Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory...Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.展开更多
AIM: To investigate insulin-like growth factor 2 (IGF2) differentially methylated region (DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.
The tumor microenvironment represents a dynamic and multifaceted milieu characterized by the complex interactions of diverse cellular and non-cellular constituents.1,2 These constituents include tumor cells,microorgan...The tumor microenvironment represents a dynamic and multifaceted milieu characterized by the complex interactions of diverse cellular and non-cellular constituents.1,2 These constituents include tumor cells,microorganisms,immune and other stromal cells,and extracellular matrices.The orchestration of these components intricately contributes to tumor evolution and shapes responses to cancer treatment(Figure 1).A better understanding of the tumor microenvironment is critical to elucidate the etiology of cancer and develop more efficient therapeutic strategies.展开更多
基金Supported by grant from United States National Institute of Health(NIH),No.P01 CA87969(to SE Hankinson),No.UM1 CA167552,and No.P01 CA55075(to WC Willett),No.R01 CA137178(to AT Chan),No.P50 CA127003(to CS Fuchs),No.R01 CA151993(to S Ogino)Bennett Family Fund for Targeted Therapies ResearchEntertainment Industry Foundation through National Colorectal Cancer Research Alliance
文摘Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.
基金Supported by The Japan Society for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research,grant No.23790800(to Nosho K)and 23390200(to Shinomura Y)A-STEP(Adaptable and Seamless Technology Transfer Program through Targetdriven R and D)(to Nosho K)+4 种基金Daiwa Securities Health Foundation(to Nosho K)Kobayashi Foundation for Cancer Research(to Nosho K)Sagawa Foundation for Promotion of Cancer Research(to Nosho K)Suzuken Memorial Foundation(to Nosho K),and Takeda Science Foundation(to Nosho K)USA National Institute of Health,grant number R01 CA151993(to Ogino S)
文摘AIM: To investigate insulin-like growth factor 2 (IGF2) differentially methylated region (DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.
基金supported in part by the Cancer Research UK Cancer Grand Challenge Award(6340201/A27140)NIH grant(R01 CA248857)+1 种基金T.U.was supported by NIH grant R50 CA27412a Brigham and Women’s Hospital Faculty Career Development Award,an Investigator Initiated Grant from the American Institute for Cancer Research(AICR),a Prevent Cancer Foundation Fellowship,and the Harvey V.Fineberg Fellowship in Cancer Prevention from Harvard T.H.Chan School of Public Health.S.U.was supported by a grant from the Uehara Memorial Foundation.S.O.is an American Cancer Society Clinical Research Professor。
文摘The tumor microenvironment represents a dynamic and multifaceted milieu characterized by the complex interactions of diverse cellular and non-cellular constituents.1,2 These constituents include tumor cells,microorganisms,immune and other stromal cells,and extracellular matrices.The orchestration of these components intricately contributes to tumor evolution and shapes responses to cancer treatment(Figure 1).A better understanding of the tumor microenvironment is critical to elucidate the etiology of cancer and develop more efficient therapeutic strategies.
