Tumor Cell Metabolism: Cancer's Achilles' Heel

Astrocytes become activated (reactive) in response to many CNS pathologies, such as stroke, trauma, growth of a tumor, or neurodegenerative disease. The process of astrocyte activation remains rather enigmatic and results in so-called "reactive gliosis," a reaction with specific structural and functional characteristics. In stroke or in CNS trauma, the lesion itself, the ischemic environment, disrupted blood-brain barrier, the inflammatory response, as well as in metabolic, excitotoxic, and in some cases oxidative crises--all affect the extent and quality of reactive gliosis. The fact that astrocytes function as a syncytium of interconnected cells both in health and in disease, rather than as individual cells, adds yet another dimension to this picture. This review focuses on several aspects of astrocyte activation and reactive gliosis and discusses its possible roles in the CNS trauma and ischemia. Particular emphasis is placed on the lessons learnt from mouse genetic models in which the absence of intermediate filament proteins in astrocytes leads to attenuation of reactive gliosis with distinct pathophysiological and clinical consequences.

Astrocyte activation and reactive gliosis

It is now well established that the glial fibrillary acidic protein (GFAP) is the principal 8-9 nm intermediate filament in mature astrocytes of the central nervous system (CNS). Over a decade ago, the value of GFAP as a prototype antigen in nervous tissue identification and as a standard marker for fundamental and applied research at an interdisciplinary level was recognized (Raine, 135). As a member of the cytoskeletal protein family, GFAP is thought to be important in modulating astrocyte motility and shape by providing structural stability to astrocytic processes. In the CNS of higher vertebrates, following injury, either as a result of trauma, disease, genetic disorders, or chemical insult, astrocytes become reactive and respond in a typical manner, termed astrogliosis. Astrogliosis is characterized by rapid synthesis of GFAP and is demonstrated by increase in protein content or by immunostaining with GFAP antibody. In addition to the major application of GFAP antisera for routine use in astrocyte identification in the CNS, the molecular cloning of the mouse gene in 1985 has opened a new and rich realm for GFAP studies. These include antisense, null mice, and numerous promoter studies. Studies showing that mice lacking GFAP are hypersensitive to cervical spinal cord injury caused by sudden acceleration of the head have provided more direct evidence for a structural role of GFAP. While the structural function of GFAP has become more acceptable, the use of GFAP antibodies and promoters continue to be valuable in studying CNS injury, disease, and development.

Glial Fibrillary Acidic Protein: GFAP-Thirty-One Years (1969–2000)

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Logistic Regression A Self Learning Text

Rupture of an intracranial aneurysm is the leading cause of subarachnoid hemorrhage not due to trauma. This review summarizes both the approach to establishing the diagnosis and treatment options, including the placement of intravascular coils to arrest the bleeding. Common management problems include vasospasm, hydrocephalus, and rebleeding.

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Aneurysmal subarachnoid hemorrhage.

L-type amino acid transporter 1 (LAT1) is a Na+-independent neutral amino acid transport agency and essential for the transport of large neutral amino acids. LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells. LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells. We have investigated for the first time, the expression of the transporter in the human primary astrocytic tumor tissue from 60 patients. LAT1 is unique because it requires an additional single membrane spanning protein, the heavy chain of 4F2 cell surface antigen (4F2hc), for its functional expression. 4F2hc expression was also determined by immunohistochemistry. Kaplan-Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p < 0.0001) and for those with glioblastoma multiforme in particular (p = 0.0001). Cox regression analyses demonstrated that LAT1 expression was one of significant predictors of outcome, independent of all other variables. On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2-aminobicyclo-2 (2,2,1)-heptane-2-carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model. BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose-dependent manner. Kaplan-Meier survival data of rats treated with BCH were significant. These findings suggest that LAT1 could be one of the molecular targets in glioma therapy. © 2006 Wiley-Liss, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.21866

L‐type amino acid transporter 1 as a potential molecular target in human astrocytic tumors

L‐type amino acid transporter 1 (LAT1) is a Na+‐independent neutral amino acid transport agency and essential for the transport of large neutral amino acids. LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells. LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells. We have investigated for the first time, the expression of the transporter in the human primary astrocytic tumor tissue from 60 patients. LAT1 is unique because it requires an additional single membrane spanning protein, the heavy chain of 4F2 cell surface antigen (4F2hc), for its functional expression. 4F2hc expression was also determined by immunohistochemistry. Kaplan‐Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p < 0.0001) and for those with glioblastoma multiforme in particular (p = 0.0001). Cox regression analyses demonstrated that LAT1 expression was one of significant predictors of outcome, independent of all other variables. On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2‐aminobicyclo‐2 (2,2,1)‐heptane‐2‐carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model. BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose‐dependent manner. Kaplan‐Meier survival data of rats treated with BCH were significant. These findings suggest that LAT1 could be one of the molecular targets in glioma therapy. © 2006 Wiley‐Liss, Inc.

