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Li YT, Shao WQ, Chen ZM, Ma XC, Yi CH, Tao BR, Zhang B, Ma Y, Zhang G, Zhang R, Geng Y, Lin J, Chen JH. GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in metabolic dysfunction-associated steatohepatitis livers. Clin Mol Hepatol 2025; 31:409-425. [PMID: 39657752 PMCID: PMC12016653 DOI: 10.3350/cmh.2024.0657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND/AIMS Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. METHODS The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. RESULTS MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. CONCLUSION In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.
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Affiliation(s)
- Yi-Tong Li
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Wei-Qing Shao
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhen-Mei Chen
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiao-Chen Ma
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Chen-He Yi
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Bao-Rui Tao
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Bo Zhang
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yue Ma
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Guo Zhang
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Rui Zhang
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yan Geng
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jing Lin
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jin-Hong Chen
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Shi W, Xu W, Song L, Zeng Q, Qi G, Qin Y, Li Z, Liu X, Jiao Z, Zhao Y, Liu N, Lu H. A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses. Mol Ther 2024; 32:4482-4496. [PMID: 39489922 PMCID: PMC11638872 DOI: 10.1016/j.ymthe.2024.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 09/20/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024] Open
Abstract
It is a challenge to invigorate tumor-infiltrating lymphocytes without causing immune-related adverse events, which also stands as a primary factor contributing to resistance against cancer immunotherapies. Interleukin (IL)-15 can potently promote expansion and activation of T cells, but its clinical use has been limited by dose-limiting toxicities. In this study, we develop a tumor-conditional IL-15 (pro-IL-15), which masks IL-15 with steric hindrance caused by Fc fragment and IL-15Rα-sushi domain. Upon reaching the tumor site, it can be cleaved by tumor-associated proteases to release an IL-15 superagonist, resulting in potent antitumor activities. Systemic delivery of pro-IL-15 demonstrates significantly reduced toxicity but uncompromised antitumor efficacy. Pro-IL-15 can yield better effectors and vitalize terminally exhausted CD8+ T cells to overcome checkpoint blockade resistance. Moreover, pro-IL-15 promotes chemotaxis and activation of adoptive T cells, leading to eradication of advanced solid tumors and durable cures. Furthermore, pro-IL-15 shows promise for synergizing with other immunotherapies like IL-12 and oncolytic virus by improving the CD8/Treg ratio and interferon-γ levels, resulting in substantial regression of both local and metastatic cold tumors. Collectively, our results suggest that pro-IL-15 represents a compelling strategy for overcoming resistance to current immunotherapies while avoiding toxicities.
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Affiliation(s)
- Wenqiang Shi
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Wei Xu
- Department of Orthopedics, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai 200336, China
| | - Luyao Song
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Qiongya Zeng
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Gen Qi
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Ying Qin
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Zhikun Li
- Department of Orthopedics, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai 200336, China
| | - Xianglei Liu
- National Key Laboratory of Lead Druggability Research, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China
| | - Zheng Jiao
- Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 241 Huaihai West Road, Shanghai 200030, China
| | - Yonggang Zhao
- Suzhou HKeyBio Company Ltd, 218 Xinghu Street, Suzhou 215004, China
| | - Nan Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Huili Lu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Chongqing Research Institute, Shanghai Jiao Tong University, Chongqing 401135, China.
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McAndrews KM, Mahadevan KK, Kalluri R. Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses. Cold Spring Harb Perspect Med 2024; 14:a041411. [PMID: 38191175 PMCID: PMC11216184 DOI: 10.1101/cshperspect.a041411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components changing at different stages of progression and in response to therapy. To effectively treat cancer, an understanding of the functional role of the TME is needed. Genetically engineered mouse models have enabled comprehensive insight into the complex interactions within the TME ecosystem that regulate disease progression. Here, we review recent advances in mouse models that have been employed to understand how the TME regulates cancer initiation, progression, metastasis, and response to therapy.
