Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 58
Filter
1.
Exp Hematol Oncol ; 13(1): 20, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38388466

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. METHODS: In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. RESULTS: We defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. CONCLUSIONS: Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.

2.
Med ; 4(10): 728-743.e7, 2023 Oct 13.
Article in English | MEDLINE | ID: mdl-37633269

ABSTRACT

BACKGROUND: Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive. METHODS: Twenty-six samples from 11 patients (including 11 primary tumor tissues, 10 blood, and 5 lymph nodes) with different stages were used to develop a multiscale immune profile. High-dimensional single-cell analysis with mass cytometry was performed to search for metastasis-correlated immune changes in the microenvironment. The findings were further validated by published single-cell RNA sequencing (scRNA-seq) data and multiplex fluorescent immunohistochemistry. FINDINGS: High-dimensional single-cell profiling revealed that the three immune-relevant sites formed a distinct immune atlas. Interestingly, the PDAC microenvironment with the potential for metastatic spread to the liver was characterized by a decreased proportion of CD103+PD-1+CD39+ T cells with cytotoxic and exhausted functional status and an increased proportion of CD73+ macrophages. Analysis of scRNA-seq data of PDAC further confirmed the identified subsets and revealed strong potential interactions via various ligand-receptor pairs between the identified T subsets and the macrophages. Moreover, stratified patients with different immune compositions correlated with clinical outcomes of PDAC. CONCLUSIONS: Our study uncovered metastasis-correlated immune changes, suggesting that ecosystem-based patient classification in PDAC will facilitate the identification of candidates likely to benefit from immunotherapy. FUNDING: This work was supported by the National Key Research and Development Program of China, the Shanghai International Science and Technology Collaboration Program, the Shanghai Sailing Program, and the Key Laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of Zhejiang Province.


Subject(s)
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Pancreatic Neoplasms , Humans , Ecosystem , China , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/drug therapy , Tumor Microenvironment , Pancreatic Neoplasms
3.
Cell Rep ; 42(7): 112666, 2023 07 25.
Article in English | MEDLINE | ID: mdl-37347667

ABSTRACT

Protein lysine crotonylation has been recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism, and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation, which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in pancreatic cancer progression.


Subject(s)
Lysine , Pancreatic Neoplasms , Humans , Lysine/metabolism , Histones/metabolism , Glycolysis , Protein Processing, Post-Translational
4.
Stem Cell Res Ther ; 13(1): 233, 2022 06 03.
Article in English | MEDLINE | ID: mdl-35659296

ABSTRACT

Distinct regions harboring cancer stem cells (CSCs) have been identified within the microenvironment of various tumors, and as in the case of their healthy counterparts, these anatomical regions are termed "niche." Thus far, a large volume of studies have shown that CSC niches take part in the maintenance, regulation of renewal, differentiation and plasticity of CSCs. In this review, we summarize and discuss the latest findings regarding CSC niche morphology, physical terrain, main signaling pathways and interactions within them. The cellular and molecular components of CSCs also involve genetic and epigenetic modulations that mediate and support their maintenance, ultimately leading to cancer progression. It suggests that the crosstalk between CSCs and their niche plays an important role regarding therapy resistance and recurrence. In addition, we updated diverse therapeutic strategies in different cancers in basic research and clinical trials in this review. Understanding the complex heterogeneity of CSC niches is a necessary pre-requisite for designing superior therapeutic strategies to target CSC-specific factors and/or components of the CSC niche.


Subject(s)
Neoplasms , Tumor Microenvironment , Humans , Neoplasms/metabolism , Neoplasms/therapy , Neoplastic Stem Cells/metabolism , Signal Transduction , Stem Cell Niche/genetics
5.
Cell Mol Immunol ; 19(6): 726-737, 2022 06.
Article in English | MEDLINE | ID: mdl-35459855

