|
1
|
Zhang W, Wang S, Zhang H, Meng Y, Jiao S, An L, Zhou Z. Modeling human gastric cancers in immunocompetent mice. Cancer Biol Med 2024; 21:j.issn.2095-3941.2024.0124. [PMID: 38940675 PMCID: PMC11271222 DOI: 10.20892/j.issn.2095-3941.2024.0124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 05/14/2024] [Indexed: 06/29/2024] Open
Abstract
Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. GC is determined by multiple (epi)genetic and environmental factors; can occur at distinct anatomic positions of the stomach; and displays high heterogeneity, with different cellular origins and diverse histological and molecular features. This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics. In the past decade, great progress has been made in the study of GC, particularly in molecular subtyping, investigation of the immune microenvironment, and defining the evolutionary path and dynamics. Preclinical mouse models, particularly immunocompetent models that mimic the cellular and molecular features of human GC, in combination with organoid culture and clinical studies, have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion, and the development of novel therapeutic strategies. Herein, we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models, emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.
Collapse
Affiliation(s)
- Weihong Zhang
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shilong Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hui Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yan Meng
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
| | - Shi Jiao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liwei An
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| |
Collapse
|
|
2
|
He H, Li Y, Chen Y, Chen J, Li Z, Li L, Shi D, Zhang X, Shi H, Xue M, Feng L. NLRP1 restricts porcine deltacoronavirus infection via IL-11 inhibiting the phosphorylation of the ERK signaling pathway. J Virol 2024; 98:e0198223. [PMID: 38411106 PMCID: PMC10949457 DOI: 10.1128/jvi.01982-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/08/2024] [Indexed: 02/28/2024] Open
Abstract
Continuously emerging highly pathogenic coronaviruses remain a major threat to human and animal health. Porcine deltacoronavirus (PDCoV) is a newly emerging enterotropic swine coronavirus that causes large-scale outbreaks of severe diarrhea disease in piglets. Unlike other porcine coronaviruses, PDCoV has a wide range of species tissue tropism, including primary human cells, which poses a significant risk of cross-species transmission. Nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) has a key role in linking host innate immunity to microbes and the regulation of inflammatory pathways. We now report a role for NLRP1 in the control of PDCoV infection. Overexpression of NLRP1 remarkably suppressed PDCoV infection, whereas knockout of NLRP1 led to a significant increase in PDCoV replication. A mechanistic study revealed that NLRP1 suppressed PDCoV replication in cells by upregulating IL-11 expression, which in turn inhibited the phosphorylation of the ERK signaling pathway. Furthermore, the ERK phosphorylation inhibitor U0126 effectively hindered PDCoV replication in pigs. Together, our results demonstrated that NLRP1 exerted an anti-PDCoV effect by IL-11-mediated inhibition of the phosphorylation of the ERK signaling pathway, providing a novel antiviral signal axis of NLRP1-IL-11-ERK. This study expands our understanding of the regulatory network of NLRP1 in the host defense against virus infection and provides a new insight into the treatment of coronaviruses and the development of corresponding drugs.IMPORTANCECoronavirus, which mainly infects gastrointestinal and respiratory epithelial cells in vivo, poses a huge threat to both humans and animals. Although porcine deltacoronavirus (PDCoV) is known to primarily cause fatal diarrhea in piglets, reports detected in plasma samples from Haitian children emphasize the potential risk of animal-to-human spillover. Finding effective therapeutics against coronaviruses is crucial for controlling viral infection. Nucleotide-binding oligomerization-like receptor (NLR) family pyrin domain-containing 1 (NLRP1), a key regulatory factor in the innate immune system, is highly expressed in epithelial cells and associated with the pathogenesis of viruses. We demonstrate here that NLRP1 inhibits the infection of the intestinal coronavirus PDCoV through IL-11-mediated phosphorylation inhibition of the ERK signaling pathway. Furthermore, the ERK phosphorylation inhibitor can control the infection of PDCoV in pigs. Our study emphasizes the importance of NLRP1 as an immune regulatory factor and may open up new avenues for the treatment of coronavirus infection.
Collapse
Affiliation(s)
- Haojie He
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Yongfeng Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Yunyan Chen
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Jianfei Chen
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Zhongyuan Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Liang Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Da Shi
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Xin Zhang
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Hongyan Shi
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Mei Xue
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Li Feng
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| |
Collapse
|
|
3
|
Metcalfe RD, Hanssen E, Fung KY, Aizel K, Kosasih CC, Zlatic CO, Doughty L, Morton CJ, Leis AP, Parker MW, Gooley PR, Putoczki TL, Griffin MDW. Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant. Nat Commun 2023; 14:7543. [PMID: 37985757 PMCID: PMC10662374 DOI: 10.1038/s41467-023-42754-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 10/20/2023] [Indexed: 11/22/2023] Open
Abstract
Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
Collapse
Affiliation(s)
- Riley D Metcalfe
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702, USA
| | - Eric Hanssen
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Ian Holmes Imaging Centre, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Ka Yee Fung
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Kaheina Aizel
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Clara C Kosasih
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Courtney O Zlatic
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Larissa Doughty
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Craig J Morton
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- CSIRO Biomedical Manufacturing Program, Clayton, Victoria, 3168, Australia
| | - Andrew P Leis
- Ian Holmes Imaging Centre, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Michael W Parker
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- St Vincent's Institute of Medical Research, Fitzroy, Victoria, 3065, Australia
| | - Paul R Gooley
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Tracy L Putoczki
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia.
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia.
| |
Collapse
|
|
4
|
Xiong W, Chen Y, Zhang C, Li J, Huang H, Zhu Y, Deng G, Cheng J, Lin Y, Shi Z, Mou T. Pharmacologic inhibition of IL11/STAT3 signaling increases MHC-I expression and T cell infiltration. J Transl Med 2023; 21:416. [PMID: 37365574 DOI: 10.1186/s12967-023-04079-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 03/25/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Recent studies have discovered an emerging role of IL11 in various colitis-associated cancers, suggesting that IL11 mainly promotes tumor cell survival and proliferation in regulating tumorigenesis. Herein we aimed to reveal a novel function of IL-11 through STAT3 signaling in regulating tumor immune evasion. METHODS AOM/DSS model in Il11-/- and Apcmin/+/Il11-/- mice were used to detect tumor growth and CD8+ T infiltration. STAT1/3 phosphorylation and MHC-I, CXCL9, H2-K1 and H2-D1 expression were detected in MC38 cells and intestine organoids treated with/without recombinant IL11 to explore effect of IL11/STAT3 signaling, with IL11 mutein used to competitively inhibit IL11 and rescue inhibited STAT1 activation. Correlation between IL11 and CD8+ T infiltration was analyzed using TIMER2.0 website. IL11 expression and survival prognosis was analyzed in clinical data of patient cohort from Nanfang Hospital. RESULTS IL11 is highly expressed in CRC and indicates unfavorable prognosis. IL11 knockout increased CD8+ T cell infiltration and reduced intestinal and colon formation. Tumors were significantly suppressed while MHC-I and CXCL9 expression for CD8+ T infiltration were remarkably increased in the tumor tissues of Apcmin/+/Il11-/- mice or Il11-/- mice induced by AOM/DSS. IL11/STAT3 signaling downregulated MHC-I and CXCL9 by inhibiting IFNγ-induced STAT1 phosphorylation. IL11 mutein competitively inhibit IL11 to upregulate CXCL9 and MHC-I in tumor and attenuated tumor growth. CONCLUSIONS This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.
Collapse
Affiliation(s)
- Wenjun Xiong
- Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China
| | - Yuehong Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China
| | - Chaoting Zhang
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China
| | - Jin Li
- Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China
| | - Haipeng Huang
- Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China
| | - Yu Zhu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China
| | - Guangxu Deng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China
| | - Junhong Cheng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China
| | - Yixiong Lin
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China.
| | - Zhimin Shi
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China.
| | - Tingyu Mou
- Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China.
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, China.
| |
Collapse
|
|
5
|
Moslehian MS, Shabkhizan R, Asadi MR, Bazmani A, Mahdipour M, Haiaty S, Rahbarghazi R, Sakhinia E. Interaction of lncRNAs with mTOR in colorectal cancer: a systematic review. BMC Cancer 2023; 23:512. [PMID: 37280524 DOI: 10.1186/s12885-023-11008-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 05/25/2023] [Indexed: 06/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third most widespread cancer and the fourth leading lethal disease among different societies. It is thought that CRC accounts for about 10% of all newly diagnosed cancer cases with high-rate mortality. lncRNAs, belonging to non-coding RNAs, are involved in varied cell bioactivities. Emerging data have confirmed a significant alteration in lncRNA transcription under anaplastic conditions. This systematic review aimed to assess the possible influence of abnormal mTOR-associated lncRNAs in the tumorigenesis of colorectal tissue. In this study, the PRISMA guideline was utilized based on the systematic investigation of published articles from seven databases. Of the 200 entries, 24 articles met inclusion criteria and were used for subsequent analyses. Of note, 23 lncRNAs were prioritized in association with the mTOR signaling pathway with up-regulation (79.16%) and down-regulation (20.84%) trends. Based on the obtained data, mTOR can be stimulated or inhibited during CRC by the alteration of several lncRNAs. Determining the dynamic activity of mTOR and relevant signaling pathways via lncRNAs can help us progress novel molecular therapeutics and medications.
Collapse
Affiliation(s)
- Marziyeh Sadat Moslehian
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roya Shabkhizan
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Asadi
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Bazmani
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University Of Mashhad, Mashhad, Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, Iran
| | - Sanya Haiaty
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ebrahim Sakhinia
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Tabriz Genetic Analysis Centre (TGAC), Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
6
|
Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression. Cancers (Basel) 2022; 14:cancers14020264. [PMID: 35053428 PMCID: PMC8773769 DOI: 10.3390/cancers14020264] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/24/2021] [Accepted: 12/29/2021] [Indexed: 12/22/2022] Open
Abstract
MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130F/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130F/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity.
Collapse
|
|
7
|
Lu L, Liu YJ, Cheng PQ, Hu D, Xu HC, Ji G. Macrophages play a role in inflammatory transformation of colorectal cancer. World J Gastrointest Oncol 2021; 13:2013-2028. [PMID: 35070038 PMCID: PMC8713318 DOI: 10.4251/wjgo.v13.i12.2013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/21/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, and it is also a typical inflammatory cancer. The function of macrophages is very important in the tissue immune microenvironment during inflammatory and carcinogenic transformation. Here, we evaluated the function and mechanism of macrophages in intestinal physiology and in different pathological stages. Furthermore, the role of macrophages in the immune microenvironment of CRC and the influence of the intestinal population and hypoxic environment on macrophage function are summarized. In addition, in the era of tumor immunotherapy, CRC currently has a limited response rate to immune checkpoint inhibitors, and we summarize potential therapeutic strategies for targeting tumor-associated macrophages.
