Vasculogenic mimicry(VM),a newly-defined pattern of tumor blood supply,provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis.The biological features o...Vasculogenic mimicry(VM),a newly-defined pattern of tumor blood supply,provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis.The biological features of the tumor cells that form VM remain unknown.Cancer stem cells(CSCs)are believed to be tumorinitiating cells,capable of self-renewal and multipotent differentiation,which resemble normal stem cells in phenotype and function.Recently CSCs have been shown to contribute to VM formation as well as angiogenesis.These findings challenge the previous understanding of the cellular basis of VM formation.In this review,we present evidence for participation of CSCs in VM formation.We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche.Based on the importance of VM in tumor progression,it constitutes a novel therapeutic target for cancer.展开更多
Our previous study verified the protective effects of Lycium barbarum polysaccharides(LBP)on retinal neurons and blood vessels in acute ocular hypertension(AOH)mice.To investigate the effect of LBP on the reactivity o...Our previous study verified the protective effects of Lycium barbarum polysaccharides(LBP)on retinal neurons and blood vessels in acute ocular hypertension(AOH)mice.To investigate the effect of LBP on the reactivity of retinal glial cells,an AOH mouse model was established in one eye by maintaining ocular hypertension of 90 mm Hg for 60 minutes.Either LBP solution(1 mg/kg)or phosphate-buffered saline was administrated to the mice by gavage daily,starting 7 days before the AOH insult and continuing until the mice were sacrificed for specimen collection on day 4 post-insult.After AOH insult,increased numbers of astrocytes and microglia were observed,together with decreased expression of the following glial cell biomarkers in the retinal ganglion cells of AOH mice:glial fibrillary acidic protein,glutamine synthetase,aquaporin-4,S-100 proteins,ionized calcium-binding adaptor molecule 1,amyloid precursor protein and receptor of advanced glycosylation end-products.After intervention with LBP,the above changes were significantly reduced.Remarkably,morphological remodeling of blood vessel-associated retinal astrocytes,marked by glial fibrillary acidic protein,was also observed.These results,taken together,suggest that LBP regulated the production of amyloid-βand expression of receptor of advanced glycosylation end-products,as well as mediating the activity of retinal glial cells,which may lead to the promotion of better maintenance of the blood-retinal barrier and improved neuronal survival in AOH insult.This study was approved by the Committee for the Use of Live Animals in Teaching and Research(approval No.CULTRA-#1664-08).展开更多
The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fa...The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis,therapeutic resistance and relapse.Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population.This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations.Therefore,these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters,which are often refractory to cancer treatment and difficult to target.Moreover,interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging.This review highlights recent findings on the relationship between fatty acid metabolism,cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.展开更多
The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and ...The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell(CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cel s harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.展开更多
Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord ...Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury. In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3 K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3 K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3 K/AKT/mTOR pathway.展开更多
Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheime...Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.展开更多
The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers.CREB1 can regulate tumor cell status of proliferation and/or migration;however,the molecular basis...The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers.CREB1 can regulate tumor cell status of proliferation and/or migration;however,the molecular basis for this switch involvement in cell plasticity has not fully been understood yet.Here,we first show that knocking out CREB1 triggers a remarkable effect of epithelial-mesenchymal transition(EMT)and leads to the occurrence of inhibited proliferation and enhanced motility in HCT116colorectal cancer cells.By monitoring 45 cellular signaling pathway activities,we find that multiple growth-related pathways decline significantly while inflammatory pathways including NF-κB are largely upregulated in comparing between the CREB1wild-type and knocked out cells.Mechanistically,cells with CREB1 knocked out show downregulation of MYC as a result of impaired CREB1-dependent transcription of the oncogenic lnc RNA CCAT1.Interestingly,the unbalanced competition between the coactivator CBP/p300 for CREB1 and p65 leads to the activation of the NF-κB pathway in cells with CREB1 disrupted,which induces an obvious EMT phenotype of the cancer cells.Taken together,these studies identify previously unknown mechanisms of CREB1 in CRC cell plasticity via regulating lnc RNA CCAT1 and NF-κB pathways,providing a critical insight into a combined strategy for CREB1-targeted tumor therapies.展开更多
