In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long non...In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.展开更多
Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses.While many pivotal advances have been made in first combination therapies,then targeted therapies,and now broadening...Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses.While many pivotal advances have been made in first combination therapies,then targeted therapies,and now broadening out to immunomodulatory drugs or metabolic targeting compounds,drug resistance is still ultimately universally fatal.In this brief review,we will discuss different strategies that have been used to fight drug resistance from synthetic lethality to tumor microenvironment modulation,focusing on the DNA damage response and tumor metabolism both within tumor cells and their surrounding microenvironment.In this way,with a better understanding of both targetable mutations in combination with the metabolism,smarter drugs may be designed to combat cancer drug resistance.展开更多
Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other factors.Str...Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other factors.Stromal cells can adopt new phenotypes to promote tumor cell invasion.Adeep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions.In this review,we describe the tumor microenvironment(TME)components and associated therapeutics.We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME,the immune checkpoints and immunosuppressive chemokines,and currently used inhibitors targeting these pathways.These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME:protein kinase C(PKC)signaling,Notch,and transforming growth factor(TGF-β)signaling,Endoplasmic Reticulum(ER)stress response,lactate signaling,Metabolic reprogramming,cyclic GMP–AMP synthase(cGAS)–stimulator of interferon genes(STING)and Siglec signaling pathways.We also discuss the recent advances in Programmed Cell Death Protein 1(PD-1),Cytotoxic T-Lymphocyte Associated Protein 4(CTLA4),T-cell immunoglobulin mucin-3(TIM-3)and Lymphocyte Activating Gene 3(LAG3)immune checkpoint inhibitors along with the C-C chemokine receptor 4(CCR4)-C-C class chemokines 22(CCL22)/and 17(CCL17),C-C chemokine receptor type 2(CCR2)-chemokine(C-Cmotif)ligand 2(CCL2),C-C chemokine receptor type 5(CCR5)-chemokine(C-C motif)ligand 3(CCL3)chemokine signaling axis in the TME.In addition,this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME,which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies.We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response.Overall,this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME,highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology.We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors,such as the inhabitant human microbiome,which have the potential to modulate TME biology and drug responses.展开更多
基金supported in part by grants from the US NIH grant CA130966, CA158911 to S. Y. Chengthe Zell Scholar Award from the Zell Family Foundation and funds from Northwestern Brain Tumor Institute and Department of Neurology at Northwestern University Feinberg School of Medicine to S. Y. Chengthe Brain Cancer Research Award from the James S. McDonnell Foundation to B. Hu
文摘In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.
文摘Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses.While many pivotal advances have been made in first combination therapies,then targeted therapies,and now broadening out to immunomodulatory drugs or metabolic targeting compounds,drug resistance is still ultimately universally fatal.In this brief review,we will discuss different strategies that have been used to fight drug resistance from synthetic lethality to tumor microenvironment modulation,focusing on the DNA damage response and tumor metabolism both within tumor cells and their surrounding microenvironment.In this way,with a better understanding of both targetable mutations in combination with the metabolism,smarter drugs may be designed to combat cancer drug resistance.
基金National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT),Grant/Award Number:NRF-2022R1A2C2005057。
文摘Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other factors.Stromal cells can adopt new phenotypes to promote tumor cell invasion.Adeep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions.In this review,we describe the tumor microenvironment(TME)components and associated therapeutics.We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME,the immune checkpoints and immunosuppressive chemokines,and currently used inhibitors targeting these pathways.These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME:protein kinase C(PKC)signaling,Notch,and transforming growth factor(TGF-β)signaling,Endoplasmic Reticulum(ER)stress response,lactate signaling,Metabolic reprogramming,cyclic GMP–AMP synthase(cGAS)–stimulator of interferon genes(STING)and Siglec signaling pathways.We also discuss the recent advances in Programmed Cell Death Protein 1(PD-1),Cytotoxic T-Lymphocyte Associated Protein 4(CTLA4),T-cell immunoglobulin mucin-3(TIM-3)and Lymphocyte Activating Gene 3(LAG3)immune checkpoint inhibitors along with the C-C chemokine receptor 4(CCR4)-C-C class chemokines 22(CCL22)/and 17(CCL17),C-C chemokine receptor type 2(CCR2)-chemokine(C-Cmotif)ligand 2(CCL2),C-C chemokine receptor type 5(CCR5)-chemokine(C-C motif)ligand 3(CCL3)chemokine signaling axis in the TME.In addition,this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME,which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies.We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response.Overall,this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME,highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology.We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors,such as the inhabitant human microbiome,which have the potential to modulate TME biology and drug responses.