ABSTRACT

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) or its ligand 1 (PD-L1) antibody, in hepatocellular carcinoma (HCC) is limited, and it is recommended that they be combined with other therapies. We evaluated the combination of pegylated interferon-α (Peg-IFNα) with PD-1 blockade in HCC mouse models. METHODS: We analyzed the effects of Peg-IFNα on tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway. The in vivo efficacy of anti-PD-1 and Peg-IFNα was evaluated in both subcutaneous and orthotopic mouse models of HCC. RESULTS: The combination of Peg-IFNα with PD-1 blockade dramatically enhanced T-cell infiltration, improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy. Mechanistically, Peg-IFNα could recruit cytotoxic CD8+ T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4. Nevertheless, the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+ T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway. The combination of PD-1 blockade with Peg-IFNα could restore the cytotoxic capacity of CD8+ T cells and exerted a significant synergistic effect on HCC. CONCLUSION: These results indicate that in addition to initiating the antitumor immune response itself, Peg-IFNα can also generate a microenvironment favoring PD-1 blockade. Thus, the combination of Peg-IFNα and PD-1 blockade can be a promising strategy for HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , B7-H1 Antigen/immunology , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/immunology , Interferon-alpha/pharmacology , Liver Neoplasms/drug therapy , Liver Neoplasms/immunology , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Tumor Microenvironment
6.
Cell Rep ; 39(3): 110712, 2022 04 19.
Article in English | MEDLINE | ID: mdl-35443161

ABSTRACT

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Autophagy , Carcinoma, Hepatocellular/pathology , Cholesterol , Humans , Liver Neoplasms/pathology , Membrane Proteins/metabolism , Receptor Protein-Tyrosine Kinases
7.
Theranostics ; 12(1): 260-276, 2022.
Article in English | MEDLINE | ID: mdl-34987644

ABSTRACT

Purpose: To establish a clinically applicable genomic clustering system, we investigated the interactive landscape of driver mutations in intrahepatic cholangiocarcinoma (ICC). Methods: The genomic data of 1481 ICCs from diverse populations was analyzed to investigate the pair-wise co-occurrences or mutual exclusivities among recurrent driver mutations. Clinicopathological features and outcomes were compared among different clusters. Gene expression and DNA methylation profiling datasets were analyzed to investigate the molecular distinctions among mutational clusters. ICC cell lines with different gene mutation backgrounds were used to evaluate the cluster specific biological behaviors and drug sensitivities. Results: Statistically significant mutation-pairs were identified across 21 combinations of genes. Seven most recurrent driver mutations (TP53, KRAS, SMAD4, IDH1/2, FGFR2-fus and BAP1) showed pair-wise co-occurrences or mutual exclusivities and could aggregate into three genetic clusters: Cluster1: represented by tripartite interaction of KRAS, TP53 and SMAD4 mutations, exhibited large bile duct histological phenotype with high CA19-9 level and dismal prognosis; Cluster2: co-association of IDH/BAP1 or FGFR2-fus/BAP1 mutation, was characterized by small bile duct phenotype, low CA19-9 level and optimal prognosis; Cluster3: mutation-free ICC cases with intermediate clinicopathological features. These clusters showed distinct molecular traits, biological behaviors and responses to therapeutic drugs. Finally, we identified S100P and KRT17 as "cluster-specific", "lineage-dictating" and "prognosis-related" biomarkers, which in combination with CA19-9 could well stratify Cluster3 ICCs into two biologically and clinically distinct subtypes. Conclusions: This clinically applicable clustering system can be instructive to ICC prognostic stratification, molecular classification, and therapeutic optimization.


Subject(s)
Bile Duct Neoplasms/genetics , Biomarkers, Tumor/genetics , Cholangiocarcinoma/genetics , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Mutation , Prognosis
8.
Signal Transduct Target Ther ; 6(1): 249, 2021 07 05.
Article in English | MEDLINE | ID: mdl-34219130

ABSTRACT

Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.


Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Tumor Microenvironment/genetics , Adenocarcinoma/diagnosis , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/therapy , Humans , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/therapy , Prognosis , Pancreatic Neoplasms
9.
Theranostics ; 11(13): 6560-6572, 2021.
Article in English | MEDLINE | ID: mdl-33995676

ABSTRACT

Rationale: Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. Methods: The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The in vivo efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. Results: In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Conclusion: Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.


