As the most commonly occurring cancer in women worldwide,breast cancer poses a formidable public health challenge on a global scale.Breast cancer consists of a group of biologically and molecularly heterogeneous disea...As the most commonly occurring cancer in women worldwide,breast cancer poses a formidable public health challenge on a global scale.Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast.While the risk factors associated with this cancer varies with respect to other cancers,genetic predisposition,most notably mutations in BRCA1 or BRCA2 gene,is an important causative factor for this malignancy.Breast cancers can begin in different areas of the breast,such as the ducts,the lobules,or the tissue in between.Within the large group of diverse breast carcinomas,there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites.It is important to distinguish between the various subtypes because they have different prognoses and treatment implications.As there are remarkable parallels between normal development and breast cancer progression at the molecular level,it has been postulated that breast cancer may be derived from mammary cancer stem cells.Normal breast development and mammary stem cells are regulated by several signaling pathways,such as estrogen receptors(ERs),HER2,and Wnt/b-catenin signaling pathways,which control stem cell proliferation,cell death,cell differentiation,and cell motility.Furthermore,emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer,especially for triple-negative breast cancer.This review provides a comprehensive survey of the molecular,cellular and genetic aspects of breast cancer.展开更多
Gastric cancer(GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to underst...Gastric cancer(GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to understand the underlying mechanism of this resistance and to improve clinical outcome. It is well recognized that tumor heterogeneity, a fundamental feature of malignancy, plays an essential role in the cancer development and chemoresistance. The model of tumor-initiating cell(TIC) has been proposed to explain the genetic, histological, and phenotypical heterogeneity of GC. TIC accounts for a minor subpopulation of tumor cells with key characteristics including high tumorigenicity, maintenance of self-renewal potential, giving rise to both tumorigenic and non-tumorigenic cancer cells, and resistance to chemotherapy. Regarding tumor-initiating cell of GC(GATIC), substantial studies have been performed to(1) identify the putative specific cell markers for purification and functional validation of GATICs;(2) trace the origin of GATICs; and(3) decode the regulatory mechanism of GATICs. Furthermore, recent studies demonstrate the plasticity of GATIC and the interaction between GATIC and its surrounding factors(TIC niche or tumor microenvironment). All these investigations pave the way for the development of GATIC-targeted therapy, which is in the phase of preclinical studies and clinical trials. Here, we interpret the heterogeneity of GC from the perspectives of TIC by reviewing the above-mentioned fundamental and clinical studies of GATICs. Problems encountered during the GATIC investigations and the potential solutions are also discussed.展开更多
Single-cell RNA sequencing(scRNA-seq)is a novel technology that allows transcriptomic analyses of individual cells.During the past decade,scRNA-seq sensitivity,accuracy,and efficiency have improved due to innovations ...Single-cell RNA sequencing(scRNA-seq)is a novel technology that allows transcriptomic analyses of individual cells.During the past decade,scRNA-seq sensitivity,accuracy,and efficiency have improved due to innovations including more sensitive,automated,and cost-effective single-cell isolation methods with higher throughput as well as ongoing technological development of scRNA-seq protocols.Among the variety of current approaches with distinct features,researchers can choose the most suitable method to carry out their research.By profiling single cells in a complex population mix,scRNA-seq presents great advantages over traditional sequencing methods in dissecting heterogeneity in cell populations hidden in bulk analysis and exploring rare cell types associated with tumorigenesis and metastasis.scRNA-seq studies in recent years in the field of breast cancer research have clustered breast cancer cell populations with different molecular subtypes to identify distinct populations that may correlate with poor prognosis and drug resistance.The technology has also been used to explain tumor microenvironment heterogeneity by identifying distinct immune cell subsets that may be associated with immunosurveillance and are potential immunotherapy targets.Moreover,scRNA-seq has diverse applications in breast cancer research besides exploring heterogeneity,including the analysis of cell-cell communications,regulatory single-cell states,immune cell distributions,and more.scRNA-seq is also a promising tool that can facilitate individualized therapy due to its ability to define cell subsets with potential treatment targets.Although scRNA-seq studies of therapeutic selection in breast cancer are currently limited,the application of this technology in this field is prospective.Joint efforts and original ideas are needed to better implement scRNA-seq technologies in breast cancer research to pave the way for individualized treatment management.This review provides a brief introduction on the currently available scRNA-seq approaches a展开更多
