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Lui I, Schaefer K, Kirkemo LL, Zhou J, Perera RM, Leung KK, Wells JA. Hypoxia Induces Extensive Protein and Proteolytic Remodeling of the Cell Surface in Pancreatic Adenocarcinoma (PDAC) Cell Lines. J Proteome Res 2025. [PMID: 40312771 DOI: 10.1021/acs.jproteome.4c01037] [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: 05/03/2025]
Abstract
The tumor microenvironment (TME) plays a crucial role in cancer progression. Hypoxia is a hallmark of the TME and induces a cascade of molecular events that affect cellular processes involved in metabolism, metastasis, and proteolysis. In pancreatic ductal adenocarcinoma (PDAC), tumor tissues are extremely hypoxic. Here, we leveraged mass spectrometry technologies to examine hypoxia-induced alterations in the abundance and proteolytic modifications to cell surface and secreted proteins. Across four PDAC cell lines, we discovered extensive proteolytic remodeling of cell surface proteins involved in cellular adhesion and motility. Looking outward at the surrounding secreted space, we identified hypoxia-regulated secreted and proteolytically shed proteins involved in regulating the humoral immune and inflammatory response, and an upregulation of proteins involved in metabolic processing and tissue development. Combining cell surface N-terminomics and secretomics to evaluate the cellular response to hypoxia enabled us to identify significantly altered candidate proteins which may serve as potential biomarkers and therapeutic targets in PDAC. Furthermore, this approach provides a blueprint for studying dysregulated extracellular proteolysis in other cancers and inflammatory diseases.
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Affiliation(s)
- Irene Lui
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
| | - Kaitlin Schaefer
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
| | - Lisa L Kirkemo
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
| | - Jie Zhou
- Department of Radiation and Oncology, University of Chicago, Chicago, Illinois 60637, United States
- Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
| | - Rushika M Perera
- Department of Anatomy, University of California San Francisco, San Francisco, California 94143, United States
| | - Kevin K Leung
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
| | - James A Wells
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, United States
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Dutour A, Pasello M, Farrow L, Amer MH, Entz-Werlé N, Nathrath M, Scotlandi K, Mittnacht S, Gomez-Mascard A. Microenvironment matters: insights from the FOSTER consortium on microenvironment-driven approaches to osteosarcoma therapy. Cancer Metastasis Rev 2025; 44:44. [PMID: 40210800 PMCID: PMC11985652 DOI: 10.1007/s10555-025-10257-3] [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: 10/14/2024] [Accepted: 03/04/2025] [Indexed: 04/12/2025]
Abstract
Osteosarcoma (OS), a prevalent malignant bone tumor, has seen limited progress in treatment efficacy and patient outcomes over decades. Recent insights into the tumor microenvironment (TME) have revealed its crucial role in tumor progression and therapeutic resistance, particularly in OS. This review offers a comprehensive exploration of the OS microenvironment, meticulously dissecting its crucial components: the mesenchymal stromal TME, the immune microenvironment, hypoxia-induced adaptations, and the impact of the physical microenvironment. By demonstrating how these elements collectively drive tumor proliferation, immune evasion, and invasion, this review explores the intricate molecular and cellular dynamics at play. Furthermore, innovative approaches targeting the OS microenvironment, such as immunotherapies, are presented. This review highlights the importance of the TME in OS progression and its potential as a source of novel therapeutic strategies, offering new hope for improved patient outcomes.
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Affiliation(s)
- Aurelie Dutour
- Childhood Cancer & Cell Death Team, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008, Lyon, France
| | - Michela Pasello
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Luke Farrow
- University College London Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley St, London, WC1E 6DD, UK
| | - Mahetab H Amer
- Division of Cell Matrix & Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Natacha Entz-Werlé
- Pediatric Onco-Hematology Unit, University Hospitals of Strasbourg, Strasbourg, France
- Translational, Transversal and Therapeutic Oncology Team, Laboratory of Bioimaging and Pathologies, Faculty of Pharmacy, CNRS UMR 7021, Illkirch, France
| | - Michaela Nathrath
- Department of Pediatric Hemato-Oncology, Psychosomatics and Systemic Diseases, Children's Hospital Kassel, Kassel, Germany
- Department of Pediatrics, Children'S Cancer Research Center, School of Medicine, Technical University of Munich, Munich, Germany
| | - Katia Scotlandi
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Sibylle Mittnacht
- University College London Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley St, London, WC1E 6DD, UK
| | - Anne Gomez-Mascard
- Department of Pathology, CHU, IUCT-Oncopole, University of Toulouse, Eq19. ONCOSARC CRCT, UMR 1037 Inserm/UT3, ERL 5294 CNRS, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.
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3
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Halpin-Veszeleiova K, Mallouh MP, Williamson LM, Apro AC, Botticello-Romero NR, Bahr C, Shin M, Ward KM, Rosenberg L, Ritov VB, Sitkovsky MV, Jackson EK, Spiess BD, Hatfield SM. Oxygen-carrying nanoemulsions and respiratory hyperoxia eliminate tumor hypoxia-induced immunosuppression. JCI Insight 2025; 10:e174675. [PMID: 40125552 PMCID: PMC11949039 DOI: 10.1172/jci.insight.174675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2025] Open
Abstract
Hypoxia/hypoxia-inducible factor 1α-driven immunosuppressive transcription and cAMP-elevating signaling through A2A adenosine receptors (A2ARs) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patients refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). We show that oxygenation agent therapy (a) eliminates tumor hypoxia, (b) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby (c) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to reprogramming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immunosuppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy.
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Affiliation(s)
- Katarina Halpin-Veszeleiova
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Michael P. Mallouh
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
- Department of Surgery, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Lucy M. Williamson
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Ashley C. Apro
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Nuria R. Botticello-Romero
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Camille Bahr
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Maureen Shin
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Kelly M. Ward
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Laura Rosenberg
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Vladimir B. Ritov
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Michail V. Sitkovsky
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
| | - Edwin K. Jackson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Bruce D. Spiess
- Department of Anesthesiology, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Stephen M. Hatfield
- Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA
- Department of Chemical Engineering, College of Engineering, Northeastern University, Boston, Massachusetts, USA
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Fan Y, Ji X, Yuan K, Wu Q, Lou M. HDAC1 Mediates Immunosuppression of the Tumor Microenvironment in Non-Small Cell Lung Cancer. J Inflamm Res 2025; 18:3333-3347. [PMID: 40078575 PMCID: PMC11900795 DOI: 10.2147/jir.s509316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
Background Studies have demonstrated that histone deacetylase 1 (HDAC1) enables cancer cells to evade killing mediated by cytotoxic T lymphocytes. However, there are no studies on the immunological aspects of HDAC1 in non-small cell lung cancer (NSCLC). Methods In this research, we used the Cancer Genome Atlas (TCGA) public database combined with tissue microarray (TMA) to investigate HDAC1 expression and prognosis in NSCLC. According to the median value of HDAC1 expression in the TCGA dataset, samples of patients with NSCLC were classified into high- and low-expression cohorts. Subsequently, the biological characteristics of HDAC1 in high- and low-expression cohorts in terms of signaling pathways, immune cell infiltration, immune cell function, and genomic stability were investigated to better understand the effect of HDAC1 in the tumor microenvironment (TME) of NSCLC. Additionally, we selected tissue samples with HDAC1 overexpression in TMA2 and performed immunohistochemical staining of CD8+ T cells to observe the distribution of CD8+ T cells in the tumor. Results The findings revealed that overexpression of HDAC1 in NSCLC was associated with poor prognosis. Analysis of signaling pathway enrichment indicated that HDAC1 downregulated immune-related signaling pathways in NSCLC. Immune cell infiltration, immune cell function, and genomic stability analyses suggested that the TME alteration mediated by HDAC1 in the high-expression cohort was consistent with the "immune desert" phenotype. Furthermore, CD8+ T immunohistochemical staining experiments of tissue samples with HDAC1 overexpression in NSCLC revealed few CD8+ T cells distributed in the tumor parenchyma and interstitium. Conclusion Conclusively, our findings from several biological analyses revealed that HDAC1 is overexpressed in NSCLC and induces TME immunosuppression.