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Affiliation(s)
- Kathleen M McAndrews
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA
| | - Krishnan K Mahadevan
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA
- Department of Bioengineering, Rice University, Houston, Texas 77251, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
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Kidess E, Giesecke Y, Eichhorn I, Mohr R, Jann H, Fischer C, Wiedenmann B, Roderburg C, Tacke F, Sigal M. Osteopontin is a prognostic circulating biomarker in patients with neuroendocrine neoplasms. J Cancer Res Clin Oncol 2023; 149:10925-10933. [PMID: 37318593 PMCID: PMC10423109 DOI: 10.1007/s00432-023-04979-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 06/07/2023] [Indexed: 06/16/2023]
Abstract
PURPOSE Osteopontin (OPN), also called secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and which has been shown to be involved in tumorigenesis and metastasis in many malignancies. Its role in neuroendocrine neoplasms (NEN) remains to be established. The aim of the study was to analyze plasma concentrations of OPN in patients with NEN and to explore its diagnostic and prognostic value as a clinical biomarker. METHODS OPN plasma concentrations were measured in a total of 38 patients with histologically proven NEN at three different time points during the course of disease and therapy (at the start of the study, after 3 and 12 months, respectively) as well as in healthy controls. Clinical and imaging data as well as concentrations of Chromogranin A (CgA) and Neuron Specific Enolase (NSE) were assessed. RESULTS OPN levels were significantly higher in patients with NEN compared to healthy controls. High-grade tumors (grade 3) showed the highest OPN levels. OPN levels were neither different between male and female patients nor between different primary tumor sites. OPN correlated significantly with corresponding NSE levels, while there was no correlation with Chromogranin A. High OPN levels above a cutoff value of 200 ng/ml at initial analysis predicted a worsened prognosis with significantly shorter progression-free survival of patients with NEN, which also held true within the subgroup of well-differentiated G1/G2 tumors. CONCLUSION Our data indicate that high baseline OPN levels in patients with NEN are predictive of an adverse outcome with shorter progression-free survival, even within the group of well differentiated G1/G2 tumors. Therefore, OPN may be used as a surrogate prognostic biomarker in patients with NEN.
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Affiliation(s)
- Evelyn Kidess
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany.
| | - Yvonne Giesecke
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Ines Eichhorn
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Henning Jann
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Christian Fischer
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Christoph Roderburg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany.
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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Novoa Díaz MB, Martín MJ, Gentili C. Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance. World J Gastroenterol 2022; 28:3027-3046. [PMID: 36051330 PMCID: PMC9331520 DOI: 10.3748/wjg.v28.i26.3027] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the β-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)-INQUISUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
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Tan Y, Zhao L, Yang YG, Liu W. The Role of Osteopontin in Tumor Progression Through Tumor-Associated Macrophages. Front Oncol 2022; 12:953283. [PMID: 35898884 PMCID: PMC9309262 DOI: 10.3389/fonc.2022.953283] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 06/15/2022] [Indexed: 11/18/2022] Open
Abstract
Osteopontin (OPN) is a multifunctional phosphorylated protein. It is widely involved in solid tumor progression, such as intensification of macrophage recruitment, inhibition of T-cell activity, aggravation of tumor interstitial fibrosis, promotion of tumor metastasis, chemotherapy resistance, and angiogenesis. Most of these pathologies are affected by tumor-associated macrophages (TAMs), an important component of the tumor microenvironment (TME). TAMs have been extensively characterized, including their subsets, phenotypes, activation status, and functions, and are considered a promising therapeutic target for cancer treatment. This review focuses on the interaction between OPN and TAMs in mediating tumor progression. We discuss the strategies for targeting OPN and TAMs to treat cancer and factors that may affect the therapeutic outcomes of blocking OPN or depleting TAMs. We also discuss the role of cancer cell- vs. TAM-derived OPN in tumorigenesis, the mechanisms of how OPN affects TAM recruitment and polarization, and why OPN could mediate anti-tumor and pro-tumor effects, as well as previously reported discrepancies.
