The expression of the gap-junction proteins connexin (CX) 43 and 32 was evaluated in surgical specimens of brain tumors and perilesional cortex from patients with chronic medically intractable epilepsy. In human normal brain CX32 was expressed in neurons and oligodendrocytes. CX32 immunoreactivity (IR) was observed in the neuronal component of glioneuronal tumors and in all oligodendrogliomas, 50% of which showed strong labeling, independent of the grade of differentiation. CX43, normally expressed in astrocytes, was also detected in most of the human astrocytomas and in the astroglial component of glioneuronal tumors. Whereas most of the low-grade gliomas (>60%) showed strong membranous staining, most high-grade astrocytomas exhibited a reduction of the typical plasma membrane CX43-IR and intracytoplasmic localization. Immunoblot analysis showed different CX43 isoforms in control cortex and in low-grade gliomas. However, only one single isoform (corresponding to the non-phosphorylated form of CX43) appeared to be present in most high-grade gliomas. Increased expression of CX43 protein was present in reactive astrocytes in the epileptic cortex surrounding low-grade tumors as compared to control cortex, indicating the existence of a regulatory pathway involving CX43 in the reorganization of the astrocytic syncytium in regions undergoing reactive gliosis. The high expression of connexin proteins in low-grade tumors and in the peritumoral reactive astrocytes suggests that they could contribute to tumor-related seizures.
"The authors showed an elevation in mRNA coding for the gap junction protein Cx43 both in the patients with intractable epilepsy and in the patients with tumor with seizures and lower levels of the same protein in patients with tumor with no associated seizures. A more recent study by Aronica et al. has demonstrated strong labeling of the Cx32 gap junction protein in glioneuronal tumors (both gangliogliomas and DNETs) and also showed increased expression of the Cx43 gap junction protein in reactive astrocytes in epileptic peritumoral cortex undergoing gliosis in patients with low-grade gliomas . They suggest that the greater expression of these gap junction proteins, specifically in peritumoral astrocytes and in low-grade tumors known to be highly epileptogenic, may mean that they are implicated in synchronization (via astrocytic Ca ++ elevation) of localized peritumoral neural networks, leading to propagation of seizure activity  "
[Show abstract][Hide abstract] ABSTRACT: Seizures are a prominent symptom in patients with both primary and secondary brain tumors. Medical management of seizure control in this patient group is problematic as the mechanisms linking tumorigenesis and epileptogenesis are poorly understood. It is possible that several mechanisms contribute to tumor-associated epileptic zone formation. In this review, we discuss key candidates that may be implicated in peritumoral epileptogenesis and, in so doing, hope to highlight areas for future research. Furthermore, we summarize the current role of antiepileptic medications in this type of epilepsy and examine the changes in surgical practice which may lead to improved seizure rates after tumor surgery. Lastly, we speculate on possible future preoperative and intraoperative considerations for improving seizure control after tumor resection.
This article is part of a Special Issue entitled “NEWroscience 2013”.
"Additionally, the proteins of connexins, Cx43 and Cx32, are synthesized and integrated into the cell membranes of MCs , monocytes , leukocytes , and Kupffer cells . They have also been found in cells associated with brain tumors , reviewed in . Thus, cell types such as those of the brain and immune system can communicate with their microenvironment via expressed connexins. "
[Show abstract][Hide abstract] ABSTRACT: Background
Carcinogenesis is widely thought to originate from somatic mutations and an inhibition of growth suppressors, followed by cell proliferation, tissue invasion, and risk of metastasis. Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers. Those remaining, 70 to 80%, are called "sporadic," because they are essentially of unknown etiology. We propose a new paradigm for the origin of the majority of cancers.
Presentation of hypothesis: Our paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. If we are correct, this paradigm would suggest that the majority of the findings in cancer genetics so far reported are either late events or are epiphenomena that occur after the appearance of the pre-cancerous niche.
Testing the hypothesis
If, based on experimental and clinical findings presented here, this hypothesis is plausible, then the majority of findings in the genetics of cancer so far reported in the literature are late events or epiphenomena that could have occurred after the development of a PCN. Our model would make clear the need to establish preventive measures long before a cancer becomes clinically apparent. Future research should focus on the intermediate steps of our proposed sequence of events, which will enhance our understanding of the nature of carcinogenesis. Findings on inflammation and fibrosis would be given their warranted importance, with research in anticancer therapies focusing on suppressing the PCN state with very early intervention to detect and quantify any subclinical inflammatory change and to treat all levels of chronic inflammation and prevent fibrotic changes, and so avoid the transition from a normal cell to a cancer cell.
Implication of the hypothesis: The paradigm proposed here, if proven, spells out a sequence of steps, one or more of which could be interdicted or modulated early in carcinogenesis to prevent or, at a minimum, slow down the progression of many cancers.
BMC Cancer 05/2014; BMC Cancer(14):331. DOI:10.1186/1471-2407-14-331 · 3.36 Impact Factor
"The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease showed upregulation of Cx43 in the striatum . Upregulation of Cx43 and Cx32 has also been detected in different types of epilepsy in human beings [18,19]. Although various CNS pathological conditions could cause alteration of glial connexins, extensive loss of oligodendrocytic Cx47/32 in the anterior horns appears to be specific for mSOD1-Tg mouse spinal cord. "
[Show abstract][Hide abstract] ABSTRACT: Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which glial cells play significant roles in disease progression. Connexins (Cxs) form homotypic or heterotypic gap junctions (GJs) and allow direct intercellular communications among nervous tissue cells. The role of Cxs in motor neuron disease has never been investigated; therefore, we aimed to evaluate alterations of Cxs in mSOD1-transgenic (mSOD1-Tg) mice in comparison with their non-transgenic (non-Tg) littermates at the same ages.
We pathologically evaluated temporal changes to astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 immunoreactivities at presymptomatic, disease-progressive, and end stages, relative to aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-2 (EAAT2), myelin-oligodendrocyte glycoprotein (MOG), and Nogo-A immunoreactivities, and observed neuronal loss by NeuN and neurofilament immunostaining, and microglial response by Iba-1 immunostaining. We also performed quantitative immunoblotting and real-time PCR analyses for Cxs.
The mSOD1-Tg mice showed neuronal and axonal loss in the anterior horns of the lumbar spinal cord accompanied by increased activation of microglia compared with non-Tg mice at the disease-progressive and end stages. Expression patterns of Cxs were not different between mSOD1-Tg and non-Tg mice at the presymptomatic stage, but immunoreactivities for GFAP, Cx43, Cx30 and AQP4 were increased in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. By contrast, Cx47 and Cx32 immunoreactivities were markedly diminished in Nogo-A-positive oligodendrocytes in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages, especially in oligodendrocytes showing SOD1 accumulation. EAAT2 immunoreactivity was also diminished in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. Quantitative immunoblotting revealed a significant reduction in Cx47 and Cx32 protein levels in mSOD1-Tg mice at the disease-progressive and end stages. The levels of Cx47 and Cx32 mRNAs were also decreased at these stages.
Our findings indicate that oligodendrocytic and astrocytic GJ proteins in the anterior horns of spinal cord in mSOD1-Tg mice are profoundly affected at the disease-progressive and end stages, where disruption of GJs among glial cells may exacerbate motor neuronal death.
Journal of Neuroinflammation 03/2014; 11(1):42. DOI:10.1186/1742-2094-11-42 · 5.41 Impact Factor
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