Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.Subject terms: Cancer microenvironment, CNS cancer, Cancer therapy相似文献
Brain-derived neurotrophic factor (BDNF) signaling through its receptor,
TrkB, modulates survival, differentiation, and synaptic activity of neurons.
Both full-length TrkB (TrkB-FL) and its isoform T1 (TrkB.T1) receptors are
expressed in neurons; however, whether they follow the same endocytic pathway
after BDNF treatment is not known. In this study we report that TrkB-FL and
TrkB.T1 receptors traverse divergent endocytic pathways after binding to BDNF.
We provide evidence that in neurons TrkB.T1 receptors predominantly recycle
back to the cell surface by a “default” mechanism. However,
endocytosed TrkB-FL receptors recycle to a lesser extent in a hepatocyte
growth factor-regulated tyrosine kinase substrate (Hrs)-dependent manner which
relies on its tyrosine kinase activity. The distinct role of Hrs in promoting
recycling of internalized TrkB-FL receptors is independent of its
ubiquitin-interacting motif. Moreover, Hrs-sensitive TrkB-FL recycling plays a
role in BDNF-induced prolonged mitogen-activated protein kinase (MAPK)
activation. These observations provide evidence for differential postendocytic
sorting of TrkB-FL and TrkB.T1 receptors to alternate intracellular
pathways.Brain-derived neurotrophic factor
(BDNF)3 has been shown
to play critical roles in vertebrate nervous system development and function
(1–3).
The actions of BDNF are dictated by two classes of cell surface receptors, the
TrkB receptor and the p75 neurotrophin receptor. BDNF binding to TrkB
receptors activates several signaling cascades, including phosphatidylinositol
3-kinase, phospholipase C, and Ras/mitogen-activated protein kinase (MAPK)
pathways, that mediate growth and survival responses to BDNF
(1,
4,
5). It has been established
that upon binding neurotrophins, Trk receptors are rapidly endocytosed in a
clathrin-dependent manner (6,
7). Postendocytic sorting of
Trk receptors to diverse pathways after ligand binding has a significant
impact on the physiological responses to neurotrophins because they also
determine the strength and duration of intracellular signaling cascades
initiated by activated Trk receptors
(8). Three alternate endocytic
pathways that Trk receptors can follow are trafficking to lysosomes for
degradation, recycling back to the plasma membrane, or being retrogradely
transported
(9–13).
The degradative pathway to lysosomes is characterized by down-regulation of
the total number of receptors at the cell surface and a decreased response to
ligand. Conversely, recycling of receptors back to the plasma membrane can
lead to functional resensitization and prolongation of cell surface-specific
signaling events. A recent study has shown that recycled and re-secreted BDNF
plays an important role in mediating the maintenance of long term potentiation
in hippocampal slices, which suggests a potential role of TrkB recycling in
long term potentiation regulation
(14).Different TrkB isoforms, including the full-length TrkB (TrkB-FL) and three
truncated isoforms named TrkB.T1, TrkB.T2, and TrkB.T-Shc, exist in the
mammalian central nervous system because of alternative splicing
(15–17).
Truncated TrkB.T1 receptor lacks the kinase domain but contains short
isoform-specific cytoplasmic domain in its place
(15,
16). Many neuronal
populations, including hippocampal and cortical neurons, express both
full-length and truncated TrkB receptors
(18,
19). TrkB.T1 is expressed at
low levels in the prenatal rodent brain, but its expression increases
postnatally, ultimately exceeding the level of full-length TrkB in adulthood
(19–22).
The physiological function of the TrkB.T1 receptor remains unclear, but it may
serve as dominant-negative regulator of full-length TrkB receptors
(23–25),
may sequester ligand and limit diffusion
(26,
27), may regulate cell
morphology and dendritic growth
(28,
29), and may even autonomously
activate signaling cascades in a neurotrophin-dependent manner
(30). TrkB-FL and TrkB.T1 are
localized to both somatodendritic and axonal compartments in neurons
(31); however, little is known
about TrkB.T1 endocytic trafficking fate upon BDNF treatment.In this study we conducted an analysis of the postendocytic fates
(degradation and recycling) of TrkB-FL and TrkB.T1 receptors in PC12 cells and
neurons. We have determined that, unlike TrkB-FL, TrkB.T1 receptors recycle
more efficiently in a default pathway to plasma surface after internalization,
which is independent of hepatocyte growth factor-regulated tyrosine kinase
substrate (Hrs). Conversely, Hrs could bind with TrkB-FL in a kinase
activity-dependent manner and regulate TrkB-FL receptors postendocytic
recycling. Hrs was identified as a tyrosine-phosphorylated protein in cells
stimulated with growth factors and cytokines
(32). Hrs is expressed in the
cytoplasm of all cells and is predominantly localized to endosomes
(33). Hrs has also been
proposed to play a role in regulating cell surface receptor postendocytic
trafficking (34). These
observations provide evidence for differential postendocytic sorting to
alternate intracellular pathways between TrkB-FL and TrkB.T1 receptors after
internalization. 相似文献
Reprogrammed metabolism is a hallmark of cancer. Glioblastoma (GBM) tumor cells predominantly utilize aerobic glycolysis for the biogenesis of energy and intermediate nutrients. However, in GBM, the clinical significance of glycolysis and its underlying relations with the molecular features such as IDH1 mutation and subtype have not been elucidated yet. Herein, based on glioma datasets including TCGA (The Cancer Genome Atlas), REMBRANDT (Repository for Molecular Brain Neoplasia Data) and GSE16011, we established a glycolytic gene expression signature score (GGESS) by incorporating ten glycolytic genes. Then we performed survival analyses and investigated the correlations between GGESS and IDH1 mutation as well as the molecular subtypes in GBMs. The results showed that GGESS independently predicted unfavorable prognosis and poor response to chemotherapy of GBM patients. Notably, GGESS was high in GBMs of mesenchymal subtype but low in IDH1-mutant GBMs. Furthermore, we found that the promoter regions of tumor-promoting glycolytic genes were hypermethylated in IDH1-mutant GBMs. Finally, we found that high GGESS also predicted poor prognosis and poor response to chemotherapy when investigating IDH1-wildtype GBM patients only. Collectively, glycolysis represented by GGESS predicts unfavorable clinical outcome of GBM patients and is closely associated with mesenchymal subtype and IDH1 mutation in GBMs. 相似文献
Ganoderma spp. are medical mushrooms with various pharmacological compounds which are regarded as a nutraceutical for improving health and treating diseases. This review summarizes current progress in the studies of Gamoderma ranging from bioactive metabolites, bioactivities, production techniques to clinical trials. Traditionally, polysaccharides and ganoderic acids have been reported as the major bioactive metabolites of Ganoderma possessing anti-tumor and immunomodulation functions. Moreover, recent studies indicate that Gandoerma also exerts other bioactivities such as skin lighting, gut microbiota regulation, and anti-virus effects. However, since these medical fungi are rare in natural environment, and that the cost of cultivation of fruiting bodies is high, industrial submerged fermentation of Ganoderma mycelia promotes the development of Ganoderma by dint of an increase of biomass and bioactive metabolites used for further application. In addition, various strategies for production of different metabolites are well developed, such as gene regulation, bi-stage pH, and oxygen control. To date, Ganoderma not only has become one of the most popular nutraceuticals worldwide but also has been applied to clinical trials for advanced diseases such as breast and non-small-cell lung cancer.