Objective To investigate whether there is endogenous neural stem cell proliferation and whether these proliferated neural stem cells represent neural plasticity in the adult rats after cerebral infarction. Methods Cer...Objective To investigate whether there is endogenous neural stem cell proliferation and whether these proliferated neural stem cells represent neural plasticity in the adult rats after cerebral infarction. Methods Cerebral infarction models of rats were established and the dynamic expression of bromodeoxyuridine （BrdU）, BrdU/polysialylated neural cell adhesion molecule （PSA-NCAM） were determined by immunohistochemistry and immunofluorescence staining. BrdU was used to mark dividing neural stem cells. PSA-NCAM was used to mark the plasticity of neural stem cells. Results Compared with controls, the number of BrdU-positive cells in the subventricular zone （SVZ） and hippocampus increased significantly at 1st day after cerebral infarction （P 〈 0. 05 ）, reached maximum at 7th day, decreased markedly at 14th day, but it was still elevated compared with that of the controls （ P 〈 0. 05 ）. The number of BrdU-labeled with PSA-NCAM-positive cells increased significantly at 7th day （ P 〈 0. 05 ）, reached maximum at 14th day, markedly decreased at 28th day, but it was still elevated compared with that of the controls （P 〈 0. 05 ）. It was equal to 60% of the number of BrdU-positive cells in the same period. Conclusion Cerebral infarction may stimulate the proliferation of endogenous neural stem cells in situ and most proliferated neural stem cells represent neural plasticity.展开更多
Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant ro...Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma(HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin(CCO) and cancer-propagating cells, known as hepatic cancer stem cell(HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the existence of different cancer stem cells(CSC) subpopulations with different functions within HCC. There is a dynamic interconversion among different CSCs, and between CSC and non-CSCs. Because of that, CSC-state is currently defined as a description of a highly adaptable and dynamic intrinsic property of tumor cells, instead of a static subpopulation of a tumor. Altered conditions could trigger the gain of stemness, some of them include: EMT-MET, epigenetics, microenvironment and selective stimulus such as chemotherapy. This CSC heterogeneity and dynamism makes them out reach from therapeutic protocols directed to a single target. A further avenue of research in this line will be to uncover mechanisms that trigger this interconversion of cell populations within tumors and target it.展开更多
New neurons are continuously generated from resident pools of neural stem and precursor cells(NSPCs)in the adult brain.There are multiple pathways through which adult neurogenesis is regulated,and here we review the r...New neurons are continuously generated from resident pools of neural stem and precursor cells(NSPCs)in the adult brain.There are multiple pathways through which adult neurogenesis is regulated,and here we review the role of the N-methyl-D-aspartate receptor(NMDAR)in regulating the proliferation of NSPCs in the adult hippocampus.Hippocampal-dependent learning tasks,enriched environments,running,and activity-dependent synaptic plasticity,all potently up-regulate hippocampal NSPC proliferation.We first consider the requirement of the NMDAR in activity-dependent synaptic plasticity,and the role the induction of synaptic plasticity has in regulating NSPCs and newborn neurons.We address how specific NMDAR agonists and antagonists modulate proliferation,both in vivo and in vitro,and then review the evidence supporting the hypothesis that NMDARs are present on NSPCs.We believe it is important to understand the mechanisms underlying the activation of adult neurogenesis,given the potential that endogenous stem cell populations have for repopulating the hippocampus with functional new neurons.In conditions such as age-related memory decline,neurodegeneration and psychiatric disease,mature neurons are lost or become defective;as such,stimulating adult neurogenesis may provide a therapeutic strategy to overcome these conditions.展开更多
Multipotent mesenchymal stromal cells(MSC),have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation.The demonstration that MSCs are perivas...Multipotent mesenchymal stromal cells(MSC),have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation.The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair.However,some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist.In brain,perivascular MSCs like pericytes and adventitial cells,could constitute another stem cell population distinct to the neural stem cell pool.The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes,the demonstration of neural biomarkers expression,electrophysiological recordings,and the absence of cell fusion.The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells.It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.展开更多