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Affiliation(s)
- Yongfei Fan
- Department of Thoracic Surgery, The second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, People’s Republic of China
- Heart and Lung Disease Laboratory, The second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, People’s Republic of China
| | - Xiang Ji
- Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, People’s Republic of China
| | - Kai Yuan
- Department of Thoracic Surgery, The second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, People’s Republic of China
- Heart and Lung Disease Laboratory, The second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, People’s Republic of China
| | - Qiyong Wu
- Department of Thoracic Surgery, The second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, People’s Republic of China
- Heart and Lung Disease Laboratory, The second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, People’s Republic of China
| | - Ming Lou
- Department of Thoracic Surgery, The second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, People’s Republic of China
- Heart and Lung Disease Laboratory, The second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, People’s Republic of China
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Abualnadi R, Tarboush NA, Shhab M, Zihlif M. Gene expression alterations in hypoxic A549 lung cancer cell line. Biomed Rep 2024; 21:183. [PMID: 39420921 PMCID: PMC11484184 DOI: 10.3892/br.2024.1871] [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: 01/02/2022] [Accepted: 03/26/2024] [Indexed: 10/19/2024] Open
Abstract
Human non-small cell lung cancer (NSCLC)is a very common disease with limited treatment options. Hypoxia is a characteristic feature of solid tumors associated with the resistance of cancer cells to radiotherapy and chemotherapy. Therefore, the expression changes in cancer-resistance genes may be biomarkers of hypoxia with value in targeted therapy. The aim of the present study was to examine the effect of hypoxia on gene expression and the changes that occur in relation to drug resistance in a human NSCLC cell line (A549). A549 cells were exposed to 72-h hypoxic episodes (<1% oxygen) for a total of 10 episodes (acute). The alterations in gene expression were examined using PCR array technology after 10 episodes of acute hypoxia and compared with normoxic cells. The chemoresistance of hypoxic cells toward doxorubicin was measured using a MTT cell proliferation assay. A549 cells were affected by acute hypoxia leading to induced doxorubicin chemoresistance. Evident changes in the gene expression level were identified following episodes of acute hypoxia. The most important changes occurred in the estrogen receptor 1 (ESR1) and Finkel-Biskis-Jinkins osteosarcoma (FOS) pathways and in different nucleic transcription factors such as aryl hydrocarbon receptor and cyclin-dependent kinase inhibitor. The present study showed that exposing cells to prolonged periods of hypoxia results in different gene expression changes. There was induction of chemo-resistance due to acute hypoxia. ESR1 and c-FOS are proposed as a potential hypoxia genes in lung cancer.
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Affiliation(s)
- Rania Abualnadi
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Nafez Abu Tarboush
- Department of Physiology and Biochemistry, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Mohammad Shhab
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Malek Zihlif
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman 11942, Jordan
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6
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Casciano F, Caruso L, Zauli E, Gonelli A, Zauli G, Vaccarezza M. Emerging Mechanisms of Physical Exercise Benefits in Adjuvant and Neoadjuvant Cancer Immunotherapy. Biomedicines 2024; 12:2528. [PMID: 39595094 PMCID: PMC11591576 DOI: 10.3390/biomedicines12112528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/20/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
The primary factors that can be modified in one's lifestyle are the most influential determinants and significant preventable causes of various types of cancer. Exercise has demonstrated numerous advantages in preventing cancer and aiding in its treatment. However, the precise mechanisms behind these effects are still not fully understood. To contribute to our comprehension of exercise's impact on cancer immunotherapy and provide recommendations for future research in exercise oncology, we will examine the roles and underlying mechanisms of exercise on immune cells. In addition to reducing the likelihood of developing cancer, exercise can also improve the effectiveness of certain approved anticancer treatments, such as targeted therapy, immunotherapy, and radiotherapy. Exercise is a pivotal modulator of the immune response, and thus, it can play an emerging important role in new immunotherapies. The mechanisms responsible for these effects involve the regulation of intra-tumoral angiogenesis, myokines, adipokines, their associated pathways, cancer metabolism, and anticancer immunity. Our review assesses the potential of physical exercise as an adjuvant/neoadjuvant tool, reducing the burden of cancer relapse, and analyzes emerging molecular mechanisms predicting favorable adjuvanticity effects.
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Affiliation(s)
- Fabio Casciano
- Department of Environmental Sciences and Prevention and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
| | - Lorenzo Caruso
- Department of Environmental Sciences and Prevention, University of Ferrara, 44121 Ferrara, Italy
| | - Enrico Zauli
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Arianna Gonelli
- Department of Environmental Sciences and Prevention, University of Ferrara, 44121 Ferrara, Italy
| | - Giorgio Zauli
- Research Department, King Khaled Eye Specialistic Hospital, Riyadh 12329, Saudi Arabia
| | - Mauro Vaccarezza
- Department of Environmental Sciences and Prevention, University of Ferrara, 44121 Ferrara, Italy
- Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, WA 6102, Australia
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7
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Wang Y, Zhang X, Ma Y, Zhou X, Xu W, Qin S, Yang C. Self-assembled copper-based nanoparticles for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. J Nanobiotechnology 2024; 22:375. [PMID: 38926721 PMCID: PMC11202248 DOI: 10.1186/s12951-024-02626-x] [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: 02/12/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu2+, 3,3'-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818. The obtained TCCHA nanoparticles exhibited pH/GSH dual-responsive drug release behaviors and multienzymatic activities, including Fenton, glutathione peroxidase-, and catalase-like activities. TCCHA, a redox homeostasis disruptor, promotes ⋅OH generation and GSH depletion, thus increasing the efficacy of chemodynamic therapy. TCCHA, which has catalase-like activity, can also reinforce the efficacy of photodynamic therapy by amplifying O2 production. In vivo, TCCHA efficiently inhibited tumor angiogenesis and suppressed tumor growth without apparent systemic toxicity. Overall, this study presents a facile strategy for the preparation of multienzyme-like nanoparticles, and TCCHA nanoparticles display great potential for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic triple therapy against cancer.