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Affiliation(s)
- Yuying Tan
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National–Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Lei Zhao
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National–Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National–Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
- *Correspondence: Yong-Guang Yang, ; Wentao Liu,
| | - Wentao Liu
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National–Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
- *Correspondence: Yong-Guang Yang, ; Wentao Liu,
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Giannos P, Triantafyllidis KK, Giannos G, Kechagias KS. SPP1 in infliximab resistant ulcerative colitis and associated colorectal cancer: an analysis of differentially expressed genes. Eur J Gastroenterol Hepatol 2022; 34:598-606. [PMID: 35102110 DOI: 10.1097/meg.0000000000002349] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Infliximab, a tumour necrosis factor-α (TNFα) antagonist, has advanced the management of ulcerative colitis. Although efficacious, considerable percentage of patients are resistant to treatment. Accumulative inflammatory burden in long-term ulcerative colitis patients refractory to therapy increases the risk of developing colorectal cancer (CRC). Our study investigated anti-TNFα-naïve patients with active ulcerative colitis to identify gene biomarkers whose dysregulated expression correlated with resistance to infliximab (IFX) treatment and poor prognosis in CRC. METHODS Differentially expressed genes (DEGs) from two studies (GSE73661 and GSE14580) with colonic mucosal samples were retrieved. Noninflammatory bowel disease controls were compared with those with active ulcerative colitis that either responded or were resistant to IFX before treatment. DEGs from ulcerative colitis samples resistant to IFX were used to construct a protein-protein interaction network, and clustering gene modules were identified. Module DEGs that overlapped with ulcerative colitis samples responsive to IFX were analysed, based on topological closeness and radiality. Hub genes were obtained, and their correlation with CRC progression was evaluated. Their expression in CRC tissues and their tumour microenvironment immune status was estimated. RESULTS Three clusters composed of 582 DEGs from ulcerative colitis samples resistant to IFX were retrieved. Comparative analysis identified 305 overlapping DEGs with ulcerative colitis samples responsive to IFX. Topological analysis revealed a hub gene - SPP1 - whose overexpression in CRC tissues and patients correlated with increased infiltration of immune signatures and poor prognosis. CONCLUSION SPP1 may serve as potential gene biomarker and predictor of resistance to IFX therapy in ulcerative colitis and CRC development.
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Affiliation(s)
- Panagiotis Giannos
- Department of Life Sciences, Faculty of Natural Sciences, Imperial College London
- Society of Meta-research and Biomedical Innovation, London
| | | | - Georgios Giannos
- Second Department of Surgery, Evaggelismos Hospital, Athens
- Department of Medicine, University of Crete Medical School, Heraklion, Crete, Greece
| | - Konstantinos S Kechagias
- Society of Meta-research and Biomedical Innovation, London
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London
- Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital National Health Service (NHS) Foundation Trust, London, UK
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9
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Zhang X, Bi K, Tu X, Zhang Q, Cao Q, Liang Y, Zeng P, Wang L, Liu T, Fang W, Diao H. Interleukin-33 as an early predictor of cetuximab treatment efficacy in patients with colorectal cancer. Cancer Med 2021; 10:8338-8351. [PMID: 34664425 PMCID: PMC8633246 DOI: 10.1002/cam4.4331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/25/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cetuximab is used for colorectal cancer (CRC) treatment. However, the early biomarker of treatment efficacy of cetuximab has not been identified. METHODS After 1 year of cetuximab treatment, patients were divided into an effective group and an ineffective group. The interleukin-33 (IL-33) level and the distribution of lymphatic cells in patients were investigated by analyzing the peripheral blood mononuclear cells via flow cytometry analysis and ELISA. The correlation between IL-33 immunomodulatory effect and cetuximab treatment efficacy was determined through experiments in vivo and in vitro. RESULTS The IL-33 level in the peripheral blood was increased at 4 weeks after cetuximab administration of effective group, meanwhile, the osteopontin (OPN) was reduced. Whereas neither IL-33 level nor OPN level of ineffective patients changed. In the effective group, the number of natural killer (NK) and CD8+ T cells were increased. Moreover, CD137 and CD107a expression on NK cells were higher in the effective group compared to the ineffective group. In vitro cetuximab treatment also increased the number of NK and CD8+ T cells as well as CD137 and CD107a expression upon IL-33 stimulation. Moreover, the secretion of OPN was inhibited by IL-33 administration in cetuximab-treated PBMCs from the effective group patients. IL-33 upregulated the cytotoxicity of NK cells and inhibited tumor cells growth in the effective cetuximab treatment mice. CONCLUSION Effective cetuximab treatment induced a change of IL-33 and OPN at the early stage and triggered the NK cells antitumor activity. Consequently, significantly increased IL-33 level and decreased OPN level in the peripheral blood at the early treatment are proposed as potential predictors of cetuximab treatment efficacy.