Collapse
Affiliation(s)
- Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yu-Jing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Pei-Qiu Cheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Dan Hu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Han-Chen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| |
Collapse
|
|
8
|
Bagheri P, Hoang K, Fung AA, Hussain S, Shi L. Visualizing Cancer Cell Metabolic Dynamics Regulated With Aromatic Amino Acids Using DO-SRS and 2PEF Microscopy. Front Mol Biosci 2021; 8:779702. [PMID: 34977157 PMCID: PMC8714916 DOI: 10.3389/fmolb.2021.779702] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/22/2021] [Indexed: 12/19/2022] Open
Abstract
Oxidative imbalance plays an essential role in the progression of many diseases that include cancer and neurodegenerative diseases. Aromatic amino acids (AAA) such as phenylalanine and tryptophan have the capability of escalating oxidative stress because of their involvement in the production of Reactive Oxygen Species (ROS). Here, we use D2O (heavy water) probed stimulated Raman scattering microscopy (DO-SRS) and two Photon Excitation Fluorescence (2PEF) microscopy as a multimodal imaging approach to visualize metabolic changes in HeLa cells under excess AAA such as phenylalanine or trytophan in culture media. The cellular spatial distribution of de novo lipogenesis, new protein synthesis, NADH, Flavin, unsaturated lipids, and saturated lipids were all imaged and quantified in this experiment. Our studies reveal ∼10% increase in de novo lipogenesis and the ratio of NADH to flavin, and ∼50% increase of the ratio of unsaturated lipids to saturated lipid in cells treated with excess phenylalanine or trytophan. In contrast, these cells exhibited a decrease in the protein synthesis rate by ∼10% under these AAA treatments. The cellular metabolic activities of these biomolecules are indicators of elevated oxidative stress and mitochondrial dysfunction. Furthermore, 3D reconstruction images of lipid droplets were acquired and quantified to observe their spatial distribution around cells’ nuceli under different AAA culture media. We observed a higher number of lipid droplets in excess AAA conditions. Our study showcases that DO-SRS imaging can be used to quantitatively study how excess AAA regulates metabolic activities of cells with subcellular resolution in situ.
Collapse
|
|
9
|
Lucchetta M, Pellegrini M. Drug repositioning by merging active subnetworks validated in cancer and COVID-19. Sci Rep 2021; 11:19839. [PMID: 34615934 PMCID: PMC8494853 DOI: 10.1038/s41598-021-99399-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 09/23/2021] [Indexed: 02/08/2023] Open
Abstract
Computational drug repositioning aims at ranking and selecting existing drugs for novel diseases or novel use in old diseases. In silico drug screening has the potential for speeding up considerably the shortlisting of promising candidates in response to outbreaks of diseases such as COVID-19 for which no satisfactory cure has yet been found. We describe DrugMerge as a methodology for preclinical computational drug repositioning based on merging multiple drug rankings obtained with an ensemble of disease active subnetworks. DrugMerge uses differential transcriptomic data on drugs and diseases in the context of a large gene co-expression network. Experiments with four benchmark diseases demonstrate that our method detects in first position drugs in clinical use for the specified disease, in all four cases. Application of DrugMerge to COVID-19 found rankings with many drugs currently in clinical trials for COVID-19 in top positions, thus showing that DrugMerge can mimic human expert judgment.
Collapse
Affiliation(s)
- Marta Lucchetta
- Institute of Informatics and Telematics (IIT), CNR, Pisa, 56124, Italy
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, 53100, Italy
| | - Marco Pellegrini
- Institute of Informatics and Telematics (IIT), CNR, Pisa, 56124, Italy.
| |
Collapse
|
|
10
|
Maroni P, Bendinelli P, Ferraretto A, Lombardi G. Interleukin 11 (IL-11): Role(s) in Breast Cancer Bone Metastases. Biomedicines 2021; 9:biomedicines9060659. [PMID: 34201209 PMCID: PMC8228851 DOI: 10.3390/biomedicines9060659] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/04/2021] [Accepted: 06/05/2021] [Indexed: 12/11/2022] Open
Abstract
Bone metastases represent the main problem related to the progression of breast cancer, as they are the main cause of death for these patients. Unfortunately, to date, bone metastases are incurable and represent the main challenge for the researcher. Chemokines and cytokines affect different stages of the metastatic process, and in bone metastases, interleukin (IL) -6, IL-8, IL-1β, and IL-11 participate in the interaction between cancer cells and bone cells. This review focuses on IL-11, a pleiotropic cytokine that, in addition to its well-known effects on several tissues, also mediates certain signals in cancer cells. In particular, as IL-11 works on bone remodeling, it plays a relevant role in the osteolytic vicious cycle of bone resorption and tumour growth, which characterizes bone metastasis. IL-11 appears as a candidate for anti-metastatic therapy. Even if different therapeutic approaches have considered IL-11 and the downstream-activated gp130 signaling pathways activated downstream of gp130, further studies are needed to decipher the contribution of the different cytokines and their mechanisms of action in breast cancer progression to define therapeutic strategies.
Collapse
Affiliation(s)
- Paola Maroni
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Correspondence: ; Tel.: +39-02-6621-4759
| | - Paola Bendinelli
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via L. Mangiagalli 31, 20133 Milano, Italy;
| | - Anita Ferraretto
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via L. Mangiagalli 31, 20133 Milano, Italy;
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Królowej Jadwigi 27/39, 61-871 Poznań, Poland
| |
Collapse
|
|
11
|
Schmidt-Arras D, Rose-John S. Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors. Front Cell Dev Biol 2021; 9:688314. [PMID: 34141712 PMCID: PMC8204807 DOI: 10.3389/fcell.2021.688314] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022] Open
Abstract
Interleukin-6 (IL-6) is the name-giving cytokine of a family of eleven members, including IL-6, CNTF, LIF, and IL-27. IL-6 was first recognized as a B-cell stimulating factor but we now know that the cytokine plays a pivotal role in the orchestration of inflammatory processes as well as in inflammation associated cancer. Moreover, IL-6 is involved in metabolic regulation and it has been shown to be involved in major neural activities such as neuroprotection, which can help to repair and to reduce brain damage. Receptor complexes of all members formed at the plasma membrane contain one or two molecules of the signaling receptor subunit GP130 and the mechanisms of signal transduction are well understood. IL-6 type cytokines can also signal from endomembranes, in particular the endosome, and situations have been reported in which endocytosis of receptor complexes are a prerequisite of intracellular signaling. Moreover, pathogenic GP130 variants were shown to interfere with spatial activation of downstream signals. We here summarize the molecular mechanisms underlying spatial regulation of IL-6 family cytokine signaling and discuss its relevance for pathogenic processes.
Collapse
Affiliation(s)
- Dirk Schmidt-Arras
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| |
Collapse
|
|
12
|
Saleem Basha S, Tripathi D, Koora S, Satyanarayana K, Jayaraman S. Molecular docking analysis of potential compounds from an Indian medicinal soup "kabasura kudineer" extract with IL-6. Bioinformation 2021; 17:568-572. [PMID: 35095231 PMCID: PMC8770407 DOI: 10.6026/97320630017568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 11/23/2022] Open
Abstract
The use of "kabasura kudineer" (liquid soup made from Indian medicinal plants) for combating COVID-19 has been common in the states of Tamilnadu and Puducherry, India during the pandemic. Therefore, it is of interest to document the molecular docking analysis of IL-6 inhibitors with potential antiviral compounds from "kabasura kudineer" extract. We show the optimal binding features of gallic acid and luteolin with the Interleukin-6 protein for further consideration.
Collapse
Affiliation(s)
- S Saleem Basha
- Dept of Medical Biochemistry, School of Medicine, Haramaya University, Harar Campus, Ethiopia
| | - Dhirendra Tripathi
- Department of Otorhinolaryngology, Government Medical College, Shivpuri, Shivpuri- 473638
| | - Sravanthi Koora
- Department of Pharmacology, Government Medical College Siddipet-502103, Siddipet, Telangana
| | - K Satyanarayana
- Department of Biochemistry, Government Medical College Siddipet, Siddipet 502103 Telangana India
| | - Selvaraj Jayaraman
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai-600 077, India
| |
Collapse
|
|
13
|
Zefferino R, Piccoli C, Di Gioia S, Capitanio N, Conese M. How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease. Int J Mol Sci 2021; 22:ijms22052550. [PMID: 33806300 PMCID: PMC7961918 DOI: 10.3390/ijms22052550] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: "Activating Invasion and Metastasis" and the "Avoiding Immune Destruction", with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.