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Affiliation(s)
- Yaping Wang
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xun Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yunfeng Ma
- Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiaobo Zhou
- Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Weijun Xu
- State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an, 710049, China.
| | - Sida Qin
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Chengcheng Yang
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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Yamada A, Kitano S, Matsusaki M. Cellular memory function from 3D to 2D: Three-dimensional high density collagen microfiber cultures induce their resistance to reactive oxygen species. Mater Today Bio 2024; 26:101097. [PMID: 38827038 PMCID: PMC11140783 DOI: 10.1016/j.mtbio.2024.101097] [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: 02/10/2024] [Revised: 05/14/2024] [Accepted: 05/21/2024] [Indexed: 06/04/2024] Open
Abstract
Cell properties generally change when the culture condition is changed. However, mesenchymal stem cells cultured on a hard material surface maintain their differentiation characteristics even after being cultured on a soft material surface. This phenomenon suggests the possibility of a cell culture material to memorize stem cell function even in changing cell culture conditions. However, there are no reports about cell memory function in three-dimensional (3D) culture. In this study, colon cancer cells were cultured with collagen microfibers (CMF) in 3D to evaluate their resistance to reactive oxygen species (ROS) in comparison with a monolayer (2D) culture condition and to understand the effect of 3D-culture on cell memory function. The ratio of ROS-negative cancer cells in 3D culture increased with increasing amounts of CMF and the highest amount of CMF was revealed to be 35-fold higher than that of the 2D condition. The ROS-negative cells ratio was maintained for 7 days after re-seeding in a 2D culture condition, suggesting a 3D-memory function of ROS resistance. The findings of this study will open up new opportunities for 3D culture to induce cell memory function.
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Affiliation(s)
- Asuka Yamada
- TOPPAN HOLDINGS INC. Business Development Division, Technical Research Institute, Takanodaiminami, Sugito-machi, Saitama 345-8508, Japan
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
- Division of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Shiro Kitano
- TOPPAN HOLDINGS INC. Business Development Division, Technical Research Institute, Takanodaiminami, Sugito-machi, Saitama 345-8508, Japan
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Michiya Matsusaki
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
- Division of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
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9
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Bigos KJA, Quiles CG, Lunj S, Smith DJ, Krause M, Troost EGC, West CM, Hoskin P, Choudhury A. Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours. Front Oncol 2024; 14:1331355. [PMID: 38352889 PMCID: PMC10861654 DOI: 10.3389/fonc.2024.1331355] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/08/2024] [Indexed: 02/16/2024] Open
Abstract
Hypoxia is a common feature of solid tumours affecting their biology and response to therapy. One of the main transcription factors activated by hypoxia is hypoxia-inducible factor (HIF), which regulates the expression of genes involved in various aspects of tumourigenesis including proliferative capacity, angiogenesis, immune evasion, metabolic reprogramming, extracellular matrix (ECM) remodelling, and cell migration. This can negatively impact patient outcomes by inducing therapeutic resistance. The importance of hypoxia is clearly demonstrated by continued research into finding clinically relevant hypoxia biomarkers, and hypoxia-targeting therapies. One of the problems is the lack of clinically applicable methods of hypoxia detection, and lack of standardisation. Additionally, a lot of the methods of detecting hypoxia do not take into consideration the complexity of the hypoxic tumour microenvironment (TME). Therefore, this needs further elucidation as approximately 50% of solid tumours are hypoxic. The ECM is important component of the hypoxic TME, and is developed by both cancer associated fibroblasts (CAFs) and tumour cells. However, it is important to distinguish the different roles to develop both biomarkers and novel compounds. Fibronectin (FN), collagen (COL) and hyaluronic acid (HA) are important components of the ECM that create ECM fibres. These fibres are crosslinked by specific enzymes including lysyl oxidase (LOX) which regulates the stiffness of tumours and induces fibrosis. This is partially regulated by HIFs. The review highlights the importance of understanding the role of matrix stiffness in different solid tumours as current data shows contradictory results on the impact on therapeutic resistance. The review also indicates that further research is needed into identifying different CAF subtypes and their exact roles; with some showing pro-tumorigenic capacity and others having anti-tumorigenic roles. This has made it difficult to fully elucidate the role of CAFs within the TME. However, it is clear that this is an important area of research that requires unravelling as current strategies to target CAFs have resulted in worsened prognosis. The role of immune cells within the tumour microenvironment is also discussed as hypoxia has been associated with modulating immune cells to create an anti-tumorigenic environment. Which has led to the development of immunotherapies including PD-L1. These hypoxia-induced changes can confer resistance to conventional therapies, such as chemotherapy, radiotherapy, and immunotherapy. This review summarizes the current knowledge on the impact of hypoxia on the TME and its implications for therapy resistance. It also discusses the potential of hypoxia biomarkers as prognostic and predictive indictors of treatment response, as well as the challenges and opportunities of targeting hypoxia in clinical trials.
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Affiliation(s)
- Kamilla JA. Bigos
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Conrado G. Quiles
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Sapna Lunj
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Danielle J. Smith
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Mechthild Krause
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
- Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy and Image-guided High Precision Radiotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy and Image-guided High Precision Radiotherapy, Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- School of Medicine, Technische Universitat Dresden, Dresden, Germany
| | - Esther GC. Troost
- OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
- Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy and Image-guided High Precision Radiotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy and Image-guided High Precision Radiotherapy, Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- School of Medicine, Technische Universitat Dresden, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Institute of Radiooncology – OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Rossendorf, Germany
| | - Catharine M. West
- Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom
| | - Peter Hoskin
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
- Mount Vernon Cancer Centre, Northwood, United Kingdom
| | - Ananya Choudhury
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
- Christie Hospital NHS Foundation Trust, Manchester, Germany
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10
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Bag S, Oetjen J, Shaikh S, Chaudhary A, Arun P, Mukherjee G. Impact of spatial metabolomics on immune-microenvironment in oral cancer prognosis: a clinical report. Mol Cell Biochem 2024; 479:41-49. [PMID: 36966422 DOI: 10.1007/s11010-023-04713-3] [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: 10/21/2022] [Accepted: 03/15/2023] [Indexed: 03/27/2023]
Abstract
MALDI imaging for metabolites and immunohistochemistry for 38 immune markers was used to characterize the spatial biology of 2 primary oral tumours, one from a patient with an early recurrence (Tumour R), and the other from a patient with no recurrence 2 years after treatment completion (Tumour NR). Tumour R had an increased purine nucleotide metabolism in different regions of tumour and adenosine-mediated suppression of immune cells compared to Tumour NR. The differentially expressed markers in the different spatial locations in tumour R were CD33, CD163, TGF-β, COX2, PD-L1, CD8 and CD20. These results suggest that altered tumour metabolomics concomitant with a modified immune microenvironment could be a potential marker of recurrence.
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Affiliation(s)
- Swarnendu Bag
- Tata Medical Center, Newtown, Kolkata, 700 160, India
- CSIR-Institute of Genomics and Integrative Biology (IGIB), Mall Road, New Delhi, 110 007, India
| | | | - Soni Shaikh
- Tata Medical Center, Newtown, Kolkata, 700 160, India
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11
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Semenza GL. Targeting intratumoral hypoxia to enhance anti-tumor immunity. Semin Cancer Biol 2023; 96:5-10. [PMID: 37717718 DOI: 10.1016/j.semcancer.2023.09.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/13/2023] [Accepted: 09/14/2023] [Indexed: 09/19/2023]
Abstract
Cancers express a large battery of genes by which they establish an immunosuppressive tumor microenvironment. Many of these genes are induced by intratumoral hypoxia through transcriptional activation mediated by hypoxia-inducible factors HIF-1 and HIF-2. This review summarizes several recent reports describing hypoxia-induced mechanisms of immune evasion in sarcoma and breast, colorectal, hepatocellular, prostate and uterine cancer. These studies point to several novel therapeutic approaches to improve anti-tumor immunity and increase responses to immunotherapy.