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Affiliation(s)
- Xujun Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Kefan Bi
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaoxuan Tu
- Department of Medical OncologyFirst Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Qiong Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Qingyi Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yan Liang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Ping Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Lin Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Tianxing Liu
- Department of Biological SciencesUniversity of TorontoTorontoOntarioCanada
| | - Weijia Fang
- Department of Medical OncologyFirst Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
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10
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Wang C, Shi Z, Zhang Y, Li M, Zhu J, Huang Z, Zhang J, Chen J. CBFβ promotes colorectal cancer progression through transcriptionally activating OPN, FAM129A, and UPP1 in a RUNX2-dependent manner. Cell Death Differ 2021; 28:3176-3192. [PMID: 34050318 PMCID: PMC8563980 DOI: 10.1038/s41418-021-00810-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 05/08/2021] [Accepted: 05/17/2021] [Indexed: 02/04/2023] Open
Abstract
Colorectal cancer (CRC) is commonly associated with aberrant transcription regulation, but characteristics of the dysregulated transcription factors in CRC pathogenesis remain to be elucidated. In the present study, core-binding factor β (CBFβ) is found to be significantly upregulated in human CRC tissues and correlates with poor survival rate of CRC patients. Mechanistically, CBFβ is found to promote CRC cell proliferation, migration, invasion, and inhibit cell apoptosis in a RUNX2-dependent way. Transcriptome studies reveal that CBFβ and RUNX2 form a transcriptional complex that activates gene expression of OPN, FAM129A, and UPP1. Furthermore, CBFβ significantly promotes CRC tumor growth and live metastasis in a mouse xenograft model and a mouse liver metastasis model. In addition, tumor-suppressive miR-143/145 are found to inhibit CBFβ expression by specifically targeting its 3'-UTR region. Consistently, an inverse correlation between miR-143/miR-145 and CBFβ expression levels is present in CRC patients. Taken together, this study uncovers a novel regulatory role of CBFβ-RUNX2 complex in the transcriptional activation of OPN, FAM129A, and UPP1 during CRC development, and may provide important insights into CRC pathogenesis.
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Affiliation(s)
- Chen Wang
- grid.41156.370000 0001 2314 964XState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China
| | - Ziyu Shi
- grid.41156.370000 0001 2314 964XState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China
| | - Yuqian Zhang
- grid.41156.370000 0001 2314 964XState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China
| | - Mingyue Li
- grid.41156.370000 0001 2314 964XState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China
| | - Jie Zhu
- grid.41156.370000 0001 2314 964XState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China
| | - Zhen Huang
- grid.41156.370000 0001 2314 964XState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China
| | - Junfeng Zhang
- grid.41156.370000 0001 2314 964XState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China
| | - Jiangning Chen
- grid.41156.370000 0001 2314 964XState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China ,grid.41156.370000 0001 2314 964XState Key Laboratory of Analytical Chemistry for Life Sciences, Nanjing University, Nanjing, PR China
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11
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Ren J, Guo B, Sui H, Chen J, Zhang L, Lv C, Li B. The effects of aerobic exercise on the intestinal tumors and flora of the Apc Min/+ mouse. Clin Transl Oncol 2021; 24:305-318. [PMID: 34436759 DOI: 10.1007/s12094-021-02689-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 07/29/2021] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Intestinal tumor is one of the most common tumors that seriously threaten the health of residents all over the world. Studies suggest that the imbalance of intestinal flora is associated with tumorgenesis; meanwhile, long-term regular aerobic exercise can improve the occurrence and development of tumors. However, moderate aerobic exercise affecting the development of intestinal tumors and their related flora has not been explored. Thus, the purpose of our study is to explore the effects of aerobic exercise on intestinal tumor growth and flora changes in ApcMin/+ mice, and try to answer whether there is a correlation between them after exercise intervention. METHODS In this study, 18 required ApcMin/+ mice were randomly divided into Model group (n = 6), Exercise group (n = 6), and Aspirin group (positive control, n = 6), while C57BL/6 J wild-type mice were used as the blank control group. Each group is given corresponding