Subject(s)
Adenocarcinoma/secondary , Cholesterol/biosynthesis , Colorectal Neoplasms/metabolism , Liver Neoplasms/secondary , Adenocarcinoma/metabolism , Animals , Coculture Techniques , Colorectal Neoplasms/pathology , Genetic Vectors/pharmacology , Hepatocyte Growth Factor/physiology , Humans , Liver Neoplasms/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Proteins/metabolism , Organ Specificity , Proto-Oncogene Proteins c-met/physiology , RNA Interference , RNA, Small Interfering/genetics , Random Allocation , Signal Transduction , Simvastatin/therapeutic use , Sterol Regulatory Element Binding Protein 2/metabolism , TOR Serine-Threonine Kinases/physiology , Tumor Stem Cell Assay
10.
Am J Transl Res ; 13(1): 301-313, 2021.
Article in English | MEDLINE | ID: mdl-33527025

ABSTRACT

Tumor-associated macrophages (TAMs) and how they are activated play critical roles in tumor progression and metastasis, and in hepatocellular carcinoma (HCC), they are associated with sorafenib resistance. Reprogramming of TAMs into M1-like macrophages has been proposed as an approach to stimulate tumor regression. Here we studied the collective effects of interferon-alpha (IFN-α) and sorafenib on HCC. We found that IFN-α delayed tumor growth and inhibited pulmonary metastasis in an orthotopic HCC implantation model. Via in vitro studies, we found that IFN-α treatment could reprogram M2-like RAW264.7 and THP-1 macrophage cells toward M1-like cells. In addition, we also found that IFN-α combined with a low dose of sorafenib has a synergistic inhibitory effect on HCC tumor growth and pulmonary metastasis without obvious toxicity in an in vivo mice model. Moreover, IFN-α increased sorafenib's therapeutic efficacy by shifting TAM polarization to an M1-like phenotype, increasing and activating intratumoral CD8+ T cells in HCCs. In conclusion, a combination of IFN-α and sorafenib have synergistic inhibitory effects on HCC growth and metastasis resulting from a shift in TAM polarization rather than their depletion. Our study supports the future clinical use of a combination of IFN-α and sorafenib for the treatment of advanced HCC.

11.
World J Stem Cells ; 12(11): 1295-1306, 2020 Nov 26.
Article in English | MEDLINE | ID: mdl-33312399

ABSTRACT

Breast cancer, like many other cancers, is believed to be driven by a population of cells that display stem cell properties. Recent studies suggest that cancer stem cells (CSCs) are essential for tumor progression, and tumor relapse is thought to be caused by the presence of these cells. CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies. Additionally, the metabolic properties of cancer cells differ markedly from those of normal cells. The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells. Metabolic targeting of breast CSCs (BCSCs) may be a very effective strategy for anti-cancer treatment of breast cancer cells. Thus, in this review, we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.

12.
Front Immunol ; 11: 589997, 2020.
Article in English | MEDLINE | ID: mdl-33193421

ABSTRACT

Background and Aims: Pyruvate kinase M2 (PKM2) is an essential regulator of the Warburg effect, but its biological function promoting immune escape of hepatocellular carcinoma (HCC) is unclear. Methods: GEPIA web tool and immunohistochemistry (IHC) analysis were employed to evaluate the clinical relevance of PKM2 in HCC patients. Both in vitro CCK-8, colony formation, and transwell assays, and in vivo xenografts were performed to evaluate the malignancy of HCC cells. PKM2 and PD-L1 levels were examined by Western blot, qRT-PCR, and IHC. The role of PKM2 on in vivo immune response was also investigated. Results: PKM2 was significantly upregulated in HCC and associated with a poor prognosis of HCC patients. Knockdown of PKM2 inhibited in vitro proliferation, migration, and invasion of HCC cells, as well as in vivo tumor growth. Strikingly, PKM2 showed a strong correlation with the expression of immune inhibitory cytokines and lymphocyte infiltration in HCC. The overexpression of PKM2 sensitized HCC to immune checkpoint blockade, which enhanced IFN-γ positive CD8 T cells in HCC mice models. Conclusion: PKM2 might be a predictor and a potential therapeutic target for immune checkpoint inhibitors in HCC.


Subject(s)
Carcinoma, Hepatocellular/immunology , Carrier Proteins/immunology , Liver Neoplasms/immunology , Membrane Proteins/immunology , Thyroid Hormones/immunology , Animals , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Cell Line , Disease Progression , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immune Tolerance , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Prognosis , Tumor Microenvironment/immunology , Thyroid Hormone-Binding Proteins
13.
J Hematol Oncol ; 13(1): 152, 2020 11 10.
Article in English | MEDLINE | ID: mdl-33168028

ABSTRACT

Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.