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Affiliation(s)
- Gregg L Semenza
- Department of Genetic Medicine, Institute for Cell Engineering, and Armstrong Oxygen Biology Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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12
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Colombani T, Rogers ZJ, Bhatt K, Sinoimeri J, Gerbereux L, Hamrangsekachaee M, Bencherif SA. Hypoxia-inducing cryogels uncover key cancer-immune cell interactions in an oxygen-deficient tumor microenvironment. Bioact Mater 2023; 29:279-295. [PMID: 37600932 PMCID: PMC10432785 DOI: 10.1016/j.bioactmat.2023.06.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/22/2023] [Accepted: 06/25/2023] [Indexed: 08/22/2023] Open
Abstract
Hypoxia is a major factor shaping the immune landscape, and several cancer models have been developed to emulate hypoxic tumors. However, to date, they still have several limitations, such as the lack of reproducibility, inadequate biophysical cues, limited immune cell infiltration, and poor oxygen (O2) control, leading to non-pathophysiological tumor responses. Therefore, it is essential to develop better cancer models that mimic key features of the tumor extracellular matrix and recreate tumor-associated hypoxia while allowing cell infiltration and cancer-immune cell interactions. Herein, hypoxia-inducing cryogels (HICs) have been engineered using hyaluronic acid (HA) to fabricate three-dimensional microtissues and model a hypoxic tumor microenvironment. Specifically, tumor cell-laden HICs have been designed to deplete O2 locally and induce long-standing hypoxia. HICs promoted changes in hypoxia-responsive gene expression and phenotype, a metabolic adaptation to anaerobic glycolysis, and chemotherapy resistance. Additionally, HIC-supported tumor models induced dendritic cell (DC) inhibition, revealing a phenotypic change in the plasmacytoid DC (pDC) subset and an impaired conventional DC (cDC) response in hypoxia. Lastly, our HIC-based melanoma model induced CD8+ T cell inhibition, a condition associated with the downregulation of pro-inflammatory cytokine secretion, increased expression of immunomodulatory factors, and decreased degranulation and cytotoxic capacity of T cells. Overall, these data suggest that HICs can be used as a tool to model solid-like tumor microenvironments and has great potential to deepen our understanding of cancer-immune cell relationship in low O2 conditions and may pave the way for developing more effective therapies.
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Affiliation(s)
- Thibault Colombani
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States
| | - Zachary J. Rogers
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States
| | - Khushbu Bhatt
- Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, United States
| | - James Sinoimeri
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States
| | - Lauren Gerbereux
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States
| | | | - Sidi A. Bencherif
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States
- Department of Bioengineering, Northeastern University, Boston, MA 02115, United States
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, United States
- Biomechanics and Bioengineering (BMBI), UTC CNRS UMR 7338, University of Technology of Compiègne, Sorbonne University, 60203 Compiègne, France
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13
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Gertsenshteyn I, Epel B, Giurcanu M, Barth E, Lukens J, Hall K, Martinez JF, Grana M, Maggio M, Miller RC, Sundramoorthy SV, Krzykawska-Serda M, Pearson E, Aydogan B, Weichselbaum RR, Tormyshev VM, Kotecha M, Halpern HJ. Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models. Front Med (Lausanne) 2023; 10:1269689. [PMID: 37904839 PMCID: PMC10613495 DOI: 10.3389/fmed.2023.1269689] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 09/28/2023] [Indexed: 11/01/2023] Open
Abstract
Background Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions. Materials and methods Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment. Results An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types. Conclusion This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.
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Affiliation(s)
- Inna Gertsenshteyn
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Department of Radiology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Boris Epel
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
- O2M Technologies, Chicago, IL, United States
| | - Mihai Giurcanu
- Department of Public Health Sciences, The University of Chicago, Chicago, IL, United States
| | - Eugene Barth
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - John Lukens
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Kayla Hall
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Jenipher Flores Martinez
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Mellissa Grana
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Matthew Maggio
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Richard C. Miller
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Subramanian V. Sundramoorthy
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Martyna Krzykawska-Serda
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
- Department of Biophysics and Cancer Biology, Jagiellonian University, Kraków, Poland
| | - Erik Pearson
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
| | - Bulent Aydogan
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
| | - Ralph R. Weichselbaum
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
| | | | | | - Howard J. Halpern
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, United States
- Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, United States
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14
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Yeo KF, Ker A, Kao PE, Wang CC. Hypothetical hypoxia-driven rapid disease progression in hepatocellular carcinoma post transarterial chemoembolization: A case report. World J Clin Cases 2023; 11:4664-4669. [PMID: 37469743 PMCID: PMC10353493 DOI: 10.12998/wjcc.v11.i19.4664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 05/25/2023] [Accepted: 06/06/2023] [Indexed: 06/30/2023] Open
Abstract
BACKGROUND Transarterial chemoembolization (TACE) is widely performed for intermediate-stage or unresectable hepatocellular carcinoma (HCC), but approximately half of patients do not respond to TACE treatment. We describe a case of rapidly progressing of HCC after TACE and provide a possible hypothesis for this condition. The finding may contribute to identifying patients who obtain less benefit from TACE, thus avoiding the unnecessary waste of medical resources and treatment during the golden hour window.
CASE SUMMARY A 61-year-old woman had been diagnosed with chronic hepatitis B infection and HCC at Barcelona Clinic Liver Cancer stage B, which had been treated by segmental hepatectomy 14 mo ago. The tumor recurred in the two months after surgery. She received an initial TACE and then underwent systemic therapy with lenvatinib 8 mg daily due to an increased level of alpha-fetoprotein (AFP) after the first TACE. However, the tumor continued to progress with an increased level of AFP, and she underwent a second TACE, after which the tumor volume did not obviously decrease on the contrast-enhanced computed tomography image. One month later, she had a third TACE to control the residual HCC tumors. Two weeks after that, the HCC had increased dramatically with tea-colored urine and yellowish skin turgor. Eventually, the patient refused further treatment and went into hospice care.
