Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen se...Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases.Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis,while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix(ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.展开更多
Objective： To investigate the antitumor effect of endostatin combined with tumor antigen-pulsed dendritic cell （DC）-T cell therapy on lung cancer. Methods： Transplanted Lewis lung cancer （LLC） models of C57BL/6 ...Objective： To investigate the antitumor effect of endostatin combined with tumor antigen-pulsed dendritic cell （DC）-T cell therapy on lung cancer. Methods： Transplanted Lewis lung cancer （LLC） models of C57BL/6 mice were established by subcutaneous injection of LLC cells in left extremity axillary. Tumor antigen-pulsed DC-T cells from spleen cells and bone of mice were cultured in vitro. Tumor-bearing mice were randomly divided into three groups, including DC- T＋endostatin group, DC-T group, and phosphate-buffered saline （PBS） control group. Microvessel density （MVD） of tumor tissue in tumor-bearing mice was determined by immunohistochemistry （IHC）. The expressions of vascular endothelial growth factor （VEGF） and hypoxia-inducible factor-1α （HIF-1α） were determined by Western blotting and IHC staining. The proportions of CD8＋ T cells, mature dendritic cells （mDC）, tumor-associated macrophages [TAM （M1/M2）], and myeloid-derived suppressor cells （MDSC） in suspended cells of tumor tissue were determined by flow cytometry. The expressions of inter｜eukin （IL）-6, IL-10, IL-17, transforming growth factor-β（TGF-β） and interferon-γ （IFN-γ） in suspended cells of tumor tissue were detected by enzyme-linked immune sorbent assay （ELISA）. Results： DC-T cells combined with endostatin remarkably suppressed tumor growth. MVD of mice in DC- T＋endostatin group was significantly lower than that of the control group and DC-T monotherapy group. The expressions of VEGF, IL-6 and IL-17 in tumors were markedly decreased, but IFN-γ, and HIF-1α increased after treating with DC-T cells combined with endostatin, compared to control group and DC-T group. In the DC- T＋endostatin group, the proportions of MDSC and TAM （M2 type） were significantly decreased, mDC and TAM （Nil type） were up-regulated, and CD8＋ T cells were recruited to infiltrate tumors, in contrast to PBS control and DC-T monotherapy. DC-T cells combined with endostatin potently reduced the 展开更多
Exosomes carry and transmit signaling molecules used for intercellular communication.The generation and secretion of exosomes is a multistep interlocking process that allows simultaneous control of multiple regulatory...Exosomes carry and transmit signaling molecules used for intercellular communication.The generation and secretion of exosomes is a multistep interlocking process that allows simultaneous control of multiple regulatory sites.Protein molecules,mainly RAB GTPases,cytoskeletal proteins and soluble N-ethylmaleimide-sensitive fusion attachment protein receptor(SNARE),are specifically regulated in response to pathological conditions such as altered cellular microenvironment,stimulation by pathogenic factors,or gene mutation.This interferes with the smooth functioning of endocytosis,translocation,degradation,docking and fusion processes,leading to changes in the secretion of exosomes.Large numbers of secreted exosomes are disseminated by the flow of body fluids and absorbed by the recipient cells.By transmitting characteristic functional proteins and genetic information produced under disease conditions,exosomes can change the physiological state of the recipient cells and their microenvironment.The microenvironment,in turn,affects the occurrence and development of disease.Therefore,this review will discuss the mechanism by which exosome secretion is regulated in cells following the formation of mature secretory multivesicular bodies(MVBs).The overall aim is to find ways to eliminate disease-derived exosomes at their source,thereby providing an important new basis for the clinical treatment of disease.展开更多
There are few tumor cell subpopulations with stem cell characteristics in tumor tis-sue,defined as cancer stem cells(CSCs)or cancer stem-like cells(CSLCs),which can recon-struct neoplasms with malignant biological beh...There are few tumor cell subpopulations with stem cell characteristics in tumor tis-sue,defined as cancer stem cells(CSCs)or cancer stem-like cells(CSLCs),which can recon-struct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation.The microenvironment that CsCs depend on consists of various cellular components and corresponding medium components.Among these factors existing at a variety of levels and forms,cytokine networks and numerous signal pathways play an important role in signaling transduction.These factors promote or maintain cancer cell stem-ness,and participate in cancer recurrence,metastasis,and resistance.This review aims to summarize the recent molecular data concerning the multilayered relationship between CsCs and CsC-favorable microenvironments.We also discuss the therapeutic implications of target-ing this synergistic interplay,hoping to give an insight into targeting cancer cell stemness for tumortherapyandprognosis.展开更多
Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy.Lipid nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonst...Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy.Lipid nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonstrated efficacy in human use during the COVID-19 pandemic.This study introduces a novel biomaterial-based platform,M1-polarized macrophage-derived cellular nanovesicle-coated LNPs(M1-C-LNPs),specifically engineered for a combined gene-immunotherapy approach against solid tumor.The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles(M1-NVs),effectively facilitating apoptosis in cancer cells without impacting T and NK cells,which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication.Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs,owing to the presence of adhesion molecules on M1-NVs,thereby contributing to superior tumor growth inhibition.These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy,with significant implications for advancing biomaterial use in cancer therapeutics.展开更多
基金supported by funding from Cancer Prevention & Research Institute of Texas (CPRIT, RR140012)V Foundation (V2015-2022)+1 种基金Sabin Family Foundation Fellowship at MD Anderson (2016-00052285)generous support from the McNair Foundation
文摘Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases.Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis,while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix(ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.