Adult stem cells(SCs) exist in all tissues that promote tissue growth, regeneration, and healing throughout life. The SC niche in which they reside provides signals that direct them to proliferate, differentiate, or r...Adult stem cells(SCs) exist in all tissues that promote tissue growth, regeneration, and healing throughout life. The SC niche in which they reside provides signals that direct them to proliferate, differentiate, or remain dormant; these factors include neighboring cells, the extracellular matrix, soluble molecules, and physical stimuli. In disease and aging states, stable or transitory changes in the microenvironment can directly cause SC activation or inhibition in tissue healing as well as functional regulation. Here, we discuss the microenvironmental regulation of the behavior of SC and focus on plasticity approaches by which various environmental factors can enhance the function of SCs and more effectively direct the fate of SCs.展开更多
In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction.Mixed neuroendocrine and non-neuroendocrine neoplasms of the ga...In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction.Mixed neuroendocrine and non-neuroendocrine neoplasms of the gastrointestinal system are rare heterogeneous group of tumors characterized by a high malignant potential,rapid growth,and poor prognosis.Due to the rarity of these cancers,the standard therapy is poorly defined.The diagnosis of these tumors is based on combination of morphological features,immunohistochemical and neuroendocrine and epithelial cell markers.Both endocrine and epithelial cell components can act independently of each other and thus,careful grading of each component separately is required.These cancers are aggressive in nature and the potential of each component has paramount importance in the choice of treatment and response.Regardless of the organ of origin,these tumors portend poor prognosis with increased proportion of neuroendocrine component.Multidisciplinary services and strategies are required for the management of these mixed malignancies to provide the best oncological outcomes.The etiopathogenesis of these mixed tumors remains obscure but poses interesting question.We briefly discuss a few salient points in this editorial.展开更多
基金the National Basic Research Program of China(973 Program)(Grant No.2010CB529403)National Natural Science Foundation of China(Grant Nos.30800421,30725035 and 30930103).
文摘Vasculogenic mimicry(VM),a newly-defined pattern of tumor blood supply,provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis.The biological features of the tumor cells that form VM remain unknown.Cancer stem cells(CSCs)are believed to be tumorinitiating cells,capable of self-renewal and multipotent differentiation,which resemble normal stem cells in phenotype and function.Recently CSCs have been shown to contribute to VM formation as well as angiogenesis.These findings challenge the previous understanding of the cellular basis of VM formation.In this review,we present evidence for participation of CSCs in VM formation.We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche.Based on the importance of VM in tumor progression,it constitutes a novel therapeutic target for cancer.
基金supported in part by the National Basic Research Program of China,No.81300766(to XSM)the Cultivation and Innovation Fund from the First Affiliated Hospital of Jinan University,China,No.802168(to XSM)+2 种基金Hygiene&Health Appropriated Technology and Promoting Project of Guangdong Province of China,No.201905270933056876(to XSM)the fund of Leading Talents of Guangdong Province of China,No.87014002(to KFS)a grant from Ningxia Key Research and Development Program,and Programme of Introducing Talents of Discipline to Universities of China,No.B14036(to KFS)。
文摘Our previous study verified the protective effects of Lycium barbarum polysaccharides(LBP)on retinal neurons and blood vessels in acute ocular hypertension(AOH)mice.To investigate the effect of LBP on the reactivity of retinal glial cells,an AOH mouse model was established in one eye by maintaining ocular hypertension of 90 mm Hg for 60 minutes.Either LBP solution(1 mg/kg)or phosphate-buffered saline was administrated to the mice by gavage daily,starting 7 days before the AOH insult and continuing until the mice were sacrificed for specimen collection on day 4 post-insult.After AOH insult,increased numbers of astrocytes and microglia were observed,together with decreased expression of the following glial cell biomarkers in the retinal ganglion cells of AOH mice:glial fibrillary acidic protein,glutamine synthetase,aquaporin-4,S-100 proteins,ionized calcium-binding adaptor molecule 1,amyloid precursor protein and receptor of advanced glycosylation end-products.After intervention with LBP,the above changes were significantly reduced.Remarkably,morphological remodeling of blood vessel-associated retinal astrocytes,marked by glial fibrillary acidic protein,was also observed.These results,taken together,suggest that LBP regulated the production of amyloid-βand expression of receptor of advanced glycosylation end-products,as well as mediating the activity of retinal glial cells,which may lead to the promotion of better maintenance of the blood-retinal barrier and improved neuronal survival in AOH insult.This study was approved by the Committee for the Use of Live Animals in Teaching and Research(approval No.CULTRA-#1664-08).