The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironmen...The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironment.Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors,generating exosomes,releasing nutrients,reshaping the extracellular matrix,and suppressing the function of immune cells.CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers.Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials.Here,we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer.We hope that summarizing CAFrelated studies from a historical perspective will help to accelerate the development of CAF-targeted therapeutic strategies for breast cancer.展开更多
Hepatocellular carcinoma(HCC)is a liver cancer,highly heterogeneous both at the histopathological and molecular levels.It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in va...Hepatocellular carcinoma(HCC)is a liver cancer,highly heterogeneous both at the histopathological and molecular levels.It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways,including canonical WNT/β-catenin,AKT/mTOR,MAPK pathways as well as signaling associated with telomere maintenance,p53/cell cycle regulation,epigenetic modifiers,and oxidative stress.The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established,whereas in development and progression of HCC is extensively studied.Herein,we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development,acquisition of stemness features,metastasis,and resistance to treatment.We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC.We discuss the pivotal roles of CTNNB1 mutations,aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.展开更多
Glioma is the most common lethal tumor of the human brain.The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months.The World Health Organization classification of tumo...Glioma is the most common lethal tumor of the human brain.The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months.The World Health Organization classification of tumors of the central nervous system categorized gliomas into lower-grade gliomas and glioblastomas.Unlike primary glioblastoma that usually develop de novo in the elderly,secondary glioblastoma enriched with an isocitrate dehydrogenase mutant typically progresses from lower-grade glioma within 5-10 years from the time of diagnosis.Based on various evolutional trajectories brought on by clonal and subclonal alterations,the evolution patterns of glioma vary according to different theories.Some important features distinguish the normal brain from other tissues,e.g.,the composition of the microenvironment around the tumor cells,the presence of the blood-brain barrier,and others.The underlying mechanism of glioma recurrence and evolution patterns of glioma are different from those of other types of cancer.Several studies correlated tumor recurrence with tumor heterogeneity and the immune microenvironment.However,the detailed reasons for the progression and recurrence of glioma remain controversial.In this review,we introduce the different mechanisms involved in glioma progression,including tumor heterogeneity,the tumor microenvironment and drug resistance,and their pre-clinical implements in clinical trials.This review aimed to provide new insights into further clinical strategies for the treatment of patients with recurrent and secondary glioma.展开更多
Although the first-line rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone regimen(R-CHOP)substantially improved outcomes for patients with diffuse large B-cell lymphoma(DLBCL),40%of the patients s...Although the first-line rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone regimen(R-CHOP)substantially improved outcomes for patients with diffuse large B-cell lymphoma(DLBCL),40%of the patients suffered from relapsed/refractory disease and had poor survival outcomes.The detailed mechanism underlying R-CHOP resistance has not been well defined.For this review,we conducted a thorough search for literature and clinical trials involving DLBCL resistance.We discussed DLBCL biology,epigenetics,and aberrant signaling of the B-cell receptor(BCR),phosphatidylinositol 3-kinase(PI3K)/Akt,nuclear factor kappa light chain enhancer of activated B-cells(NF-κB),and the Janus kinase(JAK)/signal transducer and activator of transcription 3(STAT3)pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance.The cell of origin,double-or triple-hit lymphoma and double-protein-expression,clonal evolution,tumor microenvironment,and multi-drug resistance help to contextualize DLBCL resistance in an(epi)genetically and biologically comparative manner.With better understanding of the biological and molecular landscape of DLBCL,a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.展开更多
基金Research in the authors’laboratories was supported in part by research grants from the National Institutes of Health(CA226303 to TCH)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906 to TCH)the Natural Science Foundation of China(#30670811,#31171243,and#31420103915 to GR).