intervention. Weight monitoring, tumor counts, hematoxylin-eosin staining, TdT-mediated dUTP nick-end labeling (TUNEL) fluorescence assay, immunohistochemistry (IHC), fecal sampling and grouping, and bacterial 16S rDNA gene analysis were completed after 12 weeks' intervention for each group of mice. RESULTS As a result, we were able to show significant improvements in mice' body weight changing rates (Exercise group 8.6% higher than Model control group), tumor numbers (Exercise group 4.33 ± 0.94 vs. Model control group 7.33 ± 2.49, Then put the slides into xylenewith tumor inhibition rate 40.93%), tumor pathological staging (Exercise group mainly low-grade tumorous adenomas vs. Model group mainly high-grade adenomas), and TUNEL staining (Exercise group 8.59% higher positive rate of apoptotic cells in tumors than Model group). The 16s rRNA sequencing analysis results showed that aerobic exercise could regulate the abundance of some genus (16/149, P < 0.01), and the number of intestinal tumors correlates with changes in the abundance of some bacteria in the intestinal flora (positive correlation with probiotics abundance and negative correlation with conditioned pathogens). DISCUSSION Changes in flora abundance may be one of the reasons for aerobic exercise to reduce the number of intestinal tumors, probably mediated by cell apoptosis. Future studies should focus on the potential mechanism of aerobic exercise in preventing intestinal tumorgenesis, especially the molecular mechanism through intestinal flora. CONCLUSION Aerobic exercise has a preventive effect on intestinal tumors in ApcMin/+ mice, and can regulate the abundance of intestinal flora.
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Affiliation(s)
- J Ren
- Changhai Hospital of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China
| | - B Guo
- Changhai Hospital of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China
| | - H Sui
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Medical Experiment Center, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201803, China
| | - J Chen
- Changhai Hospital of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China
| | - L Zhang
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Integrated Chinese and Western Medicine, Henan Provincial Cancer Hospital, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - C Lv
- Changhai Hospital of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China
| | - B Li
- Changhai Hospital of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China.
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12
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Amilca-Seba K, Sabbah M, Larsen AK, Denis JA. Osteopontin as a Regulator of Colorectal Cancer Progression and Its Clinical Applications. Cancers (Basel) 2021; 13:cancers13153793. [PMID: 34359694 PMCID: PMC8345080 DOI: 10.3390/cancers13153793] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/29/2022] Open
Abstract
Simple Summary The mortality of colorectal cancer is principally related to metastatic disease at the time of diagnosis or to the growth of initially undetectable micro-metastasis. Current therapeutic strategies are efficient in patients with locally advanced cancer, but are rarely able to cure patients with metastatic disease. Therapeutic failure is mainly associated with drug resistance and an aggressive phenotype. The identification of new biomarkers for micro-metastasis and tumor progression remains an unmet clinical need that should allow for improved patient stratification for optimal treatment and may lead to the identification of novel therapeutic targets. Osteopontin (OPN), a multifunctional protein, has emerged as a potentially valuable biomarker in several cancer types. This review principally describes the molecular mechanisms of OPN that are associated with colorectal cancer (CRC) progression and metastasis, as well as the use of OPN as a clinical biomarker. This review identifies a role for OPN as a biomarker ready for extended clinical application and discusses its use as a therapeutic target. Abstract A high expression of the phosphoprotein osteopontin (OPN) has been associated with cancer progression in several tumor types, including breast cancer, hepatocarcinoma, ovarian cancer, and colorectal cancer (CRC). Interestingly, OPN is overexpressed in CRC and is associated with a poor prognosis linked to invasion and metastasis. Here, we review the regulation and functions of OPN with an emphasis on CRC. We examine how epigenetic and genetic regulators interact with the key signaling pathways involved in this disease. Then, we describe the role of OPN in cancer progression, including proliferation, survival, migration, invasion, and angiogenesis. Furthermore, we outline the interest of using OPN as a clinical biomarker, and discuss if and how osteopontin can be implemented as a routine assay in clinical laboratories for monitoring CRC patients. Finally, we discuss the use of OPN an attractive, but challenging, therapeutic target.