Subject(s)
Exosomes/pathology , Neoplasms/pathology , Animals , Biomarkers, Tumor/analysis , Biomarkers, Tumor/immunology , Biomarkers, Tumor/metabolism , Biomedical Research , Cell Communication , Chemical Precipitation , Exosomes/immunology , Exosomes/metabolism , Humans , Immunotherapy/methods , Lab-On-A-Chip Devices , Liquid Biopsy , Neoplasm Metastasis/immunology , Neoplasm Metastasis/pathology , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/therapy , Ultracentrifugation/methods
14.
Br J Cancer ; 122(2): 209-220, 2020 01.
Article in English | MEDLINE | ID: mdl-31819189

ABSTRACT

BACKGROUND: Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear. METHODS: The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo. RESULTS: Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-D-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1. CONCLUSIONS: Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Deoxyglucose/pharmacology , GTP Phosphohydrolases/genetics , Glucose/metabolism , Liver Neoplasms/metabolism , Mitochondrial Membrane Transport Proteins/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition/drug effects , GTP Phosphohydrolases/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Glycolysis/drug effects , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Dynamics/genetics , Mitochondrial Membrane Transport Proteins/metabolism , Neoplasm Metastasis , Oxidative Phosphorylation/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects
15.
Front Oncol ; 9: 1104, 2019.
Article in English | MEDLINE | ID: mdl-31709180

ABSTRACT

Cancer stem cells (CSCs) have been demonstrated in a variety of tumors and are thought to act as a clonogenic core for the genesis of new tumor growth. This small subpopulation of cancer cells has been proposed to help drive tumorigenesis, metastasis, recurrence and conventional therapy resistance. CSCs show self-renewal and flexible clonogenic properties and help define specific tumor microenvironments (TME). The interaction between CSCs and TME is thought to function as a dynamic support system that fosters the generation and maintenance of CSCs. Investigation of the interaction between CSCs and the TME is shedding light on the biologic mechanisms underlying the process of tumor malignancy, metastasis, and therapy resistance. We summarize recent advances in CSC biology and their environment, and discuss the challenges and future strategies for targeting this biology as a new therapeutic approach.

16.
Gut ; 68(9): 1653-1666, 2019 09.
Article in English | MEDLINE | ID: mdl-30902885

ABSTRACT

OBJECTIVE: In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models. DESIGN: We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC. RESULTS: The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhigh tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+ T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC. CONCLUSIONS: OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.


Subject(s)
B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Hepatocellular/immunology , Liver Neoplasms/immunology , Macrophage Colony-Stimulating Factor/immunology , Macrophages/immunology , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/drug therapy , Chemotaxis/immunology , Cytokines/biosynthesis , Gene Deletion , Humans , Liver Neoplasms/drug therapy , Lymphocytes, Tumor-Infiltrating/immunology , Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Male , Mice, Knockout , Molecular Targeted Therapy/methods , Osteopontin/genetics , Osteopontin/immunology , Prognosis , Pyrroles/pharmacology , Pyrroles/therapeutic use , Tumor Cells, Cultured , Tumor Escape/immunology , Tumor Microenvironment/immunology
17.
Cell Biol Toxicol ; 35(5): 407-421, 2019 10.
Article in English | MEDLINE | ID: mdl-30680600

ABSTRACT

The goal of cancer eradication has been overshadowed despite the continuous improvement in research and generation of novel cancer therapeutic drugs. One of the undeniable existing problems is drug resistance due to which the paradigm of killing all cancer cells is ineffective. Tumor microenvironment plays a crucial role in inducing drug resistance besides cancer development and progression. Recently, many efforts have been devoted to understand the role of tumor microenvironment in cancer drug resistance as it provides the shelter, nutrition, and paracrine niche for cancer cells. Cancer-associated fibroblasts (CAFs), one major component of tumor microenvironment, reside in symbiotic relationship with cancer cells, supporting them to survive from cancer drugs. The present review summarizes the recent understandings in the role of CAFs in drug resistance in various tumors. Acknowledging the fact that drug resistance depends not only upon cancer cells but also upon the microenvironment niche could guide us to formulate novel cancer drugs and provide the optimal cancer treatment.