文摘As the most commonly occurring cancer in women worldwide,breast cancer poses a formidable public health challenge on a global scale.Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast.While the risk factors associated with this cancer varies with respect to other cancers,genetic predisposition,most notably mutations in BRCA1 or BRCA2 gene,is an important causative factor for this malignancy.Breast cancers can begin in different areas of the breast,such as the ducts,the lobules,or the tissue in between.Within the large group of diverse breast carcinomas,there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites.It is important to distinguish between the various subtypes because they have different prognoses and treatment implications.As there are remarkable parallels between normal development and breast cancer progression at the molecular level,it has been postulated that breast cancer may be derived from mammary cancer stem cells.Normal breast development and mammary stem cells are regulated by several signaling pathways,such as estrogen receptors(ERs),HER2,and Wnt/b-catenin signaling pathways,which control stem cell proliferation,cell death,cell differentiation,and cell motility.Furthermore,emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer,especially for triple-negative breast cancer.This review provides a comprehensive survey of the molecular,cellular and genetic aspects of breast cancer.
基金Supported by Shanghai Jiao Tong University Medical Engineering Cross Research Fund,No.YG2014MS59
文摘Gastric cancer(GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to understand the underlying mechanism of this resistance and to improve clinical outcome. It is well recognized that tumor heterogeneity, a fundamental feature of malignancy, plays an essential role in the cancer development and chemoresistance. The model of tumor-initiating cell(TIC) has been proposed to explain the genetic, histological, and phenotypical heterogeneity of GC. TIC accounts for a minor subpopulation of tumor cells with key characteristics including high tumorigenicity, maintenance of self-renewal potential, giving rise to both tumorigenic and non-tumorigenic cancer cells, and resistance to chemotherapy. Regarding tumor-initiating cell of GC(GATIC), substantial studies have been performed to(1) identify the putative specific cell markers for purification and functional validation of GATICs;(2) trace the origin of GATICs; and(3) decode the regulatory mechanism of GATICs. Furthermore, recent studies demonstrate the plasticity of GATIC and the interaction between GATIC and its surrounding factors(TIC niche or tumor microenvironment). All these investigations pave the way for the development of GATIC-targeted therapy, which is in the phase of preclinical studies and clinical trials. Here, we interpret the heterogeneity of GC from the perspectives of TIC by reviewing the above-mentioned fundamental and clinical studies of GATICs. Problems encountered during the GATIC investigations and the potential solutions are also discussed.
基金The authors received financial support from the National Natural Science Foundation of China(Grant Number:81772797)Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20172007)Ruijin Hospital,Shanghai Jiao Tong University School of Medicine“Guangci Excellent Youth Training Program”(GCQN-2017-A18)。
文摘Single-cell RNA sequencing(scRNA-seq)is a novel technology that allows transcriptomic analyses of individual cells.During the past decade,scRNA-seq sensitivity,accuracy,and efficiency have improved due to innovations including more sensitive,automated,and cost-effective single-cell isolation methods with higher throughput as well as ongoing technological development of scRNA-seq protocols.Among the variety of current approaches with distinct features,researchers can choose the most suitable method to carry out their research.By profiling single cells in a complex population mix,scRNA-seq presents great advantages over traditional sequencing methods in dissecting heterogeneity in cell populations hidden in bulk analysis and exploring rare cell types associated with tumorigenesis and metastasis.scRNA-seq studies in recent years in the field of breast cancer research have clustered breast cancer cell populations with different molecular subtypes to identify distinct populations that may correlate with poor prognosis and drug resistance.The technology has also been used to explain tumor microenvironment heterogeneity by identifying distinct immune cell subsets that may be associated with immunosurveillance and are potential immunotherapy targets.Moreover,scRNA-seq has diverse applications in breast cancer research besides exploring heterogeneity,including the analysis of cell-cell communications,regulatory single-cell states,immune cell distributions,and more.scRNA-seq is also a promising tool that can facilitate individualized therapy due to its ability to define cell subsets with potential treatment targets.Although scRNA-seq studies of therapeutic selection in breast cancer are currently limited,the application of this technology in this field is prospective.Joint efforts and original ideas are needed to better implement scRNA-seq technologies in breast cancer research to pave the way for individualized treatment management.This review provides a brief introduction on the currently available scRNA-seq approaches a
基金National Natural Science Foundation of China,Grant/Award Numbers:81602471,81672729,81972453,81972597Natural Science Foundation of Zhejiang Province,Grant/Award Numbers:LY19H160055,LY19H160059,LR22H160011+2 种基金Natural Science Foundation of Ningbo,Grant/Award Number:2019A610315Cixi Agricultural and Social Development Science and Technology Project,Grant/Award Number:CN2020006Zheng Shu Medical Elite Scholarship Fund。
文摘The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironment.Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors,generating exosomes,releasing nutrients,reshaping the extracellular matrix,and suppressing the function of immune cells.CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers.Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials.Here,we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer.We hope that summarizing CAFrelated studies from a historical perspective will help to accelerate the development of CAF-targeted therapeutic strategies for breast cancer.
