Human malignant astrocytoma xenografts migrate in rat brain: A model for central nervous system cancer research

Bernstein, Jerald J.; Goldberg, William J.; Laws, Edward R.

doi:10.1002/jnr.490220205

Cited by 85 publications

(45 citation statements)

References 30 publications

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“…Pathological and experimental methods have confirmed that glioma cells preferentially migrate along BM (Bernstein et al, 1989(Bernstein et al, , 1990Bernstein and Woodard, 1995;Laws et al, 1993;Giese et al, 1994). In a rat homografting model, as well as in vitro models, tight masses of glioma cells are observed in close contact with the vascular BM and individual cells migrate along blood vessels outside the BM (Bernstein and Woodard, 1995).…”

Section: Ecm Composition In the Brainmentioning

confidence: 78%

“…The primary cause of this poor prognosis is the diffuse invasion of single glioma cells into the surrounding brain tissue. This invasion pattern is a common property of intrinsic brain tumors.As shown by numerous morphological studies (Scherer et al, 1940;Bernstein et al, 1989Bernstein et al, , 1990Bernstein et al, , 1995Laws et al, 1993), invading glioma cells routinely migrate to distinct anatomical structures. These structures include the basement membrane of blood vessels, the subependymal space, the glia limitans externa and parallel and intersecting nerve fiber tracts in the white matter.…”

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confidence: 99%

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ECM-mediated glioma cell invasion

Goldbrunner

Bernstein²,

Tonn

1998

Microsc. Res. Tech.

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Section: Ecm Composition In the Brainmentioning

confidence: 78%

mentioning

confidence: 99%

ECM-mediated glioma cell invasion

Goldbrunner

Bernstein²,

Tonn

1998

Microsc. Res. Tech.

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“…The prognosis for glioblastoma patients is poor despite treatment consisting of surgical debulking, radiotherapy, and chemotherapy. A unique feature contributing to the disease aggressiveness is the ability of malignant glioma cells to actively migrate along the brain vasculature (2,3) instead of passive metastasis through vascular circulation. To migrate along blood vessels through the narrow extracellular space of the brain, cells must be able to regulate their cell volume.…”

mentioning

confidence: 99%

Molecular Interaction and Functional Regulation of ClC-3 by Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) in Human Malignant Glioma

Cuddapah

Sontheimer

2010

Journal of Biological Chemistry

107

120

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Glioblastoma multiforme is the most common and lethal primary brain cancer in adults. Tumor cells diffusely infiltrate the brain making focal surgical and radiation treatment challenging. The invasion of glioma cells into normal brain is facilitated by the activity of ion channels aiding dynamic regulation of cell volume. Recent studies have specifically implicated ClC-3, a voltage-gated chloride channel, in this process. However, the interaction between ClC-3 activity and cell movement is poorly understood. Here, we demonstrate that ClC-3 is highly expressed on the plasma membrane of human glioma cells where its activity is regulated through phosphorylation via Ca 2؉ /calmodulin-dependent protein kinase II (CaMKII). Intracellular infusion of autoactivated CaMKII via patch pipette enhanced chloride currents 3-fold, and this regulation was inhibited by autocamtide-2 related inhibitory peptide, a CaMKII-specific inhibitor. CaMKII modulation of chloride currents was also lost upon stable small hairpin RNA knockdown of ClC-3 channels indicating a specific interaction of ClC-3 and CaMKII. In ClC-3-expressing cells, inhibition of CaMKII reduced glioma invasion to the same extent as direct inhibition of ClC-3. The importance of the molecular interaction of ClC-3 and CaMKII is further supported by our finding that CaMKII co-localizes and co-immunoprecipitates with ClC-3. ClC-3 and CaMKII also co-immunoprecipitate in tissue biopsies from patients diagnosed with grade IV glioblastoma. These tumor samples show 10-fold higher ClC-3 protein expression than nonmalignant brain. These data suggest that CaMKII is a molecular link translating intracellular calcium changes, which are intrinsically associated with glioma migration, to changes in ClC-3 conductance required for cell movement.Glioblastomas account for 60 -70% of malignant gliomas (1) and are the most common and lethal type of primary malignant brain tumors among adults. The prognosis for glioblastoma patients is poor despite treatment consisting of surgical debulking, radiotherapy, and chemotherapy. A unique feature contributing to the disease aggressiveness is the ability of malignant glioma cells to actively migrate along the brain vasculature (2, 3) instead of passive metastasis through vascular circulation. To migrate along blood vessels through the narrow extracellular space of the brain, cells must be able to regulate their cell volume. We hypothesize that gliomas express ion channels that endow cells with an enhanced ability to extrude osmotically active ions, leading to the release of cytoplasmic water and cell shrinkage (4). Candidate channels providing the electrochemical driving force for ion movement in glioma cells are the Ca 2ϩ -activated potassium channel BK (5-7) and the voltage-gated chloride channel ClC-3 (8 -10).ClC-3 enhances migration of nasopharyngeal carcinoma cells (11), and pharmacological inhibition with NPPB 2 demonstrates a requirement for chloride channels to support glioma invasion (8). Glioma cells express three members of the ClC family...

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“…One of these is a rapid dispersal of tumor cells throughout the CNS in a manner which cannot be accounted for by diffusion, which is essentially a local phenomenon (13)(14)(15). For example, Silbergeld and Chicoine have demonstrated that within 7 days of local implantation of human GBM cells central nervous system (1).…”

Section: C(tx) C ------------= ∇ D(x)∇c) + C(1 -------)mentioning

confidence: 99%

A novel bicompartmental mathematical model of glioblastoma multiforme

Hathout

Ellingson

Cloughesy

et al. 2014

International Journal of Oncology

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Abstract. Glioblastoma multiforme (GBM) is the most common primary CNS neoplasm, and continues to have a dismal prognosis. A widely-used approach to the mathematical modeling of GBM involves utilizing a reaction-diffusion model of cell density as a function of space and time, which accounts term, and the proliferation of tumor cells using a proliferation term. The current paper extends the standard models by incorporating an advection term to account for the so-called 'cell streaming' which is often seen with GBM, where some of the tumor cells seem to stream widely along the white matter pathways. The current paper introduces a bicompartmental GBM model in the form of coupled partial differential equations with a component of dispersive cells. The parameters needed for this model are explored. It is shown that this model can account for the rapid distant dispersal of GBM cells in the CNS, as well as such phenomena as multifocal gliomas with tumor foci distant from the core tumor site. The model suggests a higher percentage of tumor cells below the threshold of MRI images in comparison to the standard model. By incorporating an advection component, the proposed model is able to account for phenomena such as multicentric gliomas and rapid distant dispersion of a small fraction of tumor cells throughout the CNS, features important to the prognosis of GBM, but not easily accounted for by current models.

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Human malignant astrocytoma xenografts migrate in rat brain: A model for central nervous system cancer research

Cited by 85 publications

References 30 publications

ECM-mediated glioma cell invasion

ECM-mediated glioma cell invasion

Molecular Interaction and Functional Regulation of ClC-3 by Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) in Human Malignant Glioma

A novel bicompartmental mathematical model of glioblastoma multiforme

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