Subject(s)
Cancer-Associated Fibroblasts/metabolism , Drug Resistance, Neoplasm/physiology , Tumor Microenvironment/physiology , Antineoplastic Agents , Cancer-Associated Fibroblasts/physiology , Disease Progression , Fibroblasts/pathology , Humans
18.
Cell Metab ; 29(4): 886-900.e5, 2019 04 02.
Article in English | MEDLINE | ID: mdl-30661930

ABSTRACT

Metabolic reprogramming plays an important role in supporting tumor growth. However, little is known about the metabolic alterations that promote cancer metastasis. In this study, we identify acyl-CoA thioesterase 12 (ACOT12) as a key player in hepatocellular carcinoma (HCC) metastasis. The expression of ACOT12 is significantly down-regulated in HCC tissues and is closely associated with HCC metastasis and poor survival of HCC patients. Gain- and loss-of-function studies demonstrate that ACOT12 suppresses HCC metastasis both in vitro and in vivo. Further mechanistic studies reveal that ACOT12 regulates the cellular acetyl-CoA levels and histone acetylation in HCC cells and that down-regulation of ACOT12 promotes HCC metastasis by epigenetically inducing TWIST2 expression and the promotion of epithelial-mesenchymal transition. Taken together, our findings link the alteration of acetyl-CoA with HCC metastasis and imply that ACOT12 could be a prognostic marker and a potential therapeutic target for combating HCC metastasis.


Subject(s)
Acetyl Coenzyme A/metabolism , Carcinoma, Hepatocellular/metabolism , Epithelial-Mesenchymal Transition/genetics , Liver Neoplasms/metabolism , Thiolester Hydrolases/metabolism , Acetyl Coenzyme A/genetics , Animals , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Epigenesis, Genetic/genetics , HEK293 Cells , Humans , Liver Neoplasms/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Thiolester Hydrolases/genetics
19.
Aging (Albany NY) ; 10(8): 2079-2097, 2018 Aug 20.
Article in English | MEDLINE | ID: mdl-30125264

ABSTRACT

Despite the rapid growing and aging of populations worldwide, our knowledge on hepatocellular carcinoma (HCC) is still age-standardized rather than age-specific, with only few studies exploring the topic from a genetic point of view. Here, we analyze clinical and genetic aspects of HCC in patients of different age groups with the major attention directed to children (≤20 y) and elderly groups (≥80 y). A number of significant differences were found in elderly patients compared to children group, including smaller tumor size (P=0.001) and improved survival rates (P=0.002). Differences in gene mutations, copy number variants, and mRNA expressions were identified between the groups, with alteration rates for some genes like AKR1B10 increasing significantly with the age of patients. Immunohistochemistry testing of AKR1B10 showed a significant difference in expression levels at the age of 40 (30.77% high expression rate in patients younger than 40 compared to 51.57% in older patients) (P=0.043). Expression levels also differed between HCC tissues (49.64%) and near-tumor tissues (6.58%) (P<0.001). These findings contribute to the limited data available regarding the age-specific aspects of HCC patients, and support the need to address potential differences in the diagnosis, treatment, and prevention strategies of HCC.


Subject(s)
Aging/physiology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Adolescent , Aged, 80 and over , Aldehyde Reductase/genetics , Aldehyde Reductase/metabolism , Aldo-Keto Reductases , Child , DNA Copy Number Variations , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Genetic Predisposition to Disease , Humans , Male , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , RNA, Messenger , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Young Adult , beta Catenin/genetics , beta Catenin/metabolism
20.
Cell Physiol Biochem ; 47(3): 1152-1166, 2018.
Article in English | MEDLINE | ID: mdl-29913454

ABSTRACT

BACKGROUND/AIMS: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. METHODS: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. RESULTS: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. CONCLUSIONS: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.


Subject(s)
Apoptosis/drug effects , Benzylidene Compounds/pharmacology , Bile Duct Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Membrane Glycoproteins/antagonists & inhibitors , NF-kappa B/metabolism , Neoplasm Proteins , Aged , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/pathology , Cell Line, Tumor , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/pathology , Female , Humans , Intracellular Signaling Peptides and Proteins , Male , Membrane Glycoproteins/metabolism , Middle Aged , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...