Collapse
Affiliation(s)
- Roberto Zefferino
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
- Correspondence: ; Tel.: +39-0881-884673
| | - Claudia Piccoli
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (C.P.); (N.C.)
| | - Sante Di Gioia
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
| | - Nazzareno Capitanio
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (C.P.); (N.C.)
| | - Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
| |
Collapse
|
|
14
|
Yin B, Liu H, Tan B, Dong X, Chi S, Yang Q, Zhang S. MHC II-PI 3K/Akt/mTOR Signaling Pathway Regulates Intestinal Immune Response Induced by Soy Glycinin in Hybrid Grouper: Protective Effects of Sodium Butyrate. Front Immunol 2021; 11:615980. [PMID: 33537033 PMCID: PMC7849651 DOI: 10.3389/fimmu.2020.615980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 11/30/2020] [Indexed: 11/13/2022] Open
Abstract
Soy glycinin (11S) is involved in immune regulation. As an additive, sodium butyrate (SB) can relieve inflammation caused by 11S. To further delve into the mechanisms. A diet containing 50% fishmeal was the control group (FM group), and the experimental groups consisted of the FM group baseline plus 2% glycinin (GL group), 8% glycinin (GH group), and 8% glycinin + 0.13% sodium butyrate (GH-SB group). The specific growth ratio (SGR), feed utilization, and density of distal intestinal (DI) type II mucous cells were increased in the GL group. In the serum, IFN-γ was significantly upregulated in the GL group, and IgG and IL-1β were upregulated in the GH group. IgG, IL-1β, and TNF-α in the GH-SB group were significantly downregulated compared to those in the GH group. The mRNA levels of mTOR C1, mTOR C2, and Deptor were upregulated in the GL, GH, and GH-SB groups in the DI compared with those in the FM group, while the mRNA levels of mTOR C1 and Deptor in the GH group were higher than those in the GL and GH-SB groups. 4E-BP1, RICTOR, PRR5, MHC II, and CD4 were upregulated in the GH group. TSC1, mLST8, and NFY mRNA levels in the GL and GH-SB groups were upregulated compared with those in the FM and GH groups. Western blotting showed P-PI3KSer294/T-PI3K, P-AktSer473/T-Akt, and P-mTORSer2448/T-mTOR were upregulated in the GH group. Collectively, our results demonstrate that low-dose 11S could improve serum immune by secreting IFN-γ. The overexpression of IgG and IL-1β is the reason that high-dose 11S reduces serum immune function, and supplementing SB can suppress this overexpression. Low-dose 11S can block the relationship between PI3K and mTOR C2. It can also inhibit the expression of 4E-BP1 through mTOR C1. High-dose 11S upregulates 4E-BP2 through mTOR C1, aggravating intestinal inflammation. SB could relieve inflammation by blocking PI3K/mTOR C2 and inhibiting 4E-BP2. Generally speaking, the hybrid grouper obtained different serum and DI immune responses under different doses of 11S, and these responses were ultimately manifested in growth performance. SB can effectively enhance serum immunity and relieve intestinal inflammation caused by high dose 11S.
Collapse
Affiliation(s)
- Bin Yin
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Hongyu Liu
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Beiping Tan
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Xiaohui Dong
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Shuyan Chi
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Qihui Yang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Shuang Zhang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| |
Collapse
|
|
15
|
Paulino DSM, Mendes MCS, Camargo JA, Brambilla SR, Wood Dos Santos T, Ribeiro ML, Carvalheira JBC. Diacerein treatment prevents colitis-associated cancer in mice. World J Clin Oncol 2020; 11:732-746. [PMID: 33033695 PMCID: PMC7522546 DOI: 10.5306/wjco.v11.i9.732] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/06/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammation is a well-established enabling factor for cancer development and provides a framework for the high prevalence of colon cancer in inflammatory bowel disease. In accordance, chronic inflammation has recently been implicated in the development of cancer stem cells (CSCs). However, the mechanism whereby anti-inflammatory drugs act in the prevention of colitis-associated cancer (CAC) is only partially understood. AIM To evaluate the role of diacerein (DAR), an anti-inflammatory drug that mainly acts through the inhibition of interleukin (IL)-1β expression in the development of CSCs and CAC. METHODS The effects of DAR on colon inflammation in mice with CAC were evaluated by inflammatory index, reverse real-time transcription polymerase chain reaction and western blot. Cytokine levels were measured by enzyme-linked immunosorbent assay. Cells assays evaluated the effects of DAR on CSCs. Immunohistochemistry and apoptosis assays were also used to evaluate the effects of DAR on tumorigenesis associated with inflammation. RESULTS DAR treatment reduced colon inflammation as well as the number and size of tumors in azoxymethane plus dextran sulphate sodium-treated animals. Accordingly, DAR treatment was associated with reduced intracellular signals of inflammation (inhibitor of nuclear factor kappa B kinase and c-Jun N-terminal kinase phosphorylation) in the colon. In addition, DAR treatment was associated with a decrease in colon CSC formation, suggesting that besides reducing colonic inflammation, DAR has a direct effect on the inhibition of colon carcinogenesis. CONCLUSION Together, these data indicate that DAR-mediated IL-1β suppression attenuates inflammation-induced colon cancer and CSC formation, highlighting DAR as a potential candidate for the chemoprevention of CAC.
Collapse
Affiliation(s)
- Daiane S M Paulino
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Sao Paulo 13083-970, Brazil
| | - Maria Carolina S Mendes
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Sao Paulo 13083-970, Brazil
| | - Juliana A Camargo
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Sao Paulo 13083-970, Brazil
| | - Sandra R Brambilla
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Sao Paulo 13083-970, Brazil
| | - Tanila Wood Dos Santos
- Department of Clinical Pharmacology and Gastroenterology, Sao Francisco University, Sao Paulo 12916-900, Brazil
| | - Marcelo L Ribeiro
- Department of Clinical Pharmacology and Gastroenterology, Sao Francisco University, Sao Paulo 12916-900, Brazil
| | | |
Collapse
|
|
16
|
Paniri A, Akhavan-Niaki H. Emerging role of IL-6 and NLRP3 inflammasome as potential therapeutic targets to combat COVID-19: Role of lncRNAs in cytokine storm modulation. Life Sci 2020; 257:118114. [PMID: 32693241 PMCID: PMC7368418 DOI: 10.1016/j.lfs.2020.118114] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
Abstract
The world has witnessed a high morbidity and mortality caused by SARS-CoV-2, and global death toll is still rising. Exaggerated inflammatory responses are thought to be more responsible for infiltrated immune cells accumulation, organ damage especially lung, dyspnea, and respiratory failure rather than direct effect of viral replication. IL-6 and NLRP3 inflammasome are the major immune components in immune responses stimulation upon pathogen infection. It's noteworthy that the function and expression of these components are remarkably influenced by non-coding RNAs including long non-coding RNAs. Given the potential role of these components in organ damage and pathological manifestations of patients infected with COVID-19, their blockage might be a hopeful and promising treatment strategy. Notably, more study on long non-coding RNAs involved in inflammatory responses could elevate the efficacy of anti-inflammatory therapy. In this review we discuss the potential impact of IL-6 and NLRP3 inflammasome blocker drugs on inflammatory responses, viral clearance, and pathological and clinical manifestations. Collectively, anti-inflammatory strategy might pave the way to diminish clinical and pathological manifestations and thereby discharging patients infected with COVID-19 from hospital.
Collapse
Affiliation(s)
- Alireza Paniri
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Genetics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Haleh Akhavan-Niaki
- Genetics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran; Zoonoses Research Center, Pasteur Institute of Iran, Amol, Iran.
| |
Collapse
|
|
17
|
Shin J, Bae J, Park S, Kang HG, Shin SM, Won G, Kim JS, Cho SG, Choi Y, Oh SM, Shin J, Kim JS, Park HW. mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer. Cancers (Basel) 2020; 12:cancers12092515. [PMID: 32899752 PMCID: PMC7565818 DOI: 10.3390/cancers12092515] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/17/2020] [Accepted: 08/26/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Mammalian target of rapamycin complex 1 (mTORC1), a key controller of growth and environmental stress signaling, is frequently activated in human cancers. Sestrin2 (SESN2), a highly conserved stress-inducible protein, is one of the negative feedback mechanisms for inhibiting chronic activation of mTORC1. This study aimed to investigate the expression and clinical implications of SESN2 in endometrial cancer using an in vitro and in vivo approach. The analysis indicated increased levels of SESN2 and mTORC1 pathway activity in cancer tissues than in normal tissues. High SESN2 expression correlated with shorter patient survival duration. However, lentiviral overexpression of SESN2 and mTOR inhibitors suppressed cancer cell proliferation, migration, and epithelial–mesenchymal transition. Our study provides strong evidence for prognostic significance of SESN2, and its association with mTORC1 pathway and endometrial cancer growth. Thus, the results identified SESN2 as a potential therapeutic target in endometrial cancer. Abstract Oncogenic activation of the mammalian target of rapamycin complex 1 (mTORC1) leads to endometrial cancer cell growth and proliferation. Sestrin2 (SESN2), a highly conserved stress-inducible protein, is involved in homeostatic regulation via inhibition of reactive oxygen species (ROS) and mTORC1. However, the role of SESN2 in human endometrial cancer remains to be investigated. Here, we investigated expression, clinical significance, and underlying mechanisms of SESN2 in endometrial cancer. SESN2 was upregulated more in endometrial cancer tissues than in normal endometrial tissues. Furthermore, upregulation of SESN2 statistically correlated with shorter overall survival and disease-free survival in patients with endometrial cancer. SESN2 expression strongly correlated with mTORC1 activity, suggesting its impact on prognosis in endometrial cancer. Additionally, knockdown of SESN2 promoted cell proliferation, migration, and ROS production in endometrial cancer cell lines HEC-1A and Ishikawa. Treatment of these cells with mTOR inhibitors reversed endometrial cancer cell proliferation, migration, and epithelial–mesenchymal transition (EMT) marker expression. Moreover, in a xenograft nude mice model, endometrial cancer growth increased by SESN2 knockdown. Thus, our study provides evidence for the prognostic significance of SESN2, and a relationship between SESN2, the mTORC1 pathway, and endometrial cancer growth, suggesting SESN2 as a potential therapeutic target in endometrial cancer.
Collapse
Affiliation(s)
- Jiha Shin
- Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea; (J.S.); (J.B.); (S.P.); (H.-G.K.); (S.M.S.); (J.S.)
| | - Jeongyun Bae
- Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea; (J.S.); (J.B.); (S.P.); (H.-G.K.); (S.M.S.); (J.S.)
| | - Sumi Park
- Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea; (J.S.); (J.B.); (S.P.); (H.-G.K.); (S.M.S.); (J.S.)
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Korea; (G.W.); (J.-S.K.); (S.-M.O.)
| | - Hyun-Goo Kang
- Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea; (J.S.); (J.B.); (S.P.); (H.-G.K.); (S.M.S.); (J.S.)
| | - Seong Min Shin
- Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea; (J.S.); (J.B.); (S.P.); (H.-G.K.); (S.M.S.); (J.S.)
| | - Gunho Won
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Korea; (G.W.); (J.-S.K.); (S.-M.O.)
- Department Centers for Disease Control & Prevention, National Institute of Health, Cheongju 28159, Korea
| | - Jong-Seok Kim
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Korea; (G.W.); (J.-S.K.); (S.-M.O.)
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea; (S.-G.C.); (Y.C.)
| | - Youngsok Choi
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea; (S.-G.C.); (Y.C.)
| | - Sang-Muk Oh
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Korea; (G.W.); (J.-S.K.); (S.-M.O.)
- Department of Biochemistry, Konyang University College of Medicine, Daejeon 35365, Korea
| | - Jongdae Shin
- Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea; (J.S.); (J.B.); (S.P.); (H.-G.K.); (S.M.S.); (J.S.)