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Affiliation(s)
- Katyana Amilca-Seba
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France; (K.A.-S.); (M.S.); (A.K.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France
- Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, 75005 Paris, France
| | - Michèle Sabbah
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France; (K.A.-S.); (M.S.); (A.K.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France
- Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, 75005 Paris, France
- Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France
| | - Annette K. Larsen
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France; (K.A.-S.); (M.S.); (A.K.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France
- Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, 75005 Paris, France
- Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France
| | - Jérôme A. Denis
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France; (K.A.-S.); (M.S.); (A.K.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France
- Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, 75005 Paris, France
- Department of Endocrinology and Oncology Biochemistry, Pitié-Salpetrière Hospital, 75013 Paris, France
- Correspondence: ; Tel.: +33-(0)1-42-16-20-39
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13
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Larionova I, Kazakova E, Gerashchenko T, Kzhyshkowska J. New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis. Cancers (Basel) 2021; 13:cancers13133253. [PMID: 34209679 PMCID: PMC8268686 DOI: 10.3390/cancers13133253] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Since the targeting of a single pro-angiogenic factor fails to improve oncological disease outcome, significant efforts have been made to identify new pro-angiogenic factors that could compensate for the deficiency of current therapy or act independently as single drugs. Our review aims to present the state-of-the art for well-known and recently described factors produced by macrophages that induce and regulate angiogenesis. A number of positive and negative regulators of angiogenesis in the tumor microenvironment are produced by tumor-associated macrophages (TAMs). Accumulating evidence has indicated that, apart from the well-known angiogenic factors, there are plenty of novel angiogenesis-regulating proteins that belong to different classes. We summarize the data regarding the direct or indirect mechanisms of the interaction of these factors with endothelial cells during angiogenesis. We highlight the recent findings that explain the limitations in the efficiency of current anti-angiogenic therapy approaches. Abstract Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs.
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Affiliation(s)
- Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia;
- Correspondence: (I.L.); (J.K.)
| | - Elena Kazakova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
| | - Tatiana Gerashchenko
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia;
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg—Hessen, 68167 Mannheim, Germany
- Correspondence: (I.L.); (J.K.)
