料表明,常规EEG异常者16例(61.5％),而BEAM22例异常(84.6％)。EEG定位符合者7例(26.9％),不符合10例(38.5％),BEAM19例符合(73.1％),3例基本符合(11.5％),4例不符合。经统计学处理P<0.01,表明对于脑浅表部位的肿瘤,BEAM诊断阳性率和定位价值明显高于EEG。本组三种不同类型的脑肿瘤,BEAM上表现各不相同。因此,BEAM对脑肿瘤的定性有一定的鉴别诊断价值。     

Variability of postural “reflexes” in humans

Experimental Brain Research - The functional role of spinal and supraspinal EMG-responses for the maintenance of upright human posture was investigated in ten healthy subjects standing on a force...     

Slow Resting State Fluctuations Enhance Neuronal and Behavioral Responses to Looming Sounds

Brain Topography - We investigate both experimentally and using a computational model how the power of the electroencephalogram (EEG) recorded in human subjects tracks the presentation of sounds...     

The role of canal-neck interaction for the perception of horizontal trunk and head rotation

Experimental Brain Research - The present report considers the conscious perception of passive horizontal rotations of the trunk, the head, or both, by human observers. It examines in particular...     

Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization

Interactions between tumor cells and the microenvironment are crucial to tumor formation and metastasis. The central nervous system serves as a “sanctuary” site for metastasis, resulting in poor prognosis in diagnosed patients. The incidence of brain metastasis is increasing; however, little is known about interactions between the brain and metastatic cells. Brain pathology was examined in an experimental model system of brain metastasis, using a subline of MDA-MB-231 human breast cancer cells. The results were compared with an analysis of sixteen resected human brain metastases of breast cancer. Experimental metastases formed preferentially in specific brain regions, with a distribution similar to clinical cases. In both the 231-BR model, and in human specimens, Ki67 expression indicated that metastases were highly proliferative (~50%). Little apoptosis was observed in either set of tumors. In the model system, metastases elicited a brain inflammatory response, with extensive reactive gliosis surrounding metastases. Similarly, large numbers of glial cells were found within the inner tumor mass of human brain metastases. In vitro co-cultures demonstrated that glia induced a ~5-fold increase in metastatic cell proliferation (P < 0.001), suggesting that brain tissue secretes factors conducive to tumor cell growth. Molecules used to signal between tumor cells and the surrounding glia could provide a new avenue of therapeutic targets for brain metastases.     

Immunological studies of subacute measles encephalitis in ferrets: similarities to human subacute sclerosing panencephalitis.

Ferrets inoculated with subacute sclerosing panencephalitis virus strains D.R. and Biken developed a subacute encephalitis. Brain extracts, at neutral pH, from these ferrets showed high measles antibody titers, increased concentrations of immunoglobulin G (IgG), and higher IgG/albumin ratios than those of controls. Although the brain extracts of subacute encephalitic animals showed significant synthesis of measles-specific IgG (20 to 60% of the total IgG) within the central nervous system, the electrophoretic patterns of these extracts did not show oligoclonal bands in the gamma-globulin region. Brain residues from most ferrets with subacute encephalitis, when eluted at low pH, demonstrated the presence of bound measles-specific antibodies. Excluding the electrophoresis data, other results are identical to those seen in human subacute sclerosing panencephalitis, indicating that the subacute encephalitis in ferrets may serve as a model for human subacute sclerosing panencephalitis.