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Korea; (G.W.); (J.-S.K.); (S.-M.O.)
| | - Jeong Sig Kim
- Department of Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea
- Correspondence: (J.S.K.); (H.-W.P.); Tel.: +82-42-600-8677 (H.-W.P.)
| | - Hwan-Woo Park
- Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea; (J.S.); (J.B.); (S.P.); (H.-G.K.); (S.M.S.); (J.S.)
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Korea; (G.W.); (J.-S.K.); (S.-M.O.)
- Correspondence: (J.S.K.); (H.-W.P.); Tel.: +82-42-600-8677 (H.-W.P.)
| |
Collapse
|
|
18
|
Heichler C, Scheibe K, Schmied A, Geppert CI, Schmid B, Wirtz S, Thoma OM, Kramer V, Waldner MJ, Büttner C, Farin HF, Pešić M, Knieling F, Merkel S, Grüneboom A, Gunzer M, Grützmann R, Rose-John S, Koralov SB, Kollias G, Vieth M, Hartmann A, Greten FR, Neurath MF, Neufert C. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut 2020; 69:1269-1282. [PMID: 31685519 DOI: 10.1136/gutjnl-2019-319200] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/22/2019] [Accepted: 10/08/2019] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Cancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood. DESIGN We quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI-) on STAT3 activation (IL-6 vs IL-11). RESULTS The analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts. CONCLUSION Altogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.
Collapse
Affiliation(s)
- Christina Heichler
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Kristina Scheibe
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Anabel Schmied
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Carol I Geppert
- Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Benjamin Schmid
- Optical Imaging Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Stefan Wirtz
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Oana-Maria Thoma
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.,Erlangen Graduate School of Advanced Optical Technologies (SAOT), Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Viktoria Kramer
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Maximilian J Waldner
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Christian Büttner
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Henner F Farin
- German Cancer Consortium (DKTK), Heidelberg, Germany.,Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany
| | - Marina Pešić
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany
| | - Ferdinand Knieling
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.,Department of Pediatrics and Adolescent Medicine, Universitätsklinikum Erlangen Kinder- und Jugendklinik, Erlangen, Germany
| | - Susanne Merkel
- Chirurgische Klinik, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Anika Grüneboom
- Third Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Matthias Gunzer
- Institute of Experimental Immunology and Imaging, University Duisburg-Essen and University Hospital Essen, Essen, Germany
| | - Robert Grützmann
- Chirurgische Klinik, Universitätsklinikum Erlangen, Erlangen, Germany
| | | | - Sergei B Koralov
- Department of Pathology, New York University School of Medicine, New York, New York, USA
| | - George Kollias
- Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Arndt Hartmann
- Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Florian R Greten
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany
| | - Markus F Neurath
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Clemens Neufert
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| |
Collapse
|
|
19
|
Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents 2020; 55:105954. [PMID: 32234467 PMCID: PMC7118634 DOI: 10.1016/j.ijantimicag.2020.105954] [Citation(s) in RCA: 1210] [Impact Index Per Article: 242.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/14/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023]
Abstract
Since December 2019, a viral pneumonia, named coronavirus disease 2019 (COVID-19), from Wuhan, China, has swept the world. Although the case fatality rate is not high, the number of people infected is large and there is still a large number of patients dying. With the collation and publication of more and more clinical data, a large number of data suggest that there are mild or severe cytokine storms in severe patients, which is an important cause of death. Therefore, treatment of the cytokine storm has become an important part of rescuing severe COVID-19 patients. Interleukin-6 (IL-6) plays an important role in cytokine release syndrome. If it is possible to block the signal transduction pathway of IL-6, it is expected to become a new method for the treatment of severe COVID-19 patients. Tocilizumab is an IL-6 receptor (IL-6R) blocker that can effectively block the IL-6 signal transduction pathway and thus is likely to become an effective drug for patients with severe COVID-19.
Collapse
Affiliation(s)
- Chi Zhang
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Zhao Wu
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Jia-Wen Li
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Hong Zhao
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Gui-Qiang Wang
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Peking University International Hospital, Beijing, China.
| |
Collapse
|
|
20
|
Li J, Li L, Wang X, Xiao L. Porphyromonas gingivalis Inhibition of MicroRNA-205-5p Expression Modulates Proinflammatory Cytokines in Gingival Epithelial Cells. Biochem Genet 2020; 58:566-579. [PMID: 32303947 DOI: 10.1007/s10528-020-09957-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 03/11/2020] [Indexed: 01/05/2023]
Abstract
In this study, we strived to investigate the effect of miR-205-5p on JAK/STAT signaling way induced by P. gingivalis in periodontitis. Microarray analysis was conducted to find differentially expressed miRNAs in periodontitis patients. The miRNAs related to JAK/STAT signaling way were selected via DIANA TOOLS, and the targeted mRNAs of miRNAs were predicted by TargetScan. The expression of miRNAs and mRNAs, differentially expressed in periodontitis and related to JAK/STAT signaling, was detected by qRT-PCR or western blot. The relationship between miRNAs and mRNAs was confirmed by a dual luciferase assay. MiR-205-5p was downregulated and IL6ST was upregulated in periodontitis patients' clinical samples. MiR-205-5p had target binding sites of IL6ST 3' untranslated region. QRT-PCR and western blot analysis demonstrated poor expression of miR-205-5p, while IL6ST, pJAK2, p-STAT3 were extremely upregulated in gingival epithelial cells (GECs) with P. gingivalis induction. IL6ST expression in periodontitis tissue was also increased. P. gingivalis could inhibit miR-205-5p expression to activate JAK/STAT signaling in GECs and promote the occurrence and development of periodontitis.
Collapse
Affiliation(s)
- Juan Li
- Department of Stomatology, Yantai Yuhuangding Hospital, Zhifu District, No. 20 Yuhuangding East Road, Yantai, 264000, Shandong, China
| | - Li Li
- Department of Stomatology, Yantai Yuhuangding Hospital, Zhifu District, No. 20 Yuhuangding East Road, Yantai, 264000, Shandong, China
| | - Xiaoping Wang
- Department of Stomatology, Yantai Yuhuangding Hospital, Zhifu District, No. 20 Yuhuangding East Road, Yantai, 264000, Shandong, China
| | - Lei Xiao
- Department of Stomatology, Yantai Yuhuangding Hospital, Zhifu District, No. 20 Yuhuangding East Road, Yantai, 264000, Shandong, China.
| |
Collapse
|
|
21
|
Mutation in DNA Polymerase Beta Causes Spontaneous Chromosomal Instability and Inflammation-Associated Carcinogenesis in Mice. Cancers (Basel) 2019; 11:cancers11081160. [PMID: 31412651 PMCID: PMC6721533 DOI: 10.3390/cancers11081160] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/01/2019] [Accepted: 08/08/2019] [Indexed: 12/15/2022] Open
Abstract
DNA polymerase beta (Pol β) is a key enzyme in the base excision repair (BER) pathway. Pol β is mutated in approximately 40% of human tumors in small-scale studies. The 5´-deoxyribose-5-phosphate (dRP) lyase domain of Pol β is responsible for DNA end tailoring to remove the 5’ phosphate group. We previously reported that the dRP lyase activity of Pol β is critical to maintain DNA replication fork stability and prevent cellular transformation. In this study, we tested the hypothesis that the human gastric cancer associated variant of Pol β (L22P) has the ability to promote spontaneous chromosomal instability and carcinogenesis in mice. We constructed a Pol β L22P conditional knock-in mouse model and found that L22P enhances hyperproliferation and DNA double strand breaks (DSBs) in stomach cells. Moreover, mouse embryonic fibroblasts (MEFs) derived from L22P mice frequently induce abnormal numbers of chromosomes and centrosome amplification, leading to chromosome segregation errors. Importantly, L22P mice exhibit chronic inflammation accompanied by stomach tumors. These data demonstrate that the human cancer-associated variant of Pol β can contribute to chromosomal instability and cancer development.
Collapse
|
|
22
|
IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun 2019; 10:2735. [PMID: 31227713 PMCID: PMC6588585 DOI: 10.1038/s41467-019-10676-1] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 05/22/2019] [Indexed: 12/31/2022] Open
Abstract
The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer. Mast cells within the tumor microenvironment have controversial roles. Here, the authors show, using genetic mouse models, that in gastric cancer, mast cells at the periphery of the tumors are activated via cancer cell produced-IL33 and promote tumorigenesis by recruiting macrophages within the tumors.
Collapse
|
|
23
|
Notch and mTOR Signaling Pathways Promote Human Gastric Cancer Cell Proliferation. Neoplasia 2019; 21:702-712. [PMID: 31129492 PMCID: PMC6536707 DOI: 10.1016/j.neo.2019.05.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 05/02/2019] [Accepted: 05/03/2019] [Indexed: 12/11/2022] Open
Abstract
Notch pathway signaling is known to promote gastric stem cell proliferation, and constitutive pathway activation induces gastric tumors via mTORC1 activation in mouse genetic models. The purpose of this study was to determine whether human gastric adenocarcinomas are similarly dependent on Notch and mTORC1 signaling for growth. Gene expression profiling of 415 human gastric adenocarcinomas in The Cancer Genome Atlas, and a small set of locally obtained gastric cancers showed enhanced expression of Notch pathway components, including Notch ligands, receptors and downstream target genes. Human gastric adenocarcinoma tissues and chemically induced mouse gastric tumors both exhibited heightened Notch and mTORC1 pathway signaling activity, as evidenced by increased expression of the NOTCH1 receptor signaling fragment NICD, the Notch target HES1, and the mTORC1 target phosphorylated S6 ribosomal protein. Pharmacologic inhibition of either Notch or mTORC1 signaling reduced growth of human gastric cancer cell lines, with combined pathway inhibition causing a further reduction in growth, suggesting that both pathways are activated to promote gastric cancer cell proliferation. Further, mTORC1 signaling was reduced after Notch inhibition suggesting that mTOR is downstream of Notch in gastric cancer cells. Analysis of human gastric organoids derived from paired control and gastric cancer tissues also exhibited reduced growth in culture after Notch or mTOR inhibition. Thus, our studies demonstrate that Notch and mTOR signaling pathways are commonly activated in human gastric cancer to promote cellular proliferation. Targeting these pathways in combination might be an effective therapeutic strategy for gastric cancer treatment.
