Migration pathways of human glioblastoma cells xenografted into the immunosuppressed rat brain (original) (raw)
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Journal of Neurosurgery, 2002
Object. The reliable assessment of the invasiveness of gliomas in vitro has proved elusive, because most invasion assays inadequately model in vivo invasion in its complexity. Recently, organotypical brain cultures were successfully used in short-term invasion studies on glioma cell lines. In this paper the authors report that the invasiveness of human glioma biopsy specimens directly implanted into rodent brain slices by using the intraslice implantation system (ISIS) can be quantified with precision. The model was first validated by the demonstration that, in long-term studies, established glioma cells survive in the ISIS and follow pathways of invasion similar to those in vivo. Methods. Brain slices (400 µm thick) from newborn mice were maintained on millicell membranes for 15 days. Cells from two human and one rodent glioblastoma multiforme (GBM) cell lines injected into the ISIS were detected by immunohistochemistry or after transfection with green fluorescent protein—containin...
Quantitative assessment of glioblastoma invasion in vivo
Cancer Letters, 2003
The aim of this study was the quantitative assessment of the time course and spatial distribution in brain of invading glioblastoma (GBM) cells using a recently described model consisting of RT2 rat GBM cells stably transfected with enhanced green fluorescent protein (eGFP) -called RT2-eGFP -and implanted in Fischer rats. Invasion throughout the brain was verified by confocal microscopy and immunocytochemical staining for eGFP. Rats were sacrificed on post-implantation days 3, 8, and time of death (TOD). First, the entire rat brain was disaggregated at each time point and viable RT2-eGFP cells were counted using flow cytometry with fluorescence as the marker. Next, 2 mm 3 samples of cortex from each of four brain quadrants (bifrontal and bioccipital) were disaggregated at each time point, with tumor cell quantification as before. Tumor cell density, averaged over the entire brain, reached a peak mid-way through its time course, leveling out by TOD. Tumor cell density within bulk tumor (BT) was greatest early in the evolution of the brain tumor, decreasing to its final value mid-way through its time course, due to necrosis. The greatest concentration of tumor cells was within BT, with up to an order of magnitude fewer cells in the periphery, while the number of brain tumor cells invading brain distant from BT remained constant from day 3 until TOD. BT size steadily increased after implantation, with an increasing portion due to central necrosis as time progressed, suggesting that this effect is an important contributor to fatality in this model. Alternatively (or additionally), accumulation of toxins elaborated by tumor cells throughout the brain starting early in the evolution of the tumor may also contribute to fatality. q
Tumor Cell Invasion in Glioblastoma
International Journal of Molecular Sciences
Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms fo...
Molecular Mechanisms of Glioma Cell Migration and Invasion
Journal of Neuro-Oncology, 2004
Gliomas are the most common intracranial tumors. In the US, approximately 15,000 patients die with glioblastoma per year (CBTRUS 2002). Despite modern diagnostics and treatments the median survival time does not exceed 15 months. However, it has long been observed that after surgical removal, tumors recur predominantly within 1 cm of the resection cavity. This is mainly due to the fact that at the time of surgery, cells from the bulk tumor have already invaded normal brain tissue. Decades ago Matsukado showed that more than 50% of untreated brain tumors had already reached the contralateral hemisphere (J Neurosurg 18: 636-644, 1961). Therefore one of the most important hallmarks of malignant gliomas is their invasive behavior. Dandy already recognized the highly invasive characteristics of this tumor type and performed hemispherectomy in patients with preoperative hemiplegia (J Am Med Assoc 90: 823-825, 1928). Despite his and others' heroic efforts, recurrence was detected as early as 3 months after surgery (Bell, LJ: J Neurosurg 6: 285-293, 1949), leading to the discontinuation of this radical approach. Diffuse gliomas remain a particularly challenging clinical management problem. Over the last 20 years no significant increase in survival of patients suffering from this disease has been achieved. Even drugs directed against newly identified targets like MMPs or angiogenesis-related targets fail to increase survival duration (Tonn, Goldbrunner: Acta Neurochir Suppl 88: 163-167, 2003) Furthermore, anti-angiogenic drugs have been shown to increase glioma invasiveness, finally leading to gliomatosis cerebri. (Lamszus et al.: Acta Neurochir Suppl 88: 169-177, 2003). In this review we focus on the main features which may underlie the invasive phenotype of human gliomas, and offer a biological basis for optimism towards therapeutic advances to come.
Migration and Invasion of Brain Tumors
Glioma - Exploring Its Biology and Practical Relevance, 2011
Glioma-Exploring Its Biology and Practical Relevance 226 Grade I tumors typically do not invade surrounding brain and are often curable with surgery, while tumors of grades II to IV are diffuse and invade normal brain, with grade III and IV tumors being most aggressive. Grade III and IV tumors are called "high-grade" or "malignant" tumors although they almost never metastasize to other tissues of the body (Lassman, 2004). The etiological events causing glioma formation have not been clearly defined, but are thought to involve genetic alterations (Figure 1A). Such alterations disrupt cell cycle arrest pathways (
Host cell recruitment by gliomas
European Journal of Cancer Supplements, 2008
Background: Glioblastoma multiforme (GBM) is the most aggressive type of malignant primary brain tumors in adults. Molecular and genetic analysis has advanced our understanding of glioma biology, however mapping the cellular composition of the tumor microenvironment is crucial for understanding the pathology of this dreaded brain cancer. In this study we identified major cell populations attracted by glioma using orthotopic rodent models of human glioma xenografts. Marker-specific, anatomical and morphological analyses revealed a robust influx of host cells into the main tumor bed and tumor satellites.
