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Tumor-associated macrophages: from mechanisms to therapy.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

A complex network of chemokines and their receptors influences the development of primary tumours and metastases. New information about the biological role of chemokines in these processes is providing insights into host–tumour interactions, such as the role of the leukocyte infiltrate, and into the mechanisms that determine the metastatic potential and site-specific spread of cancer cells. Chemokine-receptor antagonists are showing promise in animal models of inflammation and autoimmune disease. Could manipulating the local chemokine network have therapeutic benefits in malignant disease?

Cancer and the chemokine network

https://www.cell.com/trends/neurosciences/pdf/S0166-2236(09)00153-2.pdf

Molecular dissection of reactive astrogliosis and glial scar formation.

Aim: Minocycline has neuroprotective activities in several models of neurological disorders including spinal cord injury (SCI) where it prevents axonal loss and improves functional recovery. There are still gaps of knowledge on minocycline in SCI including whether it ameliorates neuronal loss at the focal site of trauma, and whether minocycline reduces the activity of matrix metalloproteinases (MMPs), a family of enzymes implicated in the pathophysiology of SCI. This study addressed these gaps. Methods: Mice were treated with either minocycline or vehicle control after a spinal cord contusion. MMPs were compared between the two groups using real time polymerase chain reaction and zymography. Immunohistochemistry was used to examine microglial activation and neuronal cell death. Results: While several MMP members were elevated in the spinal cord following injury, treatment with minocycline did not affect their expression. Importantly, minocycline reduced the loss of neurons in the epicenter of damage to the spinal cord and in segments caudal and rostral to the injury. Conclusion: Despite the inability of minocycline to alter MMPs, the results of neuroprotection at the lesion site support the continued testing of minocycline as a neuroprotective medication in experimental and clinical SCI.

/pdf/neuroprotection-by-minocycline-in-murine-traumatic-spinal-gm9e2bzw9q.pdf

Neuroprotection by minocycline in murine traumatic spinal cord injury: analyses of matrix metalloproteinases

Remyelination occurs in Multiple Sclerosis although its extent is limited in many patients. Approaches to induce remyelination include increasing trophic support or by overcoming impediments present in the microenvironment. We have examined the expression of extracellular matrix molecules around demyelinating lesions in the dorsal column of the mouse spinal cord. Demyelination was produced by the local deposition of a toxin, lysolecithin. We found that chondroitin sulfate proteoglycans (CSPGs) accumulated early following demyelination while laminins accumulated during the period of remyelination. Microglia macrophages and reactive astrocytes were sources of CSPGs and laminins, respectively. Significantly, CSPG expression was down-regulated during remyelination, emphasizing that demyelination was correspondent with accumulation of CSPGs while remyelination was concurrent with removal of CSPGs and accumulation of laminins. In vitro, CSPG were a poor substrate for oligodendrocyte adhesion and maturation while laminin facilitated these processes. To further elucidate the relevance of CSPGs in vivo, we utilized xyloside to reduce the production of CSPGs that occur following demyelination. Xyloside treatment reduced the content of CSPGs, increased the number of oligodendrocyte precursor cells, and resulted in enhanced remyelination. These results highlight the extracellular matrix proteins around demyelinating lesions in the regulation of remyelination. In particular, we document the inhibitory roles of CSPGs, the removal of which facilitated repair.

/pdf/promoting-remyelination-by-reducing-an-inhibitory-1ad9hul3wt.pdf

Promoting remyelination by reducing an inhibitory microenvironment

https://doi.org/10.1016/j.bbih.2022.100477

Thermoregulatory dynamics reveal sex-specific inflammatory responses to experimental autoimmune encephalomyelitis in mice: Implications for multiple sclerosis-induced fatigue in females

Multiple sclerosis (MS) is a condition with extensive infiltration of leukocytes into the central nervous system (CNS) and the activation of CNS-intrinsic microglia. The neuroinflammation in MS is accompanied by the loss of oligodendrocytes and myelin, prominent injury to axons, and the death of neurons. We will refer to the collective loss of neural elements and cells herein as neurodegeneration. Much attention has been focused on the mechanisms and prevention of neurodegeneration, since it drives the progression of disability in MS. The initiating cause(s) of neurodegeneration in MS continues to be debated, with one school postulating an early role of dysfunction within the CNS that may not even be inflammatory; examples of such “inside-out”1 initiators include mitochondrial dysfunction within axons, energy insufficiency, glutamate excitotoxicity, and dysfunctional organelles. In contrast, the opposing view (“outside-in”) proposes abnormalities in immune processes outside the CNS that lead to the substantial entry of activated leukocytes into the CNS. Regardless of the initiating event, and it may be either in different MS individuals, the consequence is the over-representation of activated leukocytes and microglia within the CNS.

https://journals.sagepub.com/doi/pdf/10.1177/1352458517707266

V. Wee Yong

Papers

Neuroprotection by minocycline in murine traumatic spinal cord injury: analyses of matrix metalloproteinases

Promoting remyelination by reducing an inhibitory microenvironment

Thermoregulatory dynamics reveal sex-specific inflammatory responses to experimental autoimmune encephalomyelitis in mice: Implications for multiple sclerosis-induced fatigue in females

Stop inflammation and you stop neurodegeneration in MS – YES:

Bladder dysfunction in experimental autoimmune encephalomyelitis reflects clinical severity: A pilot study