Collapse
|
|
24
|
Wang Z, Vaughan TY, Zhu W, Chen Y, Fu G, Medrzycki M, Nishio H, Bunting ST, Hankey-Giblin PA, Nusrat A, Parkos CA, Wang D, Wen R, Bunting KD. Gab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8 + T-Cell Activation. Front Immunol 2019; 10:486. [PMID: 30936879 PMCID: PMC6431666 DOI: 10.3389/fimmu.2019.00486] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 02/22/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a multi-factorial chronic inflammation of the gastrointestinal tract prognostically linked to CD8+ T-cells, but little is known about their mechanism of activation during initiation of colitis. Here, Grb2-associated binding 2/3 adaptor protein double knockout mice (Gab2/3−/−) were generated. Gab2/3−/− mice, but not single knockout mice, developed spontaneous colitis. To analyze the cellular mechanism, reciprocal bone marrow (BM) transplantation demonstrated a Gab2/3−/− hematopoietic disease-initiating process. Adoptive transfer showed individual roles for macrophages and T-cells in promoting colitis development in vivo. In spontaneous disease, intestinal intraepithelial CD8+ but much fewer CD4+, T-cells from Gab2/3−/− mice with rectal prolapse were more proliferative. To analyze the molecular mechanism, reduced PI3-kinase/Akt/mTORC1 was observed in macrophages and T-cells, with interleukin (IL)-2 stimulated T-cells showing increased pSTAT5. These results illustrate the importance of Gab2/3 collectively in signaling responses required to control macrophage and CD8+ T-cell activation and suppress chronic colitis.
Collapse
Affiliation(s)
- Zhengqi Wang
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Tamisha Y Vaughan
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Wandi Zhu
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Yuhong Chen
- BloodCenter of Wisconsin, Milwaukee, WI, United States
| | - Guoping Fu
- BloodCenter of Wisconsin, Milwaukee, WI, United States
| | - Magdalena Medrzycki
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Hikaru Nishio
- Department of Pathology, Emory University, Atlanta, GA, United States
| | - Silvia T Bunting
- Department of Pathology, Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Pamela A Hankey-Giblin
- Department of Veterinary Science, Pennsylvania State University, University Park, PA, United States
| | - Asma Nusrat
- Department of Pathology, Emory University, Atlanta, GA, United States.,Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Charles A Parkos
- Department of Pathology, Emory University, Atlanta, GA, United States.,Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Demin Wang
- BloodCenter of Wisconsin, Milwaukee, WI, United States
| | - Renren Wen
- BloodCenter of Wisconsin, Milwaukee, WI, United States
| | - Kevin D Bunting
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| |
Collapse
|
|
25
|
Yang L, Li C, Jia Y. MicroRNA-99b promotes Helicobacter pylori-induced autophagyand suppresses carcinogenesis by targeting mTOR. Oncol Lett 2018; 16:5355-5360. [PMID: 30250606 DOI: 10.3892/ol.2018.9269] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 05/27/2017] [Indexed: 12/14/2022] Open
Abstract
The regulatory mechanism of Helicobacter pylori-induced gastric carcinogenesis remains unclear. Autophagy has previously been identified as an effective method of regulating carcinogenesis. In the present study, microRNA (miR)-99b levels increased in H. pylori-infected gastric cancer tissues and the BGC-823 gastric cancer cell line. Overexpression of miR-99b significantly enhanced autophagy, decreased intracellular bacterial loads and blocked cell proliferation. The effect on autophagy was demonstrated to be triggered by mammalian target of rapamycin inhibition. These results indicate that miR-99b expression serves a key role in preventing H. pylori-associated gastric cancer formation and this may provide potential targets for the future treatment of H. pylori-associated diseases.
Collapse
Affiliation(s)
- Liu Yang
- Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Cong Li
- Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Yujie Jia
- Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| |
Collapse
|
|
26
|
Angriman I, Furian L, Scarpa M, Fassan M, Morgan S, Porzionato A, Kotsafti A, Saadeh L, Silvestre C, De Caro R, Carraro A, Tedeschi U, Bardini R, Rigotti P, Rugge M, Castoro C, Castagliuolo I, Scarpa M. Effects of immune suppression for transplantation on inflammatory colorectal cancer progression. Oncogenesis 2018; 7:46. [PMID: 29915171 PMCID: PMC6006312 DOI: 10.1038/s41389-018-0055-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 04/10/2018] [Accepted: 05/03/2018] [Indexed: 12/21/2022] Open
Abstract
Background Ulcerative colitis patients and transplant recipients are at risk for colorectal cancer. Here, we show that immunosuppressive regimens for kidney transplants are associated with the progression of ulcerative colitis-related carcinogenesis. Methods We describe the case of a patient diagnosed with colorectal cancer in ulcerative colitis while on immunosuppressive therapy for a kidney transplant. The immunological microenvironment of the cancer and its mutational status were analyzed, and a mouse colon cancer model was created to replicate the unique clinical conditions. AOM/DSS mice were randomized into seven experimental groups that received different immunosuppressants and an untreated control group to assess the frequencies of adenocarcinoma and high-grade dysplasia. Histopathology, immunohistochemistry, and flow cytometry were also performed on the harvested mouse colons. Results All mice treated with an immunosuppressive regimen developed at least an adenoma, and several of those receiving anti-CD3, anti-CD8, and mycophenolate mofetil also developed adenocarcinomas. In contrast, mice receiving rapamycin did not develop adenocarcinomas, and the extent of high-grade dysplasia in those mice was similar to that in control mice. Conclusions Patients with pre-neoplastic conditions, such as ulcerative colitis, who are undergoing a solid organ transplant might benefit from the use of mTOR inhibitors given their intrinsic anti-tumor properties. Among transplant recipients, colorectal cancer is more aggressive. This report highlights the association between immunosuppression and the disruption of the immune surveillance mechanisms against colorectal cancer.
Collapse
Affiliation(s)
- Imerio Angriman
- General Surgery Unit, University Hospital of Padua, Padua, Italy
| | - Lucrezia Furian
- Kidney Transplant Unit, University Hospital of Padua, Padua, Italy
| | - Melania Scarpa
- Esophageal and Digestive Tract Surgical Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine DIMED, University Hospital of Padua, Padua, Italy
| | - Susan Morgan
- Pathology Unit, Sheffield Teaching Hospitals, Sheffield, UK
| | - Andrea Porzionato
- Department of Neurosciences, University Hospital of Padua, Padua, Italy
| | - Andromachi Kotsafti
- Esophageal and Digestive Tract Surgical Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Luca Saadeh
- General Surgery Unit, University Hospital of Padua, Padua, Italy
| | | | - Raffaele De Caro
- Department of Neurosciences, University Hospital of Padua, Padua, Italy
| | - Amedeo Carraro
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Umberto Tedeschi
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Romeo Bardini
- General Surgery Unit, University Hospital of Padua, Padua, Italy
| | - Paolo Rigotti
- Kidney Transplant Unit, University Hospital of Padua, Padua, Italy
| | - Massimo Rugge
- Surgical Pathology Unit, Department of Medicine DIMED, University Hospital of Padua, Padua, Italy
| | - Carlo Castoro
- Upper GI Surgery Unit, Humanitas Research Hospital, Milan, Italy
| | | | - Marco Scarpa
- Esophageal and Digestive Tract Surgical Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
| |
Collapse
|
|
27
|
Dern K, van Eps A, Wittum T, Watts M, Pollitt C, Belknap J. Effect of Continuous Digital Hypothermia on Lamellar Inflammatory Signaling When Applied at a Clinically-Relevant Timepoint in the Oligofructose Laminitis Model. J Vet Intern Med 2017; 32:450-458. [PMID: 29282770 PMCID: PMC5787192 DOI: 10.1111/jvim.15027] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 09/06/2017] [Accepted: 11/28/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Although continuous digital hypothermia (CDH) protects lamellae from injury in the oligofructose (OF) model of sepsis-related laminitis (SRL), conflicting results exist from these studies regarding effects of CDH on lamellar inflammatory events. HYPOTHESIS/OBJECTIVES To determine the effect of CDH on lamellar inflammatory events in normal and OF-treated horses when instituted at a clinically relevant time point (onset of clinical signs of sepsis in this model). ANIMALS Standardbred geldings (n = 15) aged 3-11 years were used. METHODS In a randomized, controlled discovery study, animals were administered either OF (OF group, n = 8) or water (CON group, n = 8) by nasogastric tube and CDH was initiated in one forelimb (ICE) 12 hours later. Lamellar tissue samples were collected 24 hours after initiation of CDH (ICE and ambient [AMB] forelimbs). Lamellar mRNA concentrations of inflammatory mediators and lamellar leukocyte numbers were assessed using qPCR and immunohistochemistry, respectively; values from four sample groups (CON AMB, OF AMB, CON ICE, and OF ICE) were analyzed using mixed model linear regression. RESULTS Although lamellar mRNA concentrations of multiple inflammatory mediators (IL-1β, IL-6, CXCL1, MCP2, COX-2) were increased after OF administration (OF AMB group versus CON AMB; P < 0.05), only 2 inflammatory mediators (IL-6 and COX-2) and lamellar leukocyte numbers were decreased with CDH (OF ICE versus OF AMB; P < 0.05). CONCLUSIONS AND CLINICAL IMPORTANCE Continuous digital hypothermia initiated at a time point similar to that commonly used clinically (clinical onset of sepsis) resulted in a more focused inhibition of inflammatory signaling.
Collapse
Affiliation(s)
- K Dern
- Department of Veterinary Clinical Sciences, Ohio State University, Columbus, OH, USA
| | - A van Eps
- Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Qld, Australia
| | - T Wittum
- Department of Veterinary Preventive Medicine, Ohio State University, Columbus, OH, USA
| | - M Watts
- Department of Veterinary Clinical Sciences, Ohio State University, Columbus, OH, USA
| | - C Pollitt
- Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Qld, Australia
| | - J Belknap
- Department of Veterinary Clinical Sciences, Ohio State University, Columbus, OH, USA
| |
Collapse
|
|
28
|
Liu YZ, Wang YX, Jiang CL. Inflammation: The Common Pathway of Stress-Related Diseases. Front Hum Neurosci 2017; 11:316. [PMID: 28676747 PMCID: PMC5476783 DOI: 10.3389/fnhum.2017.00316] [Citation(s) in RCA: 449] [Impact Index Per Article: 56.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 06/01/2017] [Indexed: 01/11/2023] Open
Abstract
While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%-90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases.