基金supported in part by funds from the National Institutes of Health R01DE026304 and R01CA220693(to D.K.A.)Ministry of Science and Technology,R.O.C,Special Talents Award(to C.-Y.K).
文摘The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis,therapeutic resistance and relapse.Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population.This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations.Therefore,these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters,which are often refractory to cancer treatment and difficult to target.Moreover,interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging.This review highlights recent findings on the relationship between fatty acid metabolism,cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.
文摘The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell(CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cel s harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.
基金supported by the National Key R&D Program of China,No.2020YFC2008502 (to QW)the National Natural Science Foundation of China,No. 82172534 (to QW)。
文摘Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury. In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3 K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3 K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3 K/AKT/mTOR pathway.
基金supported by the National Natural Science Foundation of China,No.82074533(to LZ).
文摘Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.
基金supported by the National Natural Science Foundation of China(31970604,31900903,31770879)the Major Research Plan of the National Natural Science Foundation of China(91940000)+3 种基金the National Key Research and Development Program of China(2017YFA0504400)in part by the Guangdong Province Key Laboratory of Computational Science(13lgjc05)the Guangdong Province Computational Science Innovative Research Team(14lgjc18)the Fundamental Research Funds for the Central Universities(20lgpy112,2021qntd26)。
文摘The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers.CREB1 can regulate tumor cell status of proliferation and/or migration;however,the molecular basis for this switch involvement in cell plasticity has not fully been understood yet.Here,we first show that knocking out CREB1 triggers a remarkable effect of epithelial-mesenchymal transition(EMT)and leads to the occurrence of inhibited proliferation and enhanced motility in HCT116colorectal cancer cells.By monitoring 45 cellular signaling pathway activities,we find that multiple growth-related pathways decline significantly while inflammatory pathways including NF-κB are largely upregulated in comparing between the CREB1wild-type and knocked out cells.Mechanistically,cells with CREB1 knocked out show downregulation of MYC as a result of impaired CREB1-dependent transcription of the oncogenic lnc RNA CCAT1.Interestingly,the unbalanced competition between the coactivator CBP/p300 for CREB1 and p65 leads to the activation of the NF-κB pathway in cells with CREB1 disrupted,which induces an obvious EMT phenotype of the cancer cells.Taken together,these studies identify previously unknown mechanisms of CREB1 in CRC cell plasticity via regulating lnc RNA CCAT1 and NF-κB pathways,providing a critical insight into a combined strategy for CREB1-targeted tumor therapies.
基金Supportedby the Early-stage Special FundforImportant Basis Research Projectfrom the Technology Department of China(2002CCAO4400)
文摘Objective To investigate whether there is endogenous neural stem cell proliferation and whether these proliferated neural stem cells represent neural plasticity in the adult rats after cerebral infarction. Methods Cerebral infarction models of rats were established and the dynamic expression of bromodeoxyuridine （BrdU）, BrdU/polysialylated neural cell adhesion molecule （PSA-NCAM） were determined by immunohistochemistry and immunofluorescence staining. BrdU was used to mark dividing neural stem cells. PSA-NCAM was used to mark the plasticity of neural stem cells. Results Compared with controls, the number of BrdU-positive cells in the subventricular zone （SVZ） and hippocampus increased significantly at 1st day after cerebral infarction （P 〈 0. 05 ）, reached maximum at 7th day, decreased markedly at 14th day, but it was still elevated compared with that of the controls （ P 〈 0. 05 ）. The number of BrdU-labeled with PSA-NCAM-positive cells increased significantly at 7th day （ P 〈 0. 05 ）, reached maximum at 14th day, markedly decreased at 28th day, but it was still elevated compared with that of the controls （P 〈 0. 05 ）. It was equal to 60% of the number of BrdU-positive cells in the same period. Conclusion Cerebral infarction may stimulate the proliferation of endogenous neural stem cells in situ and most proliferated neural stem cells represent neural plasticity.
