The aim of this study is to assess the effects of DNA methylation and historic acetylation, alone or in combination, on the expression of several tumor-associated genes and cell cycle progression in two established hu...The aim of this study is to assess the effects of DNA methylation and historic acetylation, alone or in combination, on the expression of several tumor-associated genes and cell cycle progression in two established human colon cancer cell lines: Colo-320 and SW1116. Treatments with 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin A, alone or in combination, were applied respectively. The methylation status of the CDKN2A promoter was determined by methyla-tion-specific PCR, and the acetylated status of the histones associated with the p21WAF1 and CDKN2A genes was examined by chromatin immunoprecipitation. The expression of the CDKN2A, p21WAF1, p53, p73, APC, c-myc, c-Ki-ras and survivin genes was detected by real-time RT-PCR and RT-PCR. The cell cycle profile was established by flow cytometry. We found that along with the demethylation of the CDKN2A gene promoter in both cell lines induced by 5-aza-dC alone or in combination with TSA, the expression of both CDKN2A and APC genes increased. The treatment of TSA or sodium butyrate up-regulated the transcription of p21WAF1 significantly by inducing the acetylation of histones H4 and H3, but failed to alter the acetylation level of CDKN2A-associated histones. No changes in transcription of p53, p73, c-myc, c-Ki-ras and survivin genes were observed. In addition, TSA or sodium butyrate was shown to arrest cells at the G1 phase. However, 5-aza-dC was not able to affect the cell cycle progression. In conclusion, regulation by epigenetic modification of the transcription of tumor-associated genes and the cell cycle progression in both human colon cancer cell lines Colo-320 and SW1116 is gene-specific.展开更多
Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are p...Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression,and targeting TAMs has become one of the most favored immunotherapy strategies.In addition,macrophages and liver cancer cells have distinct origins.At the early stage of liver cancer,macrophages can provide a niche for the maintenance of liver cancer stem cells.In contrast,cancer stem cells(CSCs)or poorly differentiated tumor cells are key factors modulating macrophage activation.In the present review,we first propose the origin connection between precursor macrophages and liver cancer cells.Macrophages undergo dynamic phenotypic transition during carcinogenesis.In this course of such transition,it is critical to determine the appropriate timing for therapy and block specific markers to suppress protumoral TAMs.The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews.Complex crosstalk occurs between TAMs and liver cancer cells.TAMs play indispensable roles in tumor progression,angiogenesis,and autophagy due to their heterogeneity and robust plasticity.In addition,macrophages in the TME interact with other immune cells by directing cell-to-cell contact or secreting various effector molecules.Similarly,tumor cells combined with other immune cells can drive macrophage recruitment and polarization.Despite the latest achievements and the advancements in treatment strategies following TAMs studies,comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking.In this review,we discussed the interactions between TAMs and liver cancer cells(from cell origin to maturation),the latest therapeutic strategies(including chimeric antigen receptor macrophages),and critical clinical trials for hepatocellular carcinoma(HCC)and intr展开更多
Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pall...Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pallas, can inhibit tumor growth and lung metastases of Lewis lung tumor-bearing mice. This study tried to investigate whether paeoniflorin inhibited lung cancer metastasis by inhibiting the alternative activation of macrophages(M2 macrophage). Using a viability assay, the cytotoxicity of paeoniflorin on Lewis lung cancer cells and peritoneal macrophages were investigated. In vitro scratch wound and in vivo lung metastasis experiments were used to test the ability to inhibit the migration of paeoniflorin and the function of M2 macrophages. Flow cytometry was performed to test the cell cycle of Lewis lung cancer cells, and to test the M2 macrophages in peritoneal macrophages and subcutaneous transplantable tumor. It was found that paeoniflorin showed no inhibitory effect on the growth of Lewis lung cancer cells and peritoneal macrophages of mouse in vitro. Paeoniflorin could attenuate the migration of LLC stimulated by alternatively activated macrophages(stimulated for 24 h and 48 h, paeoniflorin 1, 3, 10, 30, 100 μmol·L-1, P < 0.01 or P < 0.05 vs control group). Paeoniflorin could decrease the cell populations at S phases(paeoniflorin 10, 30, 100 μmol·L-1, P < 0.05 vs control group) and increase the cell populations at G0-G1 phases of Lewis lung cancer cells(paeoniflorin 100 μmol·L-1, P < 0.05 vs control group) and reduce the numbers of M2 macrophages in peritoneal macrophages induced by IL-4(paeoniflorin 1, 3, 10, 30, 100 μmol·L-1, P < 0.01 vs Control group). Paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft and decrease the numbers of M2 macrophages in subcutaneous xenograft tumour in vivo(paeoniflorin 20, 40 mg·kg-1, P < 0.01 vs control group). These results suggest that paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft partly through 展开更多
Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hemat...Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer.Data sources: The data on CAR-T therapy related to liver cancers were collected by searching Pub Med and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor","CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching Clinical Trials.gov.Results: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied.Conclusions: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we ar展开更多
Although intestinal microbiome have been established as an important biomarker and regulator of cancer development and therapeutic response, less is known about the role of microbiome at other body sites in cancer. Em...Although intestinal microbiome have been established as an important biomarker and regulator of cancer development and therapeutic response, less is known about the role of microbiome at other body sites in cancer. Emerging evidence has revealed that the local microbiota make up an important part of the tumor microenvironment across many types of cancer, especially in cancers arising from mucosal sites, including the lung, skin and gastrointestinal tract. The populations of bacteria that reside specifically within tumors have been found to be tumor-type specific, and mechanistic studies have demonstrated that tumor-associated microbiota may directly regulate cancer initiation, progression and responses to chemo- or immuno-therapies. This review aims to provide a comprehensive review of the important literature on the microbiota in the cancerous tissue, and their function and mechanism of action in cancer development and treatment.展开更多
Macrophages have a leading position in the tumor microenvironment(TME)which paves the way to carcinogenesis.Initially,monocytes and macrophages are recruited to the sites where the tumor develops.Under the guidance of...Macrophages have a leading position in the tumor microenvironment(TME)which paves the way to carcinogenesis.Initially,monocytes and macrophages are recruited to the sites where the tumor develops.Under the guidance of different microenvironmental signals,macrophages would polarize into two functional phenotypes,named as classically activated macrophages(M1)and alternatively activated macrophages(M2).Contrary to the anti-tumor effect of M1,M2 exerts anti-inflammatory and tumorigenic characters.In progressive tumor,M2 tumor-associated macrophages(TAMs)are in the majority,being vital regulators reacting upon TME.This review elaborates on the role of TAMs in tumor progression.Furthermore,prospective macrophage-focused therapeutic strategies,including drugs not only in clinical trials but also at primary research stages,are summarized followed by a discussion about their clinical application values.Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.展开更多
基金This work was supported in part by National Natural Science Foundation of China(No.30170413)the Foundation for Jing Yuan FANG of National Excellent Doctoral Dissertation of China(No.199946)the Foundation of Shanghai Education Committee(Shuguang Plan,No.02SG45).
文摘The aim of this study is to assess the effects of DNA methylation and historic acetylation, alone or in combination, on the expression of several tumor-associated genes and cell cycle progression in two established human colon cancer cell lines: Colo-320 and SW1116. Treatments with 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin A, alone or in combination, were applied respectively. The methylation status of the CDKN2A promoter was determined by methyla-tion-specific PCR, and the acetylated status of the histones associated with the p21WAF1 and CDKN2A genes was examined by chromatin immunoprecipitation. The expression of the CDKN2A, p21WAF1, p53, p73, APC, c-myc, c-Ki-ras and survivin genes was detected by real-time RT-PCR and RT-PCR. The cell cycle profile was established by flow cytometry. We found that along with the demethylation of the CDKN2A gene promoter in both cell lines induced by 5-aza-dC alone or in combination with TSA, the expression of both CDKN2A and APC genes increased. The treatment of TSA or sodium butyrate up-regulated the transcription of p21WAF1 significantly by inducing the acetylation of histones H4 and H3, but failed to alter the acetylation level of CDKN2A-associated histones. No changes in transcription of p53, p73, c-myc, c-Ki-ras and survivin genes were observed. In addition, TSA or sodium butyrate was shown to arrest cells at the G1 phase. However, 5-aza-dC was not able to affect the cell cycle progression. In conclusion, regulation by epigenetic modification of the transcription of tumor-associated genes and the cell cycle progression in both human colon cancer cell lines Colo-320 and SW1116 is gene-specific.