Collapse
Affiliation(s)
- Yun-Zi Liu
- Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical UniversityShanghai, China
| | - Yun-Xia Wang
- Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical UniversityShanghai, China
| | - Chun-Lei Jiang
- Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical UniversityShanghai, China
| |
Collapse
|
|
29
|
Poh AR, Love CG, Masson F, Preaudet A, Tsui C, Whitehead L, Monard S, Khakham Y, Burstroem L, Lessene G, Sieber O, Lowell C, Putoczki TL, O'Donoghue RJJ, Ernst M. Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression. Cancer Cell 2017; 31:563-575.e5. [PMID: 28399411 PMCID: PMC5479329 DOI: 10.1016/j.ccell.2017.03.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 01/08/2017] [Accepted: 03/16/2017] [Indexed: 12/17/2022]
Abstract
Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.
Collapse
Affiliation(s)
- Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Christopher G Love
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Frederick Masson
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia
| | - Adele Preaudet
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Cary Tsui
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Lachlan Whitehead
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Simon Monard
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Yelena Khakham
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Lotta Burstroem
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Guillaume Lessene
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Oliver Sieber
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Colorectal Surgery, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia; School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia
| | - Clifford Lowell
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA 94143, USA
| | - Tracy L Putoczki
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Robert J J O'Donoghue
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
| |
Collapse
|
|
30
|
Abstract
Research of the last two decades showed that chronic low-grade inflammation, elevated blood glucose and insulin levels may play role in the onset of a number of non-communicable diseases such as type 2 diabetes and some forms of cancer. Regular exercise and fasting can ameliorate high blood glucose and insulin levels as well as increase the concentration of plasma ketone bodies. These, in consequence, may lead to reduction of inflammation. Exercise or severe restriction of caloric intake is not always advisable for patients, in particular those suffering from cancer. The ketogenic diet (KD), characterized by high fat, moderate protein and very low carbohydrate composition can evoke a physiological state similar to that triggered by exercise or fasting. These attributes of KD prompted its possible use in treatment of a number of metabolic diseases, including several types of malignancies. Although results from clinical studies employing KD in the treatment of cancer are still limited, the results obtained from animal models are encouraging and show that KD presents a viable option as an adjunct therapy for cancer.
Collapse
|
|
31
|
Syu LJ, Zhao X, Zhang Y, Grachtchouk M, Demitrack E, Ermilov A, Wilbert DM, Zheng X, Kaatz A, Greenson JK, Gumucio DL, Merchant JL, di Magliano MP, Samuelson LC, Dlugosz AA. Invasive mouse gastric adenocarcinomas arising from Lgr5+ stem cells are dependent on crosstalk between the Hedgehog/GLI2 and mTOR pathways. Oncotarget 2016; 7:10255-70. [PMID: 26859571 PMCID: PMC4891118 DOI: 10.18632/oncotarget.7182] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 01/24/2016] [Indexed: 02/07/2023] Open
Abstract
Gastric adenocarcinoma is the third most common cause of cancer-related death worldwide. Here we report a novel, highly-penetrant mouse model of invasive gastric cancer arising from deregulated Hedgehog/Gli2 signaling targeted to Lgr5-expressing stem cells in adult stomach. Tumor development progressed rapidly: three weeks after inducing the Hh pathway oncogene GLI2A, 65% of mice harbored in situ gastric cancer, and an additional 23% of mice had locally invasive tumors. Advanced mouse gastric tumors had multiple features in common with human gastric adenocarcinomas, including characteristic histological changes, expression of RNA and protein markers, and the presence of major inflammatory and stromal cell populations. A subset of tumor cells underwent epithelial-mesenchymal transition, likely mediated by focal activation of canonical Wnt signaling and Snail1 induction. Strikingly, mTOR pathway activation, based on pS6 expression, was robustly activated in mouse gastric adenocarcinomas from the earliest stages of tumor development, and treatment with rapamycin impaired tumor growth. GLI2A-expressing epithelial cells were detected transiently in intestine, which also contains Lgr5+ stem cells, but they did not give rise to epithelial tumors in this organ. These findings establish that deregulated activation of Hedgehog/Gli2 signaling in Lgr5-expressing stem cells is sufficient to drive gastric adenocarcinoma development in mice, identify a critical requirement for mTOR signaling in the pathogenesis of these tumors, and underscore the importance of tissue context in defining stem cell responsiveness to oncogenic stimuli.
Collapse
Affiliation(s)
- Li-Jyun Syu
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Xinyi Zhao
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | | | - Elise Demitrack
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Alexandre Ermilov
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Dawn M Wilbert
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Xinlei Zheng
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Ashley Kaatz
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Joel K Greenson
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Deborah L Gumucio
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Juanita L Merchant
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.,Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | | | - Linda C Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.,Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Andrzej A Dlugosz
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.,Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| |
Collapse
|
|
32
|
Atapattu L, Saha N, Chheang C, Eissman MF, Xu K, Vail ME, Hii L, Llerena C, Liu Z, Horvay K, Abud HE, Kusebauch U, Moritz RL, Ding BS, Cao Z, Rafii S, Ernst M, Scott AM, Nikolov DB, Lackmann M, Janes PW. An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth. J Exp Med 2016; 213:1741-57. [PMID: 27503072 PMCID: PMC4995075 DOI: 10.1084/jem.20151095] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 06/28/2016] [Indexed: 12/16/2022] Open
Abstract
The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance.
Collapse
Affiliation(s)
- Lakmali Atapattu
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Nayanendu Saha
- Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
| | - Chanly Chheang
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Moritz F Eissman
- Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
| | - Kai Xu
- Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
| | - Mary E Vail
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Linda Hii
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Carmen Llerena
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Zhanqi Liu
- Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
| | - Katja Horvay
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Helen E Abud
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia
| | | | | | - Bi-Sen Ding
- Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065
| | - Zhongwei Cao
- Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065
| | - Shahin Rafii
- Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065
| | - Matthias Ernst
- Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
| | - Andrew M Scott
- Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
| | - Dimitar B Nikolov
- Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
| | - Martin Lackmann
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Peter W Janes
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| |
Collapse
|
|
33
|
Poh AR, O'Donoghue RJJ, Ernst M, Putoczki TL. Mouse models for gastric cancer: Matching models to biological questions. J Gastroenterol Hepatol 2016; 31:1257-72. [PMID: 26809278 PMCID: PMC5324706 DOI: 10.1111/jgh.13297] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics.
Collapse
Affiliation(s)
- Ashleigh R Poh
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
| | - Robert J J O'Donoghue
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Matthias Ernst
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Tracy L Putoczki
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
| |
Collapse
|
|
34
|
Lesovaya EA, Kirsanov KI, Antoshina EE, Trukhanova LS, Gorkova TG, Shipaeva EV, Salimov RM, Belitsky GA, Blagosklonny MV, Yakubovskaya MG, Chernova OB. Rapatar, a nanoformulation of rapamycin, decreases chemically-induced benign prostate hyperplasia in rats. Oncotarget 2016; 6:9718-27. [PMID: 25991667 PMCID: PMC4496392 DOI: 10.18632/oncotarget.3929] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 04/15/2015] [Indexed: 12/11/2022] Open
Abstract
Benign prostatic hyperplasia (BPH) is the most common age-related disease in men. Here we tested the efficacy of Rapatar, a micellar nanoformulation of rapamycin, in two rat models of BPH: testosterone-induced and sulpiride-induced hyperplasia in ventral lobes and lateral/dorsal lobes, respectively. We found that Rapatar prevented hypertrophic and hyperplastic abnormalities and degenerative alterations in both BPH models. Rapatar normalized weight of the lateral lobes in sulpiride-induced BPH, the most relevant animal model of human BPH. Unlike Finasteride, a standard therapy of BPH, Rapatar reduced inflammation caused by sulpiride. No obvious side effects of Rapatar were detected. Our data provide a rationale for clinical trials of Rapatar in patients suffering from BPH.
Collapse
Affiliation(s)
- Ekaterina A Lesovaya
- Department of Chemical Carcinogenesis, Blokhin Cancer Research Center, Moscow, Russia
| | - Kirill I Kirsanov
- Department of Chemical Carcinogenesis, Blokhin Cancer Research Center, Moscow, Russia
| | - Elena E Antoshina
- Department of Chemical Carcinogenesis, Blokhin Cancer Research Center, Moscow, Russia
| | - Lubov S Trukhanova
- Department of Chemical Carcinogenesis, Blokhin Cancer Research Center, Moscow, Russia
| | - Tatiana G Gorkova
- Department of Chemical Carcinogenesis, Blokhin Cancer Research Center, Moscow, Russia
| | | | | | - Gennady A Belitsky
- Department of Chemical Carcinogenesis, Blokhin Cancer Research Center, Moscow, Russia
| | | | | | | |
Collapse
|
|
35
|
Ro SH, Xue X, Ramakrishnan SK, Cho CS, Namkoong S, Jang I, Semple IA, Ho A, Park HW, Shah YM, Lee JH. Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis. eLife 2016; 5:e12204. [PMID: 26913956 PMCID: PMC4805551 DOI: 10.7554/elife.12204] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 02/24/2016] [Indexed: 12/13/2022] Open
Abstract
The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53's control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis.
Collapse
Affiliation(s)
- Seung-Hyun Ro
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.,Department of Biochemistry, University of Nebraska, Lincoln, United States
| | - Xiang Xue
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| | - Sadeesh K Ramakrishnan
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| | - Chun-Seok Cho
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| | - Sim Namkoong
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| | - Insook Jang
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| | - Ian A Semple
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| | - Allison Ho
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| | - Hwan-Woo Park
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.,Department of Cell Biology, College of Medicine, Konyang University, Daejeon, Republic of Korea.,Myung-Gok Eye Research Institute, Konyang University, Seoul, Republic of Korea
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| | - Jun Hee Lee
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
| |
Collapse
|
|
36
|
Malley CO, Pidgeon GP. The mTOR pathway in obesity driven gastrointestinal cancers: Potential targets and clinical trials. BBA CLINICAL 2015; 5:29-40. [PMID: 27051587 PMCID: PMC4802403 DOI: 10.1016/j.bbacli.2015.11.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 11/03/2015] [Accepted: 11/11/2015] [Indexed: 12/20/2022]
Abstract
The mechanistic target of rapamycin (mTOR) is a crucial point of convergence between growth factor signalling, metabolism, nutrient status and cellular proliferation. The mTOR pathway is heavily implicated in the progression of many cancers and is emerging as an important driver of gastrointestinal (GI) malignancies. Due to its central role in adapting metabolism to environmental conditions, mTOR signalling is also believed to be critical in the development of obesity. Recent research has delineated that excessive nutrient intake can promote signalling through the mTOR pathway and possibly evoke changes to cellular metabolism that could accelerate obesity related cancers. Acting through its two effector complexes mTORC1 and mTORC2, mTOR dictates the transcription of genes important in glycolysis, lipogenesis, protein translation and synthesis and has recently been defined as a central mediator of the Warburg effect in cancer cells. Activation of the mTOR pathway is involved in both the pathogenesis of GI malignancies and development of resistance to conventional chemotherapy and radiotherapy. The use of mTOR inhibitors is a promising therapeutic option in many GI malignancies, with greatest clinical efficacy seen in combination regimens. Recent research has also provided insight into crosstalk between mTOR and other pathways which could potentially expand the list of therapeutic targets in the mTOR pathway. Here we review the available strategies for targeting the mTOR pathway in GI cancers. We discuss current clinical trials of both established and novel mTOR inhibitors, with particular focus on combinations of these drugs with conventional chemotherapy, radiotherapy and targeted therapies.