CONCLUSION Intense hypoxia induced by TACE can trigger rapid disease progression in infiltrative HCC patients with a large tumor burden
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Affiliation(s)
- Kai-Fuan Yeo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402306, Taiwan
| | - Amy Ker
- School of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan
| | - Pei-En Kao
- School of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan
| | - Chi-Chih Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402306, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan
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15
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Ailia MJ, Heo J, Yoo SY. Navigating through the PD-1/PDL-1 Landscape: A Systematic Review and Meta-Analysis of Clinical Outcomes in Hepatocellular Carcinoma and Their Influence on Immunotherapy and Tumor Microenvironment. Int J Mol Sci 2023; 24:ijms24076495. [PMID: 37047482 PMCID: PMC10095164 DOI: 10.3390/ijms24076495] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
This systematic review aimed to assess the prognostic significance of programmed cell death-ligand 1 (PDL-1) and programmed cell death protein 1 (PD-1) in hepatocellular carcinoma (HCC). Medline, EMBASE, and Cochrane Library database searches were conducted, revealing nine relevant cohort studies (seven PDL-1 and three PD-1). Our meta-analysis showed that PD-1/PDL-1 was a marker of poor survival, regardless of the assessment method (PD-1 overall survival (OS): hazard ratio (HR) 2.40; 95% confidence interval (CI), 1.30–4.42; disease-free survival (DFS): HR 2.12; 95% CI, 1.45–3.10; PDL-1: OS: HR 3.61; 95% CI, 2.75–4.75; and DFS: HR 2.74; 95% CI, 2.09–3.59). Additionally, high level of PD-1/PDL-1 expression was associated with aging, multiple tumors, high alpha-fetoprotein levels, and advanced Barcelona Clinic Liver Cancer stage. This high level significantly predicted a poor prognosis for HCC, suggesting that anti-PD-1 therapy is plausible for patients with HCC. Furthermore, HIF-1 induces PD-1 expression, and PD1lowSOCS3high is associated with a better prognosis. Taken together, combination therapy may be the key to effective immunotherapy. Thus, exploring other markers, such as HIF-1 and SOCS3, along with PD-1/PDL-1 immunotherapy, may lead to improved outcomes.
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Affiliation(s)
- Muhammad Joan Ailia
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
- Correspondence: or ; Tel.: +82-51-510-3402
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16
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Thomas JA, Gireesh Moly AG, Xavier H, Suboj P, Ladha A, Gupta G, Singh SK, Palit P, Babykutty S. Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point? Front Oncol 2023; 13:1063051. [PMID: 37056346 PMCID: PMC10088512 DOI: 10.3389/fonc.2023.1063051] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 02/17/2023] [Indexed: 03/30/2023] Open
Abstract
Breast cancer ranks second among the causes of cancer-related deaths in women. In spite of the recent advances achieved in the diagnosis and treatment of breast cancer, further study is required to overcome the risk of cancer resistance to treatment and thereby improve the prognosis of individuals with advanced-stage breast cancer. The existence of a hypoxic microenvironment is a well-known event in the development of mutagenesis and rapid proliferation of cancer cells. Tumor cells, purposefully cause local hypoxia in order to induce angiogenesis and growth factors that promote tumor growth and metastatic characteristics, while healthy tissue surrounding the tumor suffers damage or mutate. It has been found that these settings with low oxygen levels cause immunosuppression and a lack of immune surveillance by reducing the activation and recruitment of tumor infiltrating leukocytes (TILs). The immune system is further suppressed by hypoxic tumor endothelium through a variety of ways, which creates an immunosuppressive milieu in the tumor microenvironment. Non responsiveness of tumor endothelium to inflammatory signals or endothelial anergy exclude effector T cells from the tumor milieu. Expression of endothelial specific antigens and immunoinhibitory molecules like Programmed death ligand 1,2 (PDL-1, 2) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) by tumor endothelium adds fuel to the fire by inhibiting T lymphocytes while promoting regulatory T cells. The hypoxic microenvironment in turn recruits Myeloid Derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs) and T regulatory cells (Treg). The structure and function of newly generated blood vessels within tumors, on the other hand, are aberrant, lacking the specific organization of normal tissue vasculature. Vascular normalisation may work for a variety of tumour types and show to be an advantageous complement to immunotherapy for improving tumour access. By enhancing immune response in the hypoxic tumor microenvironment, via immune-herbal therapeutic and immune-nutraceuticals based approaches that leverage immunological evasion of tumor, will be briefly reviewed in this article. Whether these tactics may be the game changer for emerging immunological switch point to attenuate the breast cancer growth and prevent metastatic cell division, is the key concern of the current study.
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Affiliation(s)
- Juvin Ann Thomas
- Centre for Tumor Immunology and Microenvironment, Department of Zoology, Mar Ivanios College, Nalanchira, Thiruvananthapuram, Kerala, India
| | - Athira Gireesh Gireesh Moly
- Centre for Tumor Immunology and Microenvironment, Department of Zoology, Mar Ivanios College, Nalanchira, Thiruvananthapuram, Kerala, India
| | - Hima Xavier
- Centre for Tumor Immunology and Microenvironment, Department of Zoology, Mar Ivanios College, Nalanchira, Thiruvananthapuram, Kerala, India
| | - Priya Suboj
- Department of Botany and Biotechnology, St. Xaviers College, Thumba, Thiruvananthapuram, Kerala, India
| | - Amit Ladha
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham, West-Midlands, United Kingdom
| | - Gaurav Gupta
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
| | - Santosh Kumar Singh
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Partha Palit
- Drug Discovery Research Laboratory, Assam University, Silchar, Department of Pharmaceutical Sciences, Assam, India
| | - Suboj Babykutty
- Centre for Tumor Immunology and Microenvironment, Department of Zoology, Mar Ivanios College, Nalanchira, Thiruvananthapuram, Kerala, India
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17
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Tímár J, Honn KV, Hendrix MJC, Marko-Varga G, Jalkanen S. Newly identified form of phenotypic plasticity of cancer: immunogenic mimicry. Cancer Metastasis Rev 2023; 42:323-334. [PMID: 36754910 PMCID: PMC10014767 DOI: 10.1007/s10555-023-10087-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/18/2023] [Indexed: 02/10/2023]
Abstract
Cancer plasticity is now a recognized new hallmark of cancer which is due to disturbances of cell differentiation programs. It is manifested not only in various forms like the best-known epithelial-mesenchymal transition (EMT) but also in vasculogenic and megakaryocytic mimicries regulated by EMT-specific or less-specific transcription factors such as HIF1a or STAT1/2. Studies in the past decades provided ample data that cancer plasticity can be manifested also in the expression of a vast array of immune cell genes; best-known examples are PDL1/CD274, CD47, or IDO, and we termed it immunogenic mimicry (IGM). However, unlike other types of plasticities which are epigenetically regulated, expression of IGM genes are frequently due to gene amplifications. It is important that the majority of the IGM genes are regulated by interferons (IFNs) suggesting that their protein expressions are regulated by the immune microenvironment. Most of the IGM genes have been shown to be involved in immune escape of cancers broadening the repertoire of these mechanisms and offering novel targets for immunotherapeutics.