基金supported by Natural Science Foundation of Shandong province,China(No.ZR2010HL015)Natural Science Youth Foundation of Shandong province,China(No.ZR2013HQ017)
文摘Objective： To investigate the antitumor effect of endostatin combined with tumor antigen-pulsed dendritic cell （DC）-T cell therapy on lung cancer. Methods： Transplanted Lewis lung cancer （LLC） models of C57BL/6 mice were established by subcutaneous injection of LLC cells in left extremity axillary. Tumor antigen-pulsed DC-T cells from spleen cells and bone of mice were cultured in vitro. Tumor-bearing mice were randomly divided into three groups, including DC- T＋endostatin group, DC-T group, and phosphate-buffered saline （PBS） control group. Microvessel density （MVD） of tumor tissue in tumor-bearing mice was determined by immunohistochemistry （IHC）. The expressions of vascular endothelial growth factor （VEGF） and hypoxia-inducible factor-1α （HIF-1α） were determined by Western blotting and IHC staining. The proportions of CD8＋ T cells, mature dendritic cells （mDC）, tumor-associated macrophages [TAM （M1/M2）], and myeloid-derived suppressor cells （MDSC） in suspended cells of tumor tissue were determined by flow cytometry. The expressions of inter｜eukin （IL）-6, IL-10, IL-17, transforming growth factor-β（TGF-β） and interferon-γ （IFN-γ） in suspended cells of tumor tissue were detected by enzyme-linked immune sorbent assay （ELISA）. Results： DC-T cells combined with endostatin remarkably suppressed tumor growth. MVD of mice in DC- T＋endostatin group was significantly lower than that of the control group and DC-T monotherapy group. The expressions of VEGF, IL-6 and IL-17 in tumors were markedly decreased, but IFN-γ, and HIF-1α increased after treating with DC-T cells combined with endostatin, compared to control group and DC-T group. In the DC- T＋endostatin group, the proportions of MDSC and TAM （M2 type） were significantly decreased, mDC and TAM （Nil type） were up-regulated, and CD8＋ T cells were recruited to infiltrate tumors, in contrast to PBS control and DC-T monotherapy. DC-T cells combined with endostatin potently reduced the
基金supported by grants from Natural Science Foundation of Jiangsu Province,China(No.BK20211105)the Key Research and Development Plan of Jiangsu Province,China(No.BE2019692)+2 种基金the Health Project of Jiangsu Province,China(No.H2019072)the Social Development Foundation of Nantong City,China(No.MS22020005,JCZ21061,MSZ20076 and JCZ20065)the Postgraduate Research&Practice Innovation Program of Jiangsu Province,China(No.KYCX20_2673,KYCX20_2681 and KYCX21_3112).
文摘Exosomes carry and transmit signaling molecules used for intercellular communication.The generation and secretion of exosomes is a multistep interlocking process that allows simultaneous control of multiple regulatory sites.Protein molecules,mainly RAB GTPases,cytoskeletal proteins and soluble N-ethylmaleimide-sensitive fusion attachment protein receptor(SNARE),are specifically regulated in response to pathological conditions such as altered cellular microenvironment,stimulation by pathogenic factors,or gene mutation.This interferes with the smooth functioning of endocytosis,translocation,degradation,docking and fusion processes,leading to changes in the secretion of exosomes.Large numbers of secreted exosomes are disseminated by the flow of body fluids and absorbed by the recipient cells.By transmitting characteristic functional proteins and genetic information produced under disease conditions,exosomes can change the physiological state of the recipient cells and their microenvironment.The microenvironment,in turn,affects the occurrence and development of disease.Therefore,this review will discuss the mechanism by which exosome secretion is regulated in cells following the formation of mature secretory multivesicular bodies(MVBs).The overall aim is to find ways to eliminate disease-derived exosomes at their source,thereby providing an important new basis for the clinical treatment of disease.
基金supported by the National Natural Science Foundation of China(No.82173842,82204432)the Medical Science and Technology Research Project of Henan Province,China(No.SBGJ202003010)+1 种基金the Henan Province Science and Technology Research Project(No.222102310414)the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions(China).
文摘There are few tumor cell subpopulations with stem cell characteristics in tumor tis-sue,defined as cancer stem cells(CSCs)or cancer stem-like cells(CSLCs),which can recon-struct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation.The microenvironment that CsCs depend on consists of various cellular components and corresponding medium components.Among these factors existing at a variety of levels and forms,cytokine networks and numerous signal pathways play an important role in signaling transduction.These factors promote or maintain cancer cell stem-ness,and participate in cancer recurrence,metastasis,and resistance.This review aims to summarize the recent molecular data concerning the multilayered relationship between CsCs and CsC-favorable microenvironments.We also discuss the therapeutic implications of target-ing this synergistic interplay,hoping to give an insight into targeting cancer cell stemness for tumortherapyandprognosis.
基金supported by a Basic Science Research Program grant through the National Research Foundation of Korea(NRF)grants(Nos.2021R1A2C4001776,RS-2023-00218648,RS-2023-00242443,and 2023-00208913)of the Republic of Koreafunded by the Ministry of Science and ICT(MSIT)of the Republic of Korea+2 种基金a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(No.RS-2023-00266015)the KIST Institutional Program(No.2E32351-23-130)of the Republic of Korea.
文摘Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy.Lipid nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonstrated efficacy in human use during the COVID-19 pandemic.This study introduces a novel biomaterial-based platform,M1-polarized macrophage-derived cellular nanovesicle-coated LNPs(M1-C-LNPs),specifically engineered for a combined gene-immunotherapy approach against solid tumor.The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles(M1-NVs),effectively facilitating apoptosis in cancer cells without impacting T and NK cells,which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication.Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs,owing to the presence of adhesion molecules on M1-NVs,thereby contributing to superior tumor growth inhibition.These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy,with significant implications for advancing biomaterial use in cancer therapeutics.