文摘Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma(HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin(CCO) and cancer-propagating cells, known as hepatic cancer stem cell(HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the existence of different cancer stem cells(CSC) subpopulations with different functions within HCC. There is a dynamic interconversion among different CSCs, and between CSC and non-CSCs. Because of that, CSC-state is currently defined as a description of a highly adaptable and dynamic intrinsic property of tumor cells, instead of a static subpopulation of a tumor. Altered conditions could trigger the gain of stemness, some of them include: EMT-MET, epigenetics, microenvironment and selective stimulus such as chemotherapy. This CSC heterogeneity and dynamism makes them out reach from therapeutic protocols directed to a single target. A further avenue of research in this line will be to uncover mechanisms that trigger this interconversion of cell populations within tumors and target it.
文摘New neurons are continuously generated from resident pools of neural stem and precursor cells(NSPCs)in the adult brain.There are multiple pathways through which adult neurogenesis is regulated,and here we review the role of the N-methyl-D-aspartate receptor(NMDAR)in regulating the proliferation of NSPCs in the adult hippocampus.Hippocampal-dependent learning tasks,enriched environments,running,and activity-dependent synaptic plasticity,all potently up-regulate hippocampal NSPC proliferation.We first consider the requirement of the NMDAR in activity-dependent synaptic plasticity,and the role the induction of synaptic plasticity has in regulating NSPCs and newborn neurons.We address how specific NMDAR agonists and antagonists modulate proliferation,both in vivo and in vitro,and then review the evidence supporting the hypothesis that NMDARs are present on NSPCs.We believe it is important to understand the mechanisms underlying the activation of adult neurogenesis,given the potential that endogenous stem cell populations have for repopulating the hippocampus with functional new neurons.In conditions such as age-related memory decline,neurodegeneration and psychiatric disease,mature neurons are lost or become defective;as such,stimulating adult neurogenesis may provide a therapeutic strategy to overcome these conditions.
基金Supported by INSERM and the Ligue contre le Cancer Isère-Rhne Alpes
文摘Multipotent mesenchymal stromal cells(MSC),have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation.The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair.However,some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist.In brain,perivascular MSCs like pericytes and adventitial cells,could constitute another stem cell population distinct to the neural stem cell pool.The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes,the demonstration of neural biomarkers expression,electrophysiological recordings,and the absence of cell fusion.The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells.It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.
基金supported in part by the National Basic Research Program of China(2012CB518103,2012CB518105)National High Technology Research and Development Program of Ministry of Science and Technology of China(2013AA020105,2012AA020502)National Natural Science Foundation of China(81121004,81230041,31400822)
文摘Adult stem cells(SCs) exist in all tissues that promote tissue growth, regeneration, and healing throughout life. The SC niche in which they reside provides signals that direct them to proliferate, differentiate, or remain dormant; these factors include neighboring cells, the extracellular matrix, soluble molecules, and physical stimuli. In disease and aging states, stable or transitory changes in the microenvironment can directly cause SC activation or inhibition in tissue healing as well as functional regulation. Here, we discuss the microenvironmental regulation of the behavior of SC and focus on plasticity approaches by which various environmental factors can enhance the function of SCs and more effectively direct the fate of SCs.
文摘In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction.Mixed neuroendocrine and non-neuroendocrine neoplasms of the gastrointestinal system are rare heterogeneous group of tumors characterized by a high malignant potential,rapid growth,and poor prognosis.Due to the rarity of these cancers,the standard therapy is poorly defined.The diagnosis of these tumors is based on combination of morphological features,immunohistochemical and neuroendocrine and epithelial cell markers.Both endocrine and epithelial cell components can act independently of each other and thus,careful grading of each component separately is required.These cancers are aggressive in nature and the potential of each component has paramount importance in the choice of treatment and response.Regardless of the organ of origin,these tumors portend poor prognosis with increased proportion of neuroendocrine component.Multidisciplinary services and strategies are required for the management of these mixed malignancies to provide the best oncological outcomes.The etiopathogenesis of these mixed tumors remains obscure but poses interesting question.We briefly discuss a few salient points in this editorial.