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Affiliation(s)
- József Tímár
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary.
| | - Kenneth V Honn
- Departments of Pathology, Oncology and Chemistry, Wayne State University, Detroit, MI, USA.,Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA
| | - Mary J C Hendrix
- Department of Biology, Shepherd University, Shepherdstown, WV, USA
| | - György Marko-Varga
- Clinical Protein Science and Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - Sirpa Jalkanen
- Medicity Research Laboratories, Turku, Finland.,InFLAMES Flagship, University of Turku, Turku, Finland
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18
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Wu J, Liu Y, Cao M, Zheng N, Ma H, Ye X, Yang N, Liu Z, Liao W, Sun L. Cancer-Responsive Multifunctional Nanoplatform Based on Peptide Self-Assembly for Highly Efficient Combined Cancer Therapy by Alleviating Hypoxia and Improving the Immunosuppressive Microenvironment. ACS APPLIED MATERIALS & INTERFACES 2023; 15:5667-5678. [PMID: 36651290 DOI: 10.1021/acsami.2c20388] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Hypoxia, as a main feature of the tumor microenvironment, has greatly limited the efficacy of photodynamic therapy (PDT), as well as its clinical application. Here, a multifunctional composite nanoplatform, the peptide/Ce6/MnO2 nanocomposite (RKCM), has been constructed to alleviate tumor hypoxia and increase the efficacy of PDT using rationally designed peptide fibrils to encapsulate chlorin e6 (Ce6) inside and to mineralize MnO2 nanoparticles on the surface. As a result, RKCM significantly improved the PDT efficacy by increasing reactive oxygen species (ROS) generation, decreasing tumor cell viability, and inhibiting tumor growth and metastasis. Besides, decreased HIF-1α expression and increased immune-activated cell infiltration were also observed in RKCM/laser treatment xenograft. Mechanically, (1) Ce6 can induce singlet oxygen (1O2) generation under laser irradiation to give photodynamic therapy (PDT); (2) MnO2 can react with H2O2 in situ to supply additional O2 to alleviate tumor hypoxia; and (3) the released Mn2+ ions can induce a Fenton-like reaction to generate •OH for chemical dynamic therapy (CDT). Moreover, RKCM/laser treatment also presented with an abscopal effect to block the occurrence of lung metastasis by remolding the pre-metastasis immune microenvironment. With these several aspects working together, the peptide/Ce6/MnO2 nanoplatform can achieve highly efficient tumor therapy. Such a strategy based on peptide self-assembly provides a promising way to rationally design a cancer-responsive multifunctional nanoplatform for highly efficient combined cancer therapy by alleviating hypoxia and improving the immune microenvironment.
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Affiliation(s)
- Jingjing Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Thoracic Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No. 1 East Banshan Road, Gongshu District, Hangzhou, Zhejiang 310022, China
| | - Yang Liu
- State Key Laboratory of Heavy Oil Processing and Centre for Bioengineering and Biotechnology, College of Chemical Engineering, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China
| | - Meiwen Cao
- State Key Laboratory of Heavy Oil Processing and Centre for Bioengineering and Biotechnology, College of Chemical Engineering, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China
| | - Nannan Zheng
- State Key Laboratory of Heavy Oil Processing and Centre for Bioengineering and Biotechnology, College of Chemical Engineering, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China
| | - Hongchao Ma
- State Key Laboratory of Heavy Oil Processing and Centre for Bioengineering and Biotechnology, College of Chemical Engineering, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China
| | - Xiandong Ye
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Nanyan Yang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhihong Liu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Li Sun
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Oncology, Air Force Medical Center of PLA, Air Force Medical University, Beijing 100089, China
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19
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Colombani T, Rogers ZJ, Bhatt K, Sinoimeri J, Gerbereux L, Hamrangsekachaee M, Bencherif SA. Hypoxia-inducing cryogels uncover key cancer-immune cell interactions in an oxygen-deficient tumor microenvironment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.10.523477. [PMID: 36711715 PMCID: PMC9882080 DOI: 10.1101/2023.01.10.523477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Hypoxia, an important feature of solid tumors, is a major factor shaping the immune landscape, and several cancer models have been developed to emulate hypoxic tumors. However, to date, they still have several limitations, such as the lack of reproducibility, inadequate biophysical cues, limited immune cell infiltration, and poor oxygen (O 2 ) control, leading to non-pathophysiological tumor responses. As a result, it is essential to develop new and improved cancer models that mimic key features of the tumor extracellular matrix and recreate tumor-associated hypoxia while allowing cell infiltration and cancer-immune cell interactions. Herein, hypoxia-inducing cryogels (HICs) have been engineered using hyaluronic acid (HA) as macroporous scaffolds to fabricate three-dimensional microtissues and model a hypoxic tumor microenvironment. Specifically, tumor cell-laden HICs have been designed to deplete O 2 locally and induce long-standing hypoxia. This state of low oxygen tension, leading to HIF-1α stabilization in tumor cells, resulted in changes in hypoxia-responsive gene expression and phenotype, a metabolic adaptation to anaerobic glycolysis, and chemotherapy resistance. Additionally, HIC-supported tumor models induced dendritic cell (DC) inhibition, revealing a phenotypic change in plasmacytoid B220 + DC (pDC) subset and an impaired conventional B220 - DC (cDC) response in hypoxia. Lastly, our HIC-based melanoma model induced CD8+ T cell inhibition, a condition associated with the downregulation of pro-inflammatory cytokine secretion, increased expression of immunomodulatory factors, and decreased degranulation and cytotoxic capacity of T cells. Overall, these data suggest that HICs can be used as a tool to model solid-like tumor microenvironments and identify a phenotypic transition from cDC to pDC in hypoxia and the key contribution of HA in retaining cDC phenotype and inducing their hypoxia-mediated immunosuppression. This technology has great potential to deepen our understanding of the complex relationships between cancer and immune cells in low O 2 conditions and may pave the way for developing more effective therapies.
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Affiliation(s)
- Thibault Colombani
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States of America
| | - Zachary J. Rogers
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States of America
| | - Khushbu Bhatt
- Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, United States
| | - James Sinoimeri
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States of America
| | - Lauren Gerbereux
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States of America
| | - Mohammad Hamrangsekachaee
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States of America
| | - Sidi A. Bencherif
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States of America
- Department of Bioengineering, Northeastern University, Boston, MA 02115, United States of America
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, United States of America
- Biomechanics and Bioengineering (BMBI), UTC CNRS UMR 7338, University of Technology of Compiègne, Sorbonne University, 60203 Compiègne, France
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20
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Wang C, Tang Y, Ma H, Wei S, Hu X, Zhao L, Wang G. Identification of Hypoxia-Related Subtypes, Establishment of Prognostic Models, and Characteristics of Tumor Microenvironment Infiltration in Colon Cancer. Front Genet 2022; 13:919389. [PMID: 35783281 PMCID: PMC9247151 DOI: 10.3389/fgene.2022.919389] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 04/25/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Immunotherapy is a treatment that can significantly improve the prognosis of patients with colon cancer, but the response to immunotherapy is different in patients with colon cancer because of the heterogeneity of colon carcinoma and the complex nature of the tumor microenvironment (TME). In the precision therapy mode, finding predictive biomarkers that can accurately identify immunotherapy-sensitive types of colon cancer is essential. Hypoxia plays an important role in tumor proliferation, apoptosis, angiogenesis, invasion and metastasis, energy metabolism, and chemotherapy and immunotherapy resistance. Thus, understanding the mechanism of hypoxia-related genes (HRGs) in colon cancer progression and constructing hypoxia-related signatures will help enrich our treatment strategies and improve patient prognosis. Methods: We obtained the gene expression data and corresponding clinical information of 1,025 colon carcinoma patients from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. We identified two distinct hypoxia subtypes (subtype A and subtype B) according to unsupervised clustering analysis and assessed the clinical parameters, prognosis, and TME cell-infiltrating characteristics of patients in the two subtypes. We identified 1,132 differentially expressed genes (DEGs) between the two hypoxia subtypes, and all patients were randomly divided into the training group (n = 513) and testing groups (n = 512). Following univariate Cox regression with DEGs, we construct the prognostic model (HRG-score) including six genes (S1PR3, ETV5, CD36, FOXC1, CXCL10, and MMP12) through the LASSO–multivariate cox method in the training group. We comprehensively evaluated the sensitivity and applicability of the HRG-score model from the training group and the testing group, respectively. We explored the correlation between HRG-score and clinical parameters, tumor microenvironment, cancer stem cells (CSCs), and MMR status. In order to evaluate the value of the risk model in clinical application, we further analyzed the sensitivity of chemotherapeutics and immunotherapy between the low-risk group and high-risk group and constructed a nomogram for improving the clinical application of the HRG-score. Result: Subtype A was significantly enriched in metabolism-related pathways, and subtype B was significantly enriched in immune activation and several tumor-associated pathways. The level of immune cell infiltration and immune checkpoint-related genes, stromal score, estimate score, and immune dysfunction and exclusion (TIDE) prediction score was significantly different in subtype A and subtype B. The level of immune checkpoint-related genes and TIDE score was significantly lower in subtype A than that in subtype B, indicating that subtype A might benefit from immune checkpoint inhibitors. Finally, an HRG-score signature for predicting prognosis was constructed through the training group, and the predictive capability was validated through the testing group. The survival analysis and correlation analysis of clinical parameters revealed that the prognosis of patients in the high-risk group was significantly worse than that in the low-risk group. There were also significant differences in immune status, mismatch repair status (MMR), and cancer stem cell index (CSC), between the two risk groups. The correlation analysis of risk scores with IC50 and IPS showed that patients in the low-risk group had a higher benefit from chemotherapy and immunotherapy than those in the high-risk group, and the external validation IMvigor210 demonstrated that patients with low risk were more sensitive to immunotherapy. Conclusion: We identified two novel molecular subgroups based on HRGs and constructed an HRG-score model consisting of six genes, which can help us to better understand the mechanisms of hypoxia-related genes in the progression of colon cancer and identify patients susceptible to chemotherapy or immunotherapy, so as to achieve precision therapy for colon cancer.