Neoplasia, 2018
BACKGROUND: Widespread infiltration of tumor cells into surrounding brain parenchyma is a hallmark of malignant gliomas, but little data exist on the overall invasion pattern of tumor cells throughout the brain. METHODS: We have studied the invasive phenotype of malignant gliomas in two invasive mouse models and patients. Tumor invasion patterns were characterized in a patient-derived xenograft mouse model using brain-wide histological analysis and magnetic resonance (MR) imaging. Findings were histologically validated in a cdkn2a−/− PDGF-β lentivirus-induced mouse glioblastoma model. Clinical verification of the results was obtained by analysis of MR images of malignant gliomas. RESULTS: Histological analysis using human-specific cellular markers revealed invasive tumors with a non-radial invasion pattern. Tumors cells accumulated in structures located far from the transplant site, such as the optic white matter and pons, whereas certain adjacent regions were spared. As such, the hippocampus was remarkably free of infiltrating tumor cells despite the extensive invasion of surrounding regions. Similarly, MR images of xenografted mouse brains displayed tumors with bihemispheric pathology, while the hippocampi appeared relatively normal. In patients, most malignant temporal lobe gliomas were located lateral to the collateral sulcus. Despite widespread pathological fluid-attenuated inversion recovery signal in the temporal lobe, 74% of the "lateral tumors" did not show signs of involvement of the amygdalohippocampal complex. CONCLUSIONS: Our data provide clear evidence for a compartmental pattern of invasive growth in malignant gliomas. The observed invasion patterns suggest the presence of preferred migratory paths, as well as intra-parenchymal boundaries that may be difficult for glioma cells to traverse supporting the notion of www.neoplasia.com
Dynamic determination of human glioma invasion in vitro
Journal of Neurosurgery, 1998
Object. The goal ofthis study was to evaluate whether there is any relationship between survival of patients with brain tumor and tumor proliferation or tumor invasion in vitro. Methods. Samples of freshly resected brain tumors from 14 patients with glioblastoma multiforme (GBM) were directly grown as three-dimensional multicellular spheroids. The tumor spheroids were cocultured with fetal rat brain cell aggregates (BCAs), used to represent an organotypical normal brain tissue model. Before the coculture, the tumor spheroids and the BCAs were stained with two different carbocyanine dyes, 1,1'-dioctadecyl-3,3,3' tetramethylindocarbocyanine perchlorate (DiI) and 3,3'-dioctadecycloxacarbocyanine perchlorate (DiO), respectively. DUling the coculture, confocal laser scanning microscopy allowed a sequential analysis of tumor cell invasion by visualizing dynamic aspects of the invasive process. Single cocultures were examined at three different time points (24, 48, and 96 hours). During the observation period there was a change in the structural morphology ofthe cocultures, with a progressive decrease in BCA volume. Furthermore, the scanning confocal micrographs revealed a bidirectional movement of tumor cells and normal cells into brain and tumor tissue, respectively. It is also shown that there is a considerable variation in the rate of BCA destruction in cocultures of glioma spheroids generated directly from biopsy specimens. This variation is seen both between spheroids generated from the same biopsy as well as between spheroids that are grown from different biopsy specimens. Cell proliferation measured by Ki-67 immunohistochemical analysis of biopsy samples obtained in the same patients revealed a correlation between tumor cell proliferation and tissue destruction of the BCAs, as determined by a reduction in BCA volume (p = 0.0338). No correlation was found when survival was related to the same parameters (p> 0.05). Conclusions. The present work provides a model for quick and efficient assessment of dynamic interactions between tumor and normal brain tissue shortly after surgery.
Invasiveness in vitro and biological markers in human primary glioblastomas
Journal of neuro-oncology, 2001
Invasion of spheroids from 20 human primary glioblastomas into precultured fetal rat brain tissue in culture has been studied and quantified. Between 30 and 98 percent of the normal brain tissue was destroyed by invading glioma cells within 4 days. The degree of invasion did not correlate with patient survival. A slightly higher invasiveness and shorter survival was seen in tumors with EGF receptor overexpression, and the opposite pattern was found for tumors with a TP53 mutation. The degree of invasiveness in vitro was far higher than would be expected from the dynamics of clinically observed tumor spread. This suggests that mechanisms suppressing invasion may be operative in the normal brain; alternatively the differences may be due to a higher permissiveness of the fetal brain tissue for invasion in vitro.
2005
Glial tumors are the largest group of central nervous system tumors and glioblastoma multiforme is the most common form. Glioblastomas are anaplastic forms of gliomas. Their high incidence and malignity have led researchers to work hard to better understand and treat these tumors. It is now known that genetic factors play a role in glioma etiopathogenesis. Of the differences in genetic built, two attract the most attention: oncogenes that lead to cell division and the occurrence of cells that have lost tumor suppressor genes. After realizing that the evolution of surgery and radiotherapy would have no significant value for malignant brain tumors, the trial of potential chemotherapeutic, genetic and immunologic therapy methods in an appropriate experimental glioma model has gained in importance. The C6 rat glioma model is used in these studies because of its similarity to the human glioblastoma. In this study, we used the C6 rat glioma model which has glioblastoma-like effects and tr...