Collapse
Affiliation(s)
- Cian O Malley
- Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
| | - Graham P Pidgeon
- Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
| |
Collapse
|
|
37
|
Demitrack ES, Gifford GB, Keeley TM, Carulli AJ, VanDussen KL, Thomas D, Giordano TJ, Liu Z, Kopan R, Samuelson LC. Notch signaling regulates gastric antral LGR5 stem cell function. EMBO J 2015; 34:2522-36. [PMID: 26271103 DOI: 10.15252/embj.201490583] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 07/16/2015] [Indexed: 01/10/2023] Open
Abstract
The major signaling pathways regulating gastric stem cells are unknown. Here we report that Notch signaling is essential for homeostasis of LGR5(+) antral stem cells. Pathway inhibition reduced proliferation of gastric stem and progenitor cells, while activation increased proliferation. Notch dysregulation also altered differentiation, with inhibition inducing mucous and endocrine cell differentiation while activation reduced differentiation. Analysis of gastric organoids demonstrated that Notch signaling was intrinsic to the epithelium and regulated growth. Furthermore, in vivo Notch manipulation affected the efficiency of organoid initiation from glands and single Lgr5-GFP stem cells, suggesting regulation of stem cell function. Strikingly, constitutive Notch activation in LGR5(+) stem cells induced tissue expansion via antral gland fission. Lineage tracing using a multi-colored reporter demonstrated that Notch-activated stem cells rapidly generate monoclonal glands, suggesting a competitive advantage over unmanipulated stem cells. Notch activation was associated with increased mTOR signaling, and mTORC1 inhibition normalized NICD-induced increases in proliferation and gland fission. Chronic Notch activation induced undifferentiated, hyper-proliferative polyps, suggesting that aberrant activation of Notch in gastric stem cells may contribute to gastric tumorigenesis.
Collapse
Affiliation(s)
- Elise S Demitrack
- Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gail B Gifford
- Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA
| | - Theresa M Keeley
- Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA
| | - Alexis J Carulli
- Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kelli L VanDussen
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Dafydd Thomas
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, USA
| | - Thomas J Giordano
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, USA Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA
| | - Zhenyi Liu
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Raphael Kopan
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Linda C Samuelson
- Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA
| |
Collapse
|
|
38
|
Elevated Serum Levels of Soluble TNF Receptors and Adhesion Molecules Are Associated with Diabetic Retinopathy in Patients with Type-1 Diabetes. Mediators Inflamm 2015; 2015:279393. [PMID: 26339132 PMCID: PMC4539119 DOI: 10.1155/2015/279393] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/10/2014] [Accepted: 09/11/2014] [Indexed: 12/24/2022] Open
Abstract
Aims. To examine the association of the serum levels of TNF receptors, adhesion molecules, and inflammatory mediators with diabetic retinopathy (DR) in T1D patients. Methods. Using the multiplex immunoassay, we measured serum levels of eight proteins in 678 T1D subjects aged 20–75 years. Comparisons were made between 482 T1D patients with no complications and 196 T1D patients with DR. Results. The levels of sTNFR-I, sTNFR-II, CRP, SAA, sgp130, sIL6R, sVCAM1, and sICAM1 were significantly higher in the T1D patients with DR as compared to T1D patients with no complications. Multivariate logistic regression analysis revealed significant association for five proteins after adjustment for age, sex, and disease duration (sTNFR-I: OR = 1.57, sgp130: OR = 1.43, sVCAM1: OR = 1.27, sICAM1: OR = 1.42, and CRP: OR = 1.15). Conditional logistic regression on matched paired data revealed that subjects in the top quartile for sTNFR-I (OR = 2.13), sTNFR-II (OR = 1.66), sgp130 (OR = 1.82), sIL6R (OR = 1.75), sVCAM1 (OR = 1.98), sICAM1 (OR = 2.23), CRP (OR = 2.40) and SAA (OR = 2.03), had the highest odds of having DR. Conclusions. The circulating markers of inflammation, endothelial injury, and TNF signaling are significantly associated with DR in patients with T1D. TNFR-I and TNFR-II receptors are highly correlated, but DR associated more strongly with TNFR-I in these patients.
Collapse
|
|
39
|
Guan Y, Zhang L, Li X, Zhang X, Liu S, Gao N, Li L, Gao G, Wei G, Chen Z, Zheng Y, Ma X, Siwko S, Chen JL, Liu M, Li D. Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models. THE JOURNAL OF IMMUNOLOGY 2015; 195:339-46. [PMID: 26026060 DOI: 10.4049/jimmunol.1303356] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 05/04/2015] [Indexed: 12/21/2022]
Abstract
The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues to regulate cell growth and survival through various mechanisms. However, how mTORC1 responds to acute inflammatory signals to regulate bowel regeneration is still obscure. In this study, we investigated the role of mTORC1 in acute inflammatory bowel disease. Inhibition of mTORC1 activity by rapamycin treatment or haploinsufficiency of Rheb through genetic modification in mice impaired intestinal cell proliferation and induced cell apoptosis, leading to high mortality in dextran sodium sulfate- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis models. Through bone marrow transplantation, we found that mTORC1 in nonhematopoietic cells played a major role in protecting mice from colitis. Reactivation of mTORC1 activity by amino acids had a positive therapeutic effect in mTORC1-deficient Rheb(+/-) mice. Mechanistically, mTORC1 mediated IL-6-induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity. As mTORC1 is an important therapeutic target for multiple diseases, our findings will have important implications for the clinical usage of mTORC1 inhibitors in patients with acute inflammatory bowel disease.
Collapse
Affiliation(s)
- Yuting Guan
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Long Zhang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xia Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xinyan Zhang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Shijie Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Na Gao
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Liang Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Ganglong Gao
- Fengxian Hospital, Southern Medical University, Shanghai 201499, China; and
| | - Gaigai Wei
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Zhaohua Chen
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yansen Zheng
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xueyun Ma
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Stefan Siwko
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030
| | - Jin-Lian Chen
- Fengxian Hospital, Southern Medical University, Shanghai 201499, China; and
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China; Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030
| | - Dali Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
| |
Collapse
|
|
40
|
Ernst M, Preaudet A, Putoczki T. Non-invasive assessment of the efficacy of new therapeutics for intestinal pathologies using serial endoscopic imaging of live mice. J Vis Exp 2015:52383. [PMID: 25867916 PMCID: PMC4401233 DOI: 10.3791/52383] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Animal models of inflammatory bowel disease (IBD) and colorectal cancer (CRC) have provided significant insight into the cell intrinsic and extrinsic mechanisms that contribute to the onset and progression of intestinal diseases. The identification of new molecules that promote these pathologies has led to a flurry of activity focused on the development of potential new therapies to inhibit their function. As a result, various pre-clinical mouse models with an intact immune system and stromal microenvironment are now heavily used. Here we describe three experimental protocols to test the efficacy of new therapeutics in pre-clinical models of (1) acute mucosal damage, (2) chronic colitis and/or colitis-associated colon cancer, and (3) sporadic colorectal cancer. We also outline procedures for serial endoscopic examination that can be used to document the therapeutic response of an individual tumor and to monitor the health of individual mice. These protocols provide complementary experimental platforms to test the effectiveness of therapeutic compounds shown to be well tolerated by mice.
Collapse
Affiliation(s)
- Matthias Ernst
- The Walter and Eliza Hall Institute for Medical Research; The Department of Medical Biology, University of Melbourne; Olivia Newton-John Cancer Research Institute
| | - Adele Preaudet
- The Walter and Eliza Hall Institute for Medical Research
| | - Tracy Putoczki
- The Walter and Eliza Hall Institute for Medical Research; The Department of Medical Biology, University of Melbourne;
| |
Collapse
|
|
41
|
Zhang Q, Pan J, Lubet RA, Komas SM, Kalyanaraman B, Wang Y, You M. Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro. Cancer Prev Res (Phila) 2015; 8:318-26. [PMID: 25644152 DOI: 10.1158/1940-6207.capr-14-0142] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 01/22/2015] [Indexed: 12/26/2022]
Abstract
3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the serine/threonine protein kinase mTOR. Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single-agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-BrPA and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3-BrPA did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA-treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of GAPDH. Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-BrPA, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention.
Collapse
Affiliation(s)
- Qi Zhang
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jing Pan
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ronald A Lubet
- Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland
| | - Steven M Komas
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Yian Wang
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ming You
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
| |
Collapse
|
|
42
|
Genomic assays for Epstein-Barr virus-positive gastric adenocarcinoma. Exp Mol Med 2015; 47:e134. [PMID: 25613731 PMCID: PMC4314585 DOI: 10.1038/emm.2014.93] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 10/06/2014] [Indexed: 12/13/2022] Open
Abstract
A small set of gastric adenocarcinomas (9%) harbor Epstein–Barr virus (EBV) DNA within malignant cells, and the virus is not an innocent bystander but rather is intimately linked to pathogenesis and tumor maintenance. Evidence comes from unique genomic features of host DNA, mRNA, microRNA and CpG methylation profiles as revealed by recent comprehensive genomic analysis by The Cancer Genome Atlas Network. Their data show that gastric cancer is not one disease but rather comprises four major classes: EBV-positive, microsatellite instability (MSI), genomically stable and chromosome instability. The EBV-positive class has even more marked CpG methylation than does the MSI class, and viral cancers have a unique pattern of methylation linked to the downregulation of CDKN2A (p16) but not MLH1. EBV-positive cancers often have mutated PIK3CA and ARID1A and an amplified 9p24.1 locus linked to overexpression of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). Multiple noncoding viral RNAs are highly expressed. Patients who fail standard therapy may qualify for enrollment in clinical trials targeting cancer-related human gene pathways or promoting destruction of infected cells through lytic induction of EBV genes. Genomic tests such as the GastroGenus Gastric Cancer Classifier are available to identify actionable variants in formalin-fixed cancer tissue of affected patients.