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Affiliation(s)
- Changjing Wang
- Department of Gastrointestinal Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yujie Tang
- Department of Gastrointestinal Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hongqing Ma
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Sisi Wei
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xuhua Hu
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lianmei Zhao
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Guiying Wang, ; Lianmei Zhao,
| | - Guiying Wang
- Department of Gastrointestinal Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Guiying Wang, ; Lianmei Zhao,
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21
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Hypoxia Induces Autophagy in Human Dendritic Cells: Involvement of Class III PI3K/Vps34. Cells 2022; 11:cells11101695. [PMID: 35626732 PMCID: PMC9139568 DOI: 10.3390/cells11101695] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/09/2022] [Accepted: 05/18/2022] [Indexed: 11/16/2022] Open
Abstract
Hypoxia is a component of both physiological and pathological conditions, including inflammation, solid tumors, and lymphoid tissues, where O2 demand is not balanced by O2 supply. During their lifespan, dendritic cells (DCs) are exposed to different pO2 and activate different adaptive responses, including autophagy, to preserve their viability and functions. Autophagy plays multiple roles in DC physiology. Very recently, we demonstrated that hypoxia shapes autophagy in DCs upon their differentiation state. Here, we proposed a role for PI3Ks, and especially class III PI3K/Vps34, that could be relevant in hypoxia-induced autophagy, in either immature or mature DCs. Hypoxia inhibited mTOR phosphorylation and activated a pro-autophagic program. By using different pharmacological inhibitors, we demonstrated that hypoxia-induced autophagy was mediated by PI3Ks, especially by Vps34. Furthermore, Vps34 expression was enhanced by LPS, a TLR4 ligand, along with the promotion of autophagy under hypoxia. The Vps34 inhibitor, SAR405, abolished hypoxia-induced autophagy, inhibited pro-survival signaling and viability, and increased the expression of proinflammatory cytokines. Our results underlined the impact of autophagy in the maintenance of DC homeostasis at both cell survival and inflammatory response levels, therefore, contributing to a better understanding of the significance of autophagy in DC physiology and pathology.
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22
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Liu Y, Xu D, Liu Y, Zheng X, Zang J, Ye W, Zhao Y, He R, Ruan S, Zhang T, Dong H, Li Y, Li Y. Remotely boosting hyaluronidase activity to normalize the hypoxic immunosuppressive tumor microenvironment for photothermal immunotherapy. Biomaterials 2022; 284:121516. [DOI: 10.1016/j.biomaterials.2022.121516] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/03/2022] [Accepted: 04/05/2022] [Indexed: 12/20/2022]
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23
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Drehmer D, Mesquita Luiz JP, Hernandez CAS, Alves-Filho JC, Hussell T, Townsend PA, Moncada S. Nitric oxide favours tumour-promoting inflammation through mitochondria-dependent and -independent actions on macrophages. Redox Biol 2022; 54:102350. [PMID: 35660630 PMCID: PMC9511697 DOI: 10.1016/j.redox.2022.102350] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/12/2022] [Accepted: 05/21/2022] [Indexed: 12/22/2022] Open
Abstract
Production of nitric oxide (NO) has been demonstrated in several malignancies, however its role remains not fully understood, specifically in relation to the metabolic and functional implications that it may have on immune cells participating in tumorigenesis. Here, we show that inducible NO synthase (iNOS) is expressed in cancers of the colon and the prostate, mainly by tumour cells, and NO generation is evidenced by widespread nitrotyrosine (NT) staining in tumour tissue. Furthermore, presence of NT is observed in the majority of tumour-associated macrophages (TAMs), despite low iNOS expression by these cells, suggesting that NO from the tumour microenvironment affects TAMs. Indeed, using a co-culture model, we demonstrate that NO produced by colon and prostate cancer cells is sufficient to induce NT formation in neighbouring macrophages. Moreover, exposure to exogenous NO promotes mitochondria-dependent and -independent changes in macrophages, which orientate their polarity towards an enhanced pro-inflammatory phenotype, whilst decreasing antigen-presenting function and wound healing capacity. Abrogating endogenous NO generation in murine macrophages, on the other hand, decreases their pro-inflammatory phenotype. These results suggest that the presence of NO in cancer may regulate TAM metabolism and function, favouring the persistence of inflammation, impairing healing and subverting adaptive immunity responses.
Nitric oxide (NO) from the cancer microenvironment acts on tumour-associated macrophages (TAMs). NO induces a phenotypic shift in macrophages through mitochondria-dependent and -independent pathways. NO favours pro-inflammatory cytokine production whilst decreasing macrophage function as antigen presenting cell. NO impairs repair function of macrophages. Presence of NO in cancer may regulate TAM metabolism and function, favouring tumour-promoting inflammation.