基金supported by the research funding of the Medical University of Lodz(No.503/1-156-01/503-11-001).
文摘Hepatocellular carcinoma(HCC)is a liver cancer,highly heterogeneous both at the histopathological and molecular levels.It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways,including canonical WNT/β-catenin,AKT/mTOR,MAPK pathways as well as signaling associated with telomere maintenance,p53/cell cycle regulation,epigenetic modifiers,and oxidative stress.The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established,whereas in development and progression of HCC is extensively studied.Herein,we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development,acquisition of stemness features,metastasis,and resistance to treatment.We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC.We discuss the pivotal roles of CTNNB1 mutations,aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.
基金This study was funded by National Natural Science Foundation of China(Nos.81972337 and 81773208)Beijing Natural Science Foundation(No.JQ20030)+9 种基金Beijing Talents Foundation from Organization Department of Municipal Committee of the CPC(No.2017000021223ZK32)Beijing Nova Program(No.Z171100001117022)the National Key Research and Development Plan(No.2016YFC0902500)Beijing Science and Technology Plan (No.Z141100000214009)Capital Medical Development Research Fund(No.2016-1-1072)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(No.ZYLX201708)National Natural Science Foundation of China(NSFC)/Research Grants Council(RGC)Joint Research Scheme(No.81761168038 to Tao Jiang and No.N_HKUST606/17 to Jiguang Wang)Beijing Municipal Administration of Hospitals’Mission Plan(No.SML20180501)and Beijing Tiantan Hospital Young Scientist Program(No.YSP201701).Jiguang Wang was also supported by Collaborative Research Fund,Hong Kong(No.C6002-17GF)Hong Kong Epigenomics Project(No.LKCCFL18SC01-E)。
文摘Glioma is the most common lethal tumor of the human brain.The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months.The World Health Organization classification of tumors of the central nervous system categorized gliomas into lower-grade gliomas and glioblastomas.Unlike primary glioblastoma that usually develop de novo in the elderly,secondary glioblastoma enriched with an isocitrate dehydrogenase mutant typically progresses from lower-grade glioma within 5-10 years from the time of diagnosis.Based on various evolutional trajectories brought on by clonal and subclonal alterations,the evolution patterns of glioma vary according to different theories.Some important features distinguish the normal brain from other tissues,e.g.,the composition of the microenvironment around the tumor cells,the presence of the blood-brain barrier,and others.The underlying mechanism of glioma recurrence and evolution patterns of glioma are different from those of other types of cancer.Several studies correlated tumor recurrence with tumor heterogeneity and the immune microenvironment.However,the detailed reasons for the progression and recurrence of glioma remain controversial.In this review,we introduce the different mechanisms involved in glioma progression,including tumor heterogeneity,the tumor microenvironment and drug resistance,and their pre-clinical implements in clinical trials.This review aimed to provide new insights into further clinical strategies for the treatment of patients with recurrent and secondary glioma.
文摘Although the first-line rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone regimen(R-CHOP)substantially improved outcomes for patients with diffuse large B-cell lymphoma(DLBCL),40%of the patients suffered from relapsed/refractory disease and had poor survival outcomes.The detailed mechanism underlying R-CHOP resistance has not been well defined.For this review,we conducted a thorough search for literature and clinical trials involving DLBCL resistance.We discussed DLBCL biology,epigenetics,and aberrant signaling of the B-cell receptor(BCR),phosphatidylinositol 3-kinase(PI3K)/Akt,nuclear factor kappa light chain enhancer of activated B-cells(NF-κB),and the Janus kinase(JAK)/signal transducer and activator of transcription 3(STAT3)pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance.The cell of origin,double-or triple-hit lymphoma and double-protein-expression,clonal evolution,tumor microenvironment,and multi-drug resistance help to contextualize DLBCL resistance in an(epi)genetically and biologically comparative manner.With better understanding of the biological and molecular landscape of DLBCL,a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.