Collapse
|
|
43
|
Brücher BL, Jamall IS. Epistemology of the origin of cancer: a new paradigm. BMC Cancer 2014; 14:331. [PMID: 24885752 PMCID: PMC4026115 DOI: 10.1186/1471-2407-14-331] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 05/06/2014] [Indexed: 02/06/2023] Open
Abstract
Background Carcinogenesis is widely thought to originate from somatic mutations and an inhibition of growth suppressors, followed by cell proliferation, tissue invasion, and risk of metastasis. Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers. Those remaining, 70 to 80%, are called “sporadic,” because they are essentially of unknown etiology. We propose a new paradigm for the origin of the majority of cancers. Presentation of hypothesis Our paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. If we are correct, this paradigm would suggest that the majority of the findings in cancer genetics so far reported are either late events or are epiphenomena that occur after the appearance of the pre-cancerous niche. Testing the hypothesis If, based on experimental and clinical findings presented here, this hypothesis is plausible, then the majority of findings in the genetics of cancer so far reported in the literature are late events or epiphenomena that could have occurred after the development of a PCN. Our model would make clear the need to establish preventive measures long before a cancer becomes clinically apparent. Future research should focus on the intermediate steps of our proposed sequence of events, which will enhance our understanding of the nature of carcinogenesis. Findings on inflammation and fibrosis would be given their warranted importance, with research in anticancer therapies focusing on suppressing the PCN state with very early intervention to detect and quantify any subclinical inflammatory change and to treat all levels of chronic inflammation and prevent fibrotic changes, and so avoid the transition from a normal cell to a cancer cell. Implication of the hypothesis The paradigm proposed here, if proven, spells out a sequence of steps, one or more of which could be interdicted or modulated early in carcinogenesis to prevent or, at a minimum, slow down the progression of many cancers.
Collapse
|
|
44
|
Wang XW, Zhang YJ. Targeting mTOR network in colorectal cancer therapy. World J Gastroenterol 2014; 20:4178-88. [PMID: 24764656 PMCID: PMC3989954 DOI: 10.3748/wjg.v20.i15.4178] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/28/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
The mechanistic target of rapamycin (mTOR) integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth, proliferation and survival. A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division. Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate. Multiple genetic alterations are involved in colorectal carcinogenesis, including oncogenic Ras activation, phosphatidylinositol 3-kinase pathway hyperactivation, p53 mutation, and dysregulation of wnt pathway. Many oncogenic pathways activate the mTOR pathway. mTOR has emerged as an effective target for colorectal cancer therapy. In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives. However, the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest, especially in advanced metastatic colorectal cancer. Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy, inhibitors of vascular endothelial growth factor, epidermal growth factor receptor and Mitogen-activated protein kinase kinase (MEK) inhibitors are being intensively studied and appear to be promising. Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens. In this paper, oncogenic gene alterations in colorectal cancer, as well as their interaction with the mTOR pathway, are systematically summarized. The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed. New players in mTOR signaling pathway, such as non-steroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.
Collapse
|
|
45
|
Fisher DT, Appenheimer MM, Evans SS. The two faces of IL-6 in the tumor microenvironment. Semin Immunol 2014; 26:38-47. [PMID: 24602448 DOI: 10.1016/j.smim.2014.01.008] [Citation(s) in RCA: 503] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 01/23/2014] [Indexed: 01/11/2023]
Abstract
Within the tumor microenvironment, IL-6 signaling is generally considered a malevolent player, assuming a dark visage that promotes tumor progression. Chronic IL-6 signaling is linked to tumorigenesis in numerous mouse models as well as in human disease. IL-6 acts intrinsically on tumor cells through numerous downstream mediators to support cancer cell proliferation, survival, and metastatic dissemination. Moreover, IL-6 can act extrinsically on other cells within the complex tumor microenvironment to sustain a pro-tumor milieu by supporting angiogenesis and tumor evasion of immune surveillance. A lesser known role for IL-6 signaling has recently emerged in which it plays a beneficial role, presenting a fairer face that opposes tumor growth by mobilizing anti-tumor T cell immune responses to attain tumor control. Accumulating evidence establishes IL-6 as a key player in the activation, proliferation and survival of lymphocytes during active immune responses. IL-6 signaling can also resculpt the T cell immune response, shifting it from a suppressive to a responsive state that can effectively act against tumors. Finally, IL-6 plays an indispensable role in boosting T cell trafficking to lymph nodes and to tumor sites, where they have the opportunity to become activated and execute their cytotoxic effector functions, respectively. Here, we discuss the dual faces of IL-6 signaling in the tumor microenvironment; the dark face that drives malignancy, and the fairer aspect that promotes anti-tumor adaptive immunity.
Collapse
Affiliation(s)
- Daniel T Fisher
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, United States
| | | | - Sharon S Evans
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, United States.
| |
Collapse
|
|
46
|
Blagosklonny MV. Immunosuppressants in cancer prevention and therapy. Oncoimmunology 2013; 2:e26961. [PMID: 24575379 PMCID: PMC3926869 DOI: 10.4161/onci.26961] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 10/25/2013] [Accepted: 10/25/2013] [Indexed: 12/13/2022] Open
Abstract
Rapalogs such as rapamycin (sirolimus), everolimus, temserolimus, and deforolimus are indicated for the treatment of some malignancies. Rapamycin is the most effective cancer-preventive agent currently known, at least in mice, dramatically delaying carcinogenesis in both normal and cancer-prone murine strains. In addition, rapamycin and everolimus decrease the risk of cancer in patients receiving these drugs in the context of immunosuppressive regimens. In general, the main concern about the use of immunosuppressants in humans is an increased risk of cancer. Given that rapalogs are useful in cancer prevention and therapy, should they be viewed as immunosuppressants or immunostimulators? Or should we reconsider the role of immunity in cancer altogether? In addition to its anti-viral, anti-inflammatory, anti-angiogenic and anti-proliferative effects, rapamycin operates as a gerosuppressant, meaning that it inhibits the cellular conversion to a senescent state (the so-called geroconversion), a fundamental process involved in aging and age-related pathologies including cancer.
Collapse
|
|
47
|
|
|
48
|
Kubatzky KF, Kloos B, Hildebrand D. Signaling cascades of Pasteurella multocida toxin in immune evasion. Toxins (Basel) 2013; 5:1664-81. [PMID: 24064721 PMCID: PMC3798879 DOI: 10.3390/toxins5091664] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 09/17/2013] [Accepted: 09/17/2013] [Indexed: 12/11/2022] Open
Abstract
Pasteurella multocida toxin (PMT) is a protein toxin found in toxigenic strains of Pasteurella multocida. PMT is the causative agent for atrophic rhinitis in pigs, a disease characterized by loss of nasal turbinate bones due to an inhibition of osteoblast function and an increase in osteoclast activity and numbers. Apart from this, PMT acts as a strong mitogen, protects from apoptosis and has an impact on the differentiation and function of immune cells. Many signaling pathways have been elucidated, however, the effect of these signaling cascades as a means to subvert the host’s immune system are just beginning to unravel.
Collapse
Affiliation(s)
- Katharina F Kubatzky
- Medical Microbiology and Hygiene, Department of Infectious Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 324, Heidelberg 69120, Germany.
| | | | | |
Collapse
|
|
49
|
Garbers C, Kuck F, Aparicio-Siegmund S, Konzak K, Kessenbrock M, Sommerfeld A, Häussinger D, Lang PA, Brenner D, Mak TW, Rose-John S, Essmann F, Schulze-Osthoff K, Piekorz RP, Scheller J. Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR). Cell Cycle 2013; 12:3421-32. [PMID: 24047696 DOI: 10.4161/cc.26431] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Interleukin 6 (IL-6) signaling plays a role in inflammation, cancer, and senescence. Here, we identified soluble IL-6 receptor (sIL-6R) as a member of the senescence-associated secretory phenotype (SASP). Senescence-associated sIL-6R upregulation was mediated by mammalian target of rapamycin (mTOR). sIL-6R was mainly generated by a disintegrin and metalloprotease 10 (ADAM10)-dependent ectodomain shedding to enable IL-6 trans-signaling. In vivo, heterozygous PTEN-knockout mice exhibited higher mTOR activity and increased sIL-6R levels. Moreover, aberrant EGF receptor (EGFR) activation triggered IL-6 synthesis. In analogy to senescence, EGFR-induced activation of mTOR also induced IL-6R expression and sIL-6R generation. Hence, mTOR activation reprograms IL-6 non-responder cells into IL-6 responder cells. Our data suggest that mTOR serves as a central molecular switch to facilitate cellular IL-6 classic and trans-signaling via IL-6R upregulation with direct implications for cellular senescence and tumor development.
Collapse
Affiliation(s)
- Christoph Garbers
- Institute of Biochemistry and Molecular Biology II; Medical Faculty; Heinrich-Heine-University; Düsseldorf, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Fan W, Zhang J, Zhang Z, Wang Q, Cao F. Adaptive inflammatory microenvironment for cell-based regeneration in ischemic cardiovascular disease. Organogenesis 2013; 9:121-4. [PMID: 23974172 DOI: 10.4161/org.25586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Cell-based therapy has emerged to be a promising strategy for alleviating the heavy burden of ischemic cardiovascular disease for nearly two decades, despite a variety of pending questions about its availability and efficacy. One question is whether and how the cells behave for regeneration in vivo, which could be limited or potentiated by the inflammatory microenvironment following myocardial infarction or critical limb ischemia. To this end, we hypothesize that the "adaptive inflammatory microenvironment" is pertinent to the cell-based regeneration, and make a brief comment on it based upon recent evidence.
Collapse
Affiliation(s)
- Weiwei Fan
- Department of Cardiology & Molecular Imaging Program; Xijing Hospital; Fourth Military Medical University; Xi'an, PR China
| | | | | | | | | |
Collapse
|