Cancer stem cells(CSC) are thought to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. Studies have described CSC in various gastrointestinal neoplasms such as colon, pancr...Cancer stem cells(CSC) are thought to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. Studies have described CSC in various gastrointestinal neoplasms such as colon, pancreas and liver and gastroesophageal tumors. The mechanism by which CSC develop remains unclear. Several studies have explored the role of dysregulation of the Wnt/β-catenin, transformation growth factor-beta and hedhog pathways in generation of CSC. In this review, we discuss the various molecular abnormalities that may be related to formation of CSC in gastrointestinal malignancies, strategies to identify CSC and therapeutic strategies that are based on these concepts. Identification and targeting CSC is an intriguing area and may provide a new therapeutic option for patients with cancer including gastrointestinal malignancies. Although great progress has been made, many issues need to be addressed. Precise targeting of CSC will require precise isolation and characterization of those cells. This field is also evolving but further research is needed to identify markers that are specific for CSC.Although the application of this field has not entered the clinic yet, there continues to be significant optimism about its potential utility in overcoming cancer resistance and curing patients with cancer.展开更多
In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for t...In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.展开更多
The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of ...The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of various cell types,the extracellular matrix,and soluble factors that mediate cell-cell interaction.The brain tumor PVN controls maintenance,expansion,and differentiation of BTSCs via direct cell contact or paracrine signaling cues.BTSCs often receive bidirectional crosstalk from endothelial cells and other cell types in the niche[2].In addition,the perivascular zone may serve as a path for tumor cells to migrate over long distances(3,4)Unlike other solid tumors,glioblastoma multiforme(GBM)cells rarely metastasize to other organs,but they can invade the entire brain by migrating along specific brain tissue structures,such as blood vessels or white matter tracts,leading to high rates of relapse.Despite the success in modeling diffuse brain tumors in both genetically-modified and patient-derived xenograft(PDX)animals,there is an unmet need for an in vitro system that can bridge conventional cell culture and animal models by mimicking not only the anatomy but also the function of the PVN to study the dynamics of BTSCs.In this presentation,I will describe the use of a microvasculature-on-a-chip system as a PVN model to evaluate the dynamics of BTSCs ex vivo from 10 glioblastoma patients [5].We observed that BTSCs preferentially localize in the perivascular zone.Live cell tracking showed that the cells residing in the vicinity of microvessels had the lowest motility,while a fraction of cells on the microvessels unexpectedly possessed the highest motility and migrated over the longest distance.These results indicate that the perivascular zone is a niche for BTSCs,while the microvascular tracks are also a path for long-distance tumor cell migration and invasion.Additionally,the degree of co-localization between tumor cells and microvessels varied significantly across patients.To validate the results from our microvasculature-on-a-chip system,we used single-cell transcriptome sequencing(10 patients and 21,750 single cells in total)to identify the subtype of each tumor cell.The co-localization coefficient was found to correlate positively with proneural(stem-like)or mesenchymal(invasive)but not classical(proliferative)tumor cells.Furthermore,we found that a gene signature profile including PDGFRA correlated strongly with the'homing'of brain tumor cells to the PVN.Our findings demonstrated that ex vivo dynamics of human brain tumor cells in a microvasculature-on-a-chip model can recapitulate in vivo tumor cell dynamics,heterogeneity,and subtypes,representing a new route to the study of human tumor cell biology and uncover patient-specific tumor cell functions.Acknowledgments:We thank Drs.Laura Niklason,Eric Holland,Franziska Michor,and Frank Szulzewsky for scientific discussion.We thank Misha Guy,Vladimir Polejaev,Zhenting Jiang,and Alice Yun for suggestions and help on the simulation computing and SEM/confocal imaging process.This research was supported by the Packard Fellowship for Science and Engineering(R.F.),National Science Foundation CAREER Award CBET-1351443(R.F.),U54 CA193461(R.F.),U54CA209992(Sub-Project ID:7297 to R.F.),R01 NS095817(J.Z.),Yale Cancer Center Co-Pilot Grant(to R.F.).The molds for microfluidic devices were fabricated in the Yale School of Engineering and Applied Science cleanroom.Sequencing was performed at the Yale Center for Genome Analysis(YCGA)facility.Data was analyzed at Yale High Performance Computing(HPC)center.Super resolution confocal imaging was performed at Yale Center for Cellular and Molecular Imaging(CCMI).展开更多
In the past decade,chimeric antigen receptor(CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers,demonstrating remarkable efficacy in relapsed/refractory hematological malig...In the past decade,chimeric antigen receptor(CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers,demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients.CAR-natural killer(CAR-NK)cell complements CAR-T cell therapy by offering several distinct advantages.CAR-NK cells do not require HLA compatibility and exhibit low safety concerns.Moreover,CAR-NK cells are conducive to“off-the-shelf”therapeutics,providing significant logistic advantages over CAR-T cells.Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies.However,their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration,as well as an immuno-suppressive tumor microenvironment.In this review,we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies,with a specific focus on the obstacles to their application in solid tumors.We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization.Finally,we explore future perspectives of these adoptive immunotherapies,highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.展开更多
文摘Cancer stem cells(CSC) are thought to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. Studies have described CSC in various gastrointestinal neoplasms such as colon, pancreas and liver and gastroesophageal tumors. The mechanism by which CSC develop remains unclear. Several studies have explored the role of dysregulation of the Wnt/β-catenin, transformation growth factor-beta and hedhog pathways in generation of CSC. In this review, we discuss the various molecular abnormalities that may be related to formation of CSC in gastrointestinal malignancies, strategies to identify CSC and therapeutic strategies that are based on these concepts. Identification and targeting CSC is an intriguing area and may provide a new therapeutic option for patients with cancer including gastrointestinal malignancies. Although great progress has been made, many issues need to be addressed. Precise targeting of CSC will require precise isolation and characterization of those cells. This field is also evolving but further research is needed to identify markers that are specific for CSC.Although the application of this field has not entered the clinic yet, there continues to be significant optimism about its potential utility in overcoming cancer resistance and curing patients with cancer.