基金National Natural Science Foundation of China,Grant/Award Numbers:8187111473,8217113337。
文摘Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression,and targeting TAMs has become one of the most favored immunotherapy strategies.In addition,macrophages and liver cancer cells have distinct origins.At the early stage of liver cancer,macrophages can provide a niche for the maintenance of liver cancer stem cells.In contrast,cancer stem cells(CSCs)or poorly differentiated tumor cells are key factors modulating macrophage activation.In the present review,we first propose the origin connection between precursor macrophages and liver cancer cells.Macrophages undergo dynamic phenotypic transition during carcinogenesis.In this course of such transition,it is critical to determine the appropriate timing for therapy and block specific markers to suppress protumoral TAMs.The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews.Complex crosstalk occurs between TAMs and liver cancer cells.TAMs play indispensable roles in tumor progression,angiogenesis,and autophagy due to their heterogeneity and robust plasticity.In addition,macrophages in the TME interact with other immune cells by directing cell-to-cell contact or secreting various effector molecules.Similarly,tumor cells combined with other immune cells can drive macrophage recruitment and polarization.Despite the latest achievements and the advancements in treatment strategies following TAMs studies,comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking.In this review,we discussed the interactions between TAMs and liver cancer cells(from cell origin to maturation),the latest therapeutic strategies(including chimeric antigen receptor macrophages),and critical clinical trials for hepatocellular carcinoma(HCC)and intr
基金supported by National Natural Science Foundation of China(No.81503284)Fundamental Research Funds for the Central Universities(No.2015PY016)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)
文摘Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pallas, can inhibit tumor growth and lung metastases of Lewis lung tumor-bearing mice. This study tried to investigate whether paeoniflorin inhibited lung cancer metastasis by inhibiting the alternative activation of macrophages(M2 macrophage). Using a viability assay, the cytotoxicity of paeoniflorin on Lewis lung cancer cells and peritoneal macrophages were investigated. In vitro scratch wound and in vivo lung metastasis experiments were used to test the ability to inhibit the migration of paeoniflorin and the function of M2 macrophages. Flow cytometry was performed to test the cell cycle of Lewis lung cancer cells, and to test the M2 macrophages in peritoneal macrophages and subcutaneous transplantable tumor. It was found that paeoniflorin showed no inhibitory effect on the growth of Lewis lung cancer cells and peritoneal macrophages of mouse in vitro. Paeoniflorin could attenuate the migration of LLC stimulated by alternatively activated macrophages(stimulated for 24 h and 48 h, paeoniflorin 1, 3, 10, 30, 100 μmol·L-1, P < 0.01 or P < 0.05 vs control group). Paeoniflorin could decrease the cell populations at S phases(paeoniflorin 10, 30, 100 μmol·L-1, P < 0.05 vs control group) and increase the cell populations at G0-G1 phases of Lewis lung cancer cells(paeoniflorin 100 μmol·L-1, P < 0.05 vs control group) and reduce the numbers of M2 macrophages in peritoneal macrophages induced by IL-4(paeoniflorin 1, 3, 10, 30, 100 μmol·L-1, P < 0.01 vs Control group). Paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft and decrease the numbers of M2 macrophages in subcutaneous xenograft tumour in vivo(paeoniflorin 20, 40 mg·kg-1, P < 0.01 vs control group). These results suggest that paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft partly through
文摘Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer.Data sources: The data on CAR-T therapy related to liver cancers were collected by searching Pub Med and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor","CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching Clinical Trials.gov.Results: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied.Conclusions: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we ar
基金Figures are created with BioRender.C.J.is supported in part by a R00 Award from NIH/NCI(CA226400)an Emerson Collective Cancer Research Fund,and a Lung Cancer Research Foundation(LCRF)Pilot Grant.C.Z.is supported in part by the Intramural Research Program of the NIH,National Cancer Institute,Center for Cancer Research,SITC-AstraZeneca Immunotherapy in Lung Cancer(Early Stage NSCLC)Clinical Fellowship Award.
文摘Although intestinal microbiome have been established as an important biomarker and regulator of cancer development and therapeutic response, less is known about the role of microbiome at other body sites in cancer. Emerging evidence has revealed that the local microbiota make up an important part of the tumor microenvironment across many types of cancer, especially in cancers arising from mucosal sites, including the lung, skin and gastrointestinal tract. The populations of bacteria that reside specifically within tumors have been found to be tumor-type specific, and mechanistic studies have demonstrated that tumor-associated microbiota may directly regulate cancer initiation, progression and responses to chemo- or immuno-therapies. This review aims to provide a comprehensive review of the important literature on the microbiota in the cancerous tissue, and their function and mechanism of action in cancer development and treatment.
基金supported by the National Natural Science Foundation of China(Nos.81673022,81572952 and 81373346)National Key R&D Program of China(No.2017YFE0102200)
文摘Macrophages have a leading position in the tumor microenvironment(TME)which paves the way to carcinogenesis.Initially,monocytes and macrophages are recruited to the sites where the tumor develops.Under the guidance of different microenvironmental signals,macrophages would polarize into two functional phenotypes,named as classically activated macrophages(M1)and alternatively activated macrophages(M2).Contrary to the anti-tumor effect of M1,M2 exerts anti-inflammatory and tumorigenic characters.In progressive tumor,M2 tumor-associated macrophages(TAMs)are in the majority,being vital regulators reacting upon TME.This review elaborates on the role of TAMs in tumor progression.Furthermore,prospective macrophage-focused therapeutic strategies,including drugs not only in clinical trials but also at primary research stages,are summarized followed by a discussion about their clinical application values.Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.