FAST TRACK L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors

Astrocytes perform a variety of functions in the adult central nervous system (CNS) that contribute to the survival of neurons. Thus, it is likely that the activities of astrocytes affect the extent of brain damage after ischemic stroke. The authors tested this hypothesis by using a mouse ischemia model to compare the infarct volume produced in wild-type mice with that produced in mice lacking glial fibrillary acidic protein (GFAP), an astrocyte specific intermediate filament component. Astrocytes lacking GFAP have been shown to have defects in process formation, induction of the blood-brain barrier, and volume regulation; therefore, they might be compromised in their ability to protect the CNS after injury. The authors reported here that 48 hours after combined permanent middle cerebral artery occlusion (MCAO) and 15 minutes transient carotid artery occlusion (CAO) GFAP-null mice had a significantly (P < 0.001) larger cortical infarct volume (16.7 ± 2.2 mm3) than their wild-type littermates (10.1 ± 3.9 m...

https://journals.sagepub.com/doi/pdf/10.1097/00004647-200007000-00003

High susceptibility to cerebral ischemia in GFAP-null mice.

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed primarily in astrocytes. We have tested whether GFAP protects against mechanical stress by inducing percussive head injury in GFAP-null mice with a weight drop device. When mice were positioned on a foam bed which allowed head movement at impact, all 14 wild-type mice tested survived, but 12 of 15 GFAP-null mice died within a few minutes. The cause of death appeared to be upper cervical spinal cord injury resulting in respiratory arrest. When the foam bed was replaced by a firm support, both GFAP-null and wild-type mice survived. These results indicate that mice lacking GFAP are hypersensitive to cervical spinal cord injury caused by sudden acceleration of the head.

Mice lacking GFAP are hypersensitive to traumatic cerebrospinal injury

Background and Objective: Brain function is highly dependent on cerebral blood flow (CBF). The precise mechanisms by which blood flow is controlled by NIR laser irradiation on the central nervous system (CNS) have not been elucidated. In this study, we examined the effect of 808 nm laser diode irradiation on CBF in mice. Study Design/Materials and Methods: We examined the effect of NIR irradiation on CBF at three different power densities (0.8, 1.6 and 3.2 W/cm 2 ) and directly measured nitric oxide (NO) in brain tissue during NIR laser irradiation using an amperometric NO-selective electrode. We also examined the contribution of NO and a neurotransmitter, glutamate, to the regulation of CBF by using a nitric oxide synthase (NOS) inhibitor, N g -nitro-Larginine methyl ester hydrochloride (L-NAME), and an N-methyl-D-aspartate (NMDA) receptor blocker, MK-801, respectively. We examined the change in brain tissue temperature during NIR laser irradiation. We also investigated the protection effect of NIR laser irradiation on transient cerebral ischemia using transient bilateral common carotid artery occlusion (BCCAO) in mice. Results: We showed that NIR laser irradiation (1.6 W/cm 2 for 15–45 minutes) increased local CBF by 30% compared to that in control mice. NIR laser irradiation also induced a significant increase in cerebral NO concentration. In mice that received L-NAME, NIR laser irradiation did not induce any increase in CBF. Mice administered MK-801 showed an immediate increase but did not show a delayed additional increase in local CBF. The increase in brain tissue temperature induced by laser irradiation was estimated to be as low as 0.88C at 1.6 W/cm 2 , indicating that the heating effect is not a main mechanism of the CBF increase in this condition. Pretreatment with NIR laser irradiation improved residual CBF and reduced the numbers of apoptotic cells in the hippocampus. Conclusion: Our data suggest that NIR laser irradiation is a promising experimental and therapeutic tool in the field of cerebral circulation research. Lasers Surg. Med. 42:566– 576, 2010. 2010 Wiley-Liss, Inc.

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Hiroshi Nawashiro

Papers

L‐type amino acid transporter 1 as a potential molecular target in human astrocytic tumors

FAST TRACK L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors

High susceptibility to cerebral ischemia in GFAP-null mice.

Mice lacking GFAP are hypersensitive to traumatic cerebrospinal injury

Targeted increase in cerebral blood flow by transcranial near-infrared laser irradiation.