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14
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Hendley AM, Rao AA, Leonhardt L, Ashe S, Smith JA, Giacometti S, Peng XL, Jiang H, Berrios DI, Pawlak M, Li LY, Lee J, Collisson EA, Anderson MS, Fragiadakis GK, Yeh JJ, Ye CJ, Kim GE, Weaver VM, Hebrok M. Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree. eLife 2021; 10:e67776. [PMID: 34009124 PMCID: PMC8184217 DOI: 10.7554/elife.67776] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/18/2021] [Indexed: 12/25/2022] Open
Abstract
To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
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Affiliation(s)
- Audrey M Hendley
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
- Center for Bioengineering and Tissue Regeneration, University of California, San FranciscoSan FranciscoUnited States
| | - Arjun A Rao
- CoLabs, University of California, San FranciscoSan FranciscoUnited States
- Bakar ImmunoX Initiative, University of California, San FranciscoSan FranciscoUnited States
| | - Laura Leonhardt
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Sudipta Ashe
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Jennifer A Smith
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Simone Giacometti
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Xianlu L Peng
- Department of Pharmacology, University of North Carolina at Chapel HillChapel HillUnited States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillChapel HillUnited States
| | - Honglin Jiang
- Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San FranciscoSan FranciscoUnited States
| | - David I Berrios
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Mathias Pawlak
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's HospitalBostonUnited States
| | - Lucia Y Li
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Jonghyun Lee
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Eric A Collisson
- Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San FranciscoSan FranciscoUnited States
| | - Mark S Anderson
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
| | - Gabriela K Fragiadakis
- CoLabs, University of California, San FranciscoSan FranciscoUnited States
- Bakar ImmunoX Initiative, University of California, San FranciscoSan FranciscoUnited States
- Department of Medicine, Division of Rheumatology, University of California, San FranciscoSan FranciscoUnited States
| | - Jen Jen Yeh
- Department of Pharmacology, University of North Carolina at Chapel HillChapel HillUnited States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillChapel HillUnited States
- Department of Surgery, University of North Carolina at Chapel HillChapel HillUnited States
| | - Chun Jimmie Ye
- Parker Institute for Cancer ImmunotherapySan FranciscoUnited States
| | - Grace E Kim
- Department of Pathology, University of California, San FranciscoSan FranciscoUnited States
| | - Valerie M Weaver
- Center for Bioengineering and Tissue Regeneration, University of California, San FranciscoSan FranciscoUnited States
| | - Matthias Hebrok
- Diabetes Center, University of California, San FranciscoSan FranciscoUnited States
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15
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NUDT7 Loss Promotes KrasG12D CRC Development. Cancers (Basel) 2020; 12:cancers12030576. [PMID: 32131398 PMCID: PMC7139971 DOI: 10.3390/cancers12030576] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/02/2020] [Accepted: 02/27/2020] [Indexed: 12/21/2022] Open
Abstract
Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that KrasG12D-driven CRC tumors demonstrate dysfunctional peroxisomal β-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In KrasG12D-driven CRC tumors, the expression level of Nudt7 was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into Nudt7 knockout (Nudt7−/−) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of Nudt7-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of Nudt7−/− and Nudt7+/+ mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in Nudt7−/− colons. Upregulated levels of β-catenin were observed in the colons of KrasG12D and AOM/DSS-treated Nudt7−/− mice and downstream targets of β-catenin such as Myc, Ccdn1, and Nos2, were also significantly increased in the colon of Nudt7−/− mice. We observed an increased level of palmitic acid in the colon of Nudt7−/− mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of β-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal NUDT7 in KrasG12D-driven CRC development.
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16
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Katholnig K, Schütz B, Fritsch SD, Schörghofer D, Linke M, Sukhbaatar N, Matschinger JM, Unterleuthner D, Hirtl M, Lang M, Herac M, Spittler A, Bergthaler A, Schabbauer G, Bergmann M, Dolznig H, Hengstschläger M, Magnuson MA, Mikula M, Weichhart T. Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis. JCI Insight 2019; 4:124164. [PMID: 31619583 PMCID: PMC6824305 DOI: 10.1172/jci.insight.124164] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 09/06/2019] [Indexed: 12/30/2022] Open
Abstract
The mechanistic target of rapamycin complex 2 (mTORC2) is a potentially novel and promising anticancer target due to its critical roles in proliferation, apoptosis, and metabolic reprogramming of cancer cells. However, the activity and function of mTORC2 in distinct cells within malignant tissue in vivo is insufficiently explored. Surprisingly, in primary human and mouse colorectal cancer (CRC) samples, mTORC2 signaling could not be detected in tumor cells. In contrast, only macrophages in tumor-adjacent areas showed mTORC2 activity, which was downregulated in stromal macrophages residing within human and mouse tumor tissues. Functionally, inhibition of mTORC2 by specific deletion of Rictor in macrophages stimulated tumorigenesis in a colitis-associated CRC mouse model. This phenotype was driven by a proinflammatory reprogramming of mTORC2-deficient macrophages that promoted colitis via the cytokine SPP1/osteopontin to stimulate tumor growth. In human CRC patients, high SPP1 levels and low mTORC2 activity in tumor-associated macrophages correlated with a worsened clinical prognosis. Treatment of mice with a second-generation mTOR inhibitor that inhibits mTORC2 and mTORC1 exacerbated experimental colorectal tumorigenesis in vivo. In conclusion, mTORC2 activity is confined to macrophages in CRC and limits tumorigenesis. These results suggest activation but not inhibition of mTORC2 as a therapeutic strategy for colitis-associated CRC.