文摘In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.
文摘The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of various cell types,the extracellular matrix,and soluble factors that mediate cell-cell interaction.The brain tumor PVN controls maintenance,expansion,and differentiation of BTSCs via direct cell contact or paracrine signaling cues.BTSCs often receive bidirectional crosstalk from endothelial cells and other cell types in the niche[2].In addition,the perivascular zone may serve as a path for tumor cells to migrate over long distances(3,4)Unlike other solid tumors,glioblastoma multiforme(GBM)cells rarely metastasize to other organs,but they can invade the entire brain by migrating along specific brain tissue structures,such as blood vessels or white matter tracts,leading to high rates of relapse.Despite the success in modeling diffuse brain tumors in both genetically-modified and patient-derived xenograft(PDX)animals,there is an unmet need for an in vitro system that can bridge conventional cell culture and animal models by mimicking not only the anatomy but also the function of the PVN to study the dynamics of BTSCs.In this presentation,I will describe the use of a microvasculature-on-a-chip system as a PVN model to evaluate the dynamics of BTSCs ex vivo from 10 glioblastoma patients [5].We observed that BTSCs preferentially localize in the perivascular zone.Live cell tracking showed that the cells residing in the vicinity of microvessels had the lowest motility,while a fraction of cells on the microvessels unexpectedly possessed the highest motility and migrated over the longest distance.These results indicate that the perivascular zone is a niche for BTSCs,while the microvascular tracks are also a path for long-distance tumor cell migration and invasion.Additionally,the degree of co-localization between tumor cells and microvessels varied significantly across patients.To validate the results from our microvasculature-on-a-chip system,we used single-cell transcriptome sequencing(10 patients and 21,750 single cells in total)to identify the subtype of each tumor cell.The co-localization coefficient was found to correlate positively with proneural(stem-like)or mesenchymal(invasive)but not classical(proliferative)tumor cells.Furthermore,we found that a gene signature profile including PDGFRA correlated strongly with the'homing'of brain tumor cells to the PVN.Our findings demonstrated that ex vivo dynamics of human brain tumor cells in a microvasculature-on-a-chip model can recapitulate in vivo tumor cell dynamics,heterogeneity,and subtypes,representing a new route to the study of human tumor cell biology and uncover patient-specific tumor cell functions.Acknowledgments:We thank Drs.Laura Niklason,Eric Holland,Franziska Michor,and Frank Szulzewsky for scientific discussion.We thank Misha Guy,Vladimir Polejaev,Zhenting Jiang,and Alice Yun for suggestions and help on the simulation computing and SEM/confocal imaging process.This research was supported by the Packard Fellowship for Science and Engineering(R.F.),National Science Foundation CAREER Award CBET-1351443(R.F.),U54 CA193461(R.F.),U54CA209992(Sub-Project ID:7297 to R.F.),R01 NS095817(J.Z.),Yale Cancer Center Co-Pilot Grant(to R.F.).The molds for microfluidic devices were fabricated in the Yale School of Engineering and Applied Science cleanroom.Sequencing was performed at the Yale Center for Genome Analysis(YCGA)facility.Data was analyzed at Yale High Performance Computing(HPC)center.Super resolution confocal imaging was performed at Yale Center for Cellular and Molecular Imaging(CCMI).
基金SC is supported by the Cancer Research Institute Lloyd J.Old STAR Award(CRI4964),NIH(R33CA281702)DoD(W81XWH-21-1-0514,HT94252310472)Pershing Square Sohn Cancer Research Alliance.
文摘In the past decade,chimeric antigen receptor(CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers,demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients.CAR-natural killer(CAR-NK)cell complements CAR-T cell therapy by offering several distinct advantages.CAR-NK cells do not require HLA compatibility and exhibit low safety concerns.Moreover,CAR-NK cells are conducive to“off-the-shelf”therapeutics,providing significant logistic advantages over CAR-T cells.Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies.However,their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration,as well as an immuno-suppressive tumor microenvironment.In this review,we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies,with a specific focus on the obstacles to their application in solid tumors.We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization.Finally,we explore future perspectives of these adoptive immunotherapies,highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.