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Affiliation(s)
- Karl Katholnig
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics
| | - Birgit Schütz
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics
| | | | - David Schörghofer
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics
| | - Monika Linke
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics
| | | | | | | | - Martin Hirtl
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics
| | - Michaela Lang
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology
| | | | - Andreas Spittler
- Core Facility Flow Cytometry & Surgical Research Laboratories, Medical University of Vienna, Vienna, Austria
| | - Andreas Bergthaler
- CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
| | - Gernot Schabbauer
- Institute for Physiology, Center for Physiology and Pharmacology, and
| | - Michael Bergmann
- Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Helmut Dolznig
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics
| | | | - Mark A Magnuson
- Department of Molecular Physiology and Biophysics and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Mario Mikula
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics
| | - Thomas Weichhart
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics
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17
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Di D, Chen L, Guo Y, Wang L, Zhao C, Ju J. BCSC-1 suppresses human breast cancer metastasis by inhibiting NF-κB signaling. Int J Oncol 2018; 52:1674-1684. [PMID: 29512758 DOI: 10.3892/ijo.2018.4309] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 02/07/2018] [Indexed: 11/06/2022] Open
Abstract
Breast cancer suppressor candidate-1 (BCSC-1; also termed von Willebrand factor A domain containing 5A and LOH11CR2A) is a newly identified candidate tumor suppressor gene that has been implicated in several types of cancer in previous studies. However, there have been few reports about the association between BCSC-1 and human breast cancer in recent years. In the present study, the expression of BCSC-1 in breast cancer was determined by immunohistochemistry (IHC) staining of tissue microarrays and clinical tissue specimens. Subsequently, BCSC-1 gene expression was evaluated in different breast cancer cell lines by quantitative polymerase chain reaction and the MDA-MB-231 cell line was selected for further use in subsequent experiments, due to its low BCSC-1 expression. An MDA-MB-231 cell line with stable overexpression of BCSC-1 was established through transfection with plasmid containing the BCSC-1 gene, and then screening for G418 resistance. Wound-healing, migration and invasion assays were conducted to detect the effect of BCSC-1 on MDA-MB-231 cells. Furthermore, changes in matrix metalloproteinases (MMPs), osteopontin (OPN) and the nuclear factor-κB (NF-κB) pathway were detected in the current study. Additionally, stable silencing of BCSC-1 expression in MCF-7 cells was performed using a lentivirus. The results of IHC indicated that BCSC-1 is expressed at low levels in breast cancer tissues compared with in normal breast tissue. Results of the wound healing, migration and invasion assays demonstrated that BCSC-1 overexpression reduced the metastasis ability of MDA-MB-231 cells in vitro. Further research confirmed that the BCSC-1 overexpression reduced the expression levels of MMP7, MMP9 and OPN, and the phosphorylation of NF-κB p65. Furthermore, inhibition of BCSC-1 via lentivirus-mediated RNA interference revealed that the downregulation of BCSC-1 increased the invasive ability of MCF-7 cells. In summary, the results demonstrated that BCSC-1 is expressed at low levels in breast cancer tissues, and that it can suppress human breast cancer cell migration and invasion, potentially altering the expression of MMP7, MMP9, OPN, and the activity of the NF-κB pathway. Therefore, BCSC-1 may be useful as a biomarker for the treatment of breast cancer in the future.
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Affiliation(s)
- Dalin Di
- Department of Immunology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Lei Chen
- Department of Hematology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Yingying Guo
- Department of Immunology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Lina Wang
- Department of Immunology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Chunling Zhao
- School of Biological Science, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Jiyu Ju
- Department of Immunology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
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