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24
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The Synergistic Cooperation between TGF-β and Hypoxia in Cancer and Fibrosis. Biomolecules 2022; 12:biom12050635. [PMID: 35625561 PMCID: PMC9138354 DOI: 10.3390/biom12050635] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 03/10/2022] [Accepted: 04/14/2022] [Indexed: 12/24/2022] Open
Abstract
Transforming growth factor β (TGF-β) is a multifunctional cytokine regulating homeostasis and immune responses in adult animals and humans. Aberrant and overactive TGF-β signaling promotes cancer initiation and fibrosis through epithelial–mesenchymal transition (EMT), as well as the invasion and metastatic growth of cancer cells. TGF-β is a key factor that is active during hypoxic conditions in cancer and is thereby capable of contributing to angiogenesis in various types of cancer. Another potent role of TGF-β is suppressing immune responses in cancer patients. The strong tumor-promoting effects of TGF-β and its profibrotic effects make it a focus for the development of novel therapeutic strategies against cancer and fibrosis as well as an attractive drug target in combination with immune regulatory checkpoint inhibitors. TGF-β belongs to a family of cytokines that exert their function through signaling via serine/threonine kinase transmembrane receptors to intracellular Smad proteins via the canonical pathway and in combination with co-regulators such as the adaptor protein and E3 ubiquitin ligases TRAF4 and TRAF6 to promote non-canonical pathways. Finally, the outcome of gene transcription initiated by TGF-β is context-dependent and controlled by signals exerted by other growth factors such as EGF and Wnt. Here, we discuss the synergistic cooperation between TGF-β and hypoxia in development, fibrosis and cancer.
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25
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Abou Khouzam R, Zaarour RF, Brodaczewska K, Azakir B, Venkatesh GH, Thiery J, Terry S, Chouaib S. The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes? Front Immunol 2022; 13:828875. [PMID: 35211123 PMCID: PMC8861358 DOI: 10.3389/fimmu.2022.828875] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 01/19/2022] [Indexed: 12/15/2022] Open
Abstract
Hypoxia is an environmental stressor that is instigated by low oxygen availability. It fuels the progression of solid tumors by driving tumor plasticity, heterogeneity, stemness and genomic instability. Hypoxia metabolically reprograms the tumor microenvironment (TME), adding insult to injury to the acidic, nutrient deprived and poorly vascularized conditions that act to dampen immune cell function. Through its impact on key cancer hallmarks and by creating a physical barrier conducive to tumor survival, hypoxia modulates tumor cell escape from the mounted immune response. The tumor cell-immune cell crosstalk in the context of a hypoxic TME tips the balance towards a cold and immunosuppressed microenvironment that is resistant to immune checkpoint inhibitors (ICI). Nonetheless, evidence is emerging that could make hypoxia an asset for improving response to ICI. Tackling the tumor immune contexture has taken on an in silico, digitalized approach with an increasing number of studies applying bioinformatics to deconvolute the cellular and non-cellular elements of the TME. Such approaches have additionally been combined with signature-based proxies of hypoxia to further dissect the turbulent hypoxia-immune relationship. In this review we will be highlighting the mechanisms by which hypoxia impacts immune cell functions and how that could translate to predicting response to immunotherapy in an era of machine learning and computational biology.
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Affiliation(s)
- Raefa Abou Khouzam
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Rania Faouzi Zaarour
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Klaudia Brodaczewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland
| | - Bilal Azakir
- Faculty of Medicine, Beirut Arab University, Beirut, Lebanon
| | - Goutham Hassan Venkatesh
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Jerome Thiery
- INSERM U1186, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.,Faculty of Medicine, University Paris Sud, Le Kremlin Bicêtre, France
| | - Stéphane Terry
- INSERM U1186, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.,Faculty of Medicine, University Paris Sud, Le Kremlin Bicêtre, France.,Research Department, Inovarion, Paris, France
| | - Salem Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates.,INSERM U1186, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
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26
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Yan J, Huang YJ, Huang QY, Liu PX, Wang CS. Comprehensive analysis of the correlations of S100B with hypoxia response and immune infiltration in hepatocellular carcinoma. PeerJ 2022; 10:e13201. [PMID: 35368338 PMCID: PMC8973469 DOI: 10.7717/peerj.13201] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 03/09/2022] [Indexed: 01/12/2023] Open
Abstract
S100B has been found to be dysregulated in many cancers including hepatocellular carcinoma (HCC). However, the functions of S100B and its underlying mechanisms in HCC remain poorly understood, especially in the tumor microenvironment. In this study, functions enrichment analysis indicated that S100B expression was correlated with hypoxia and immune responses. We found that hypoxia could induce S100B expression in an HIF-1α-dependent manner in HepG2 cells. Luciferase reporter and ChIP-qRCR assays demonstrated that HIF-1α regulates S100B transcription by directly binding to hypoxia-response elements (HREs) of the S100B promoter. Functionally, knockdown of S100B reduces hypoxia-induced HepG2 cell invasion and migration. Furthermore, GSVA enrichment results displayed that S100B and its co-expressed genes were positively correlated with EMT pathway in HCC. Additionally, GO/KEGG cluster analysis results indicated that co-expressed genes of S100B were involved in biological processes of immune response and multiple tumor immune-related signaling pathways in HCC. S100B expression was positively correlated with multiple immune cells tumor infiltration and associated with chemokines/chemokine receptors and immune checkpoint genes. Moreover, S100B is predominantly expressed in immune cells, especially NK (Natural Killer) cell. In addition, the hub genes of S100B co-expression and hypoxia response in HepG2 cell were also associated with immune cells infiltration in HCC. Taken together, these findings provide a new insight into the complex networks between hypoxia response and immune cells infiltration in tumor microenvironment of liver cancer. S100B maybe serve as a novel target for future HCC therapies.
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Affiliation(s)
- Jia Yan
- Department of Bioscience, State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, China,Department of Bioscience, Inner Mongolia University, Hohhot, China
| | - Ya jun Huang
- Department of Bioscience, Inner Mongolia University, Hohhot, China
| | - Qing yu Huang
- Department of Bioscience, Inner Mongolia University, Hohhot, China
| | - Peng Xia Liu
- Department of Bioscience, Inner Mongolia University, Hohhot, China
| | - Chang Shan Wang
- Department of Bioscience, State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, China,Department of Bioscience, Inner Mongolia University, Hohhot, China
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27
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An intratumoral injectable nanozyme hydrogel for hypoxia-resistant thermoradiotherapy. Colloids Surf B Biointerfaces 2021; 207:112026. [PMID: 34384974 DOI: 10.1016/j.colsurfb.2021.112026] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/30/2021] [Accepted: 08/04/2021] [Indexed: 12/15/2022]
Abstract
Hypoxia in local tumors leads to the failure or resistance of radiotherapy (RT) and high-dose RT will cause systemic reactions and local radiation damage. As a non-chemotherapeutic intervention, photothermal therapy (PTT) can remove tumor tissues through thermal ablation as well as effectively improve the microenvironment of hypoxic cells. Therefore, the combined use of PTT and RT (thermoradiotherapy) has urgently become an efficient treatment. In this work, by encapsulating prussian blue (PB) nanoparticles in agarose hydrogel, we developed an injectable hybrid light-controlled hydrogel system as a PB reservoir and release controller (PRC) which can realize single injection and multiple treatments in vivo. Under the irradiation of 808 nm near-infrared (NIR) laser, PB nanoparticles convert laser energy into heat energy, causing degradation of agarose hydrogel and the release of PB nanoparticles. Due to the excellent photothermal properties of PB, photothermal treatment in the NIR Biological Windows can greatly enhance the sensitivity of tumor cells to RT. Meanwhile, PB nanoparticles can also be a nanozyme to drive the decomposition of endogenous hydrogen peroxide (H2O2), and then generate oxygen (O2) to improve the tumor hypoxic microenvironment, achieving the further enhancement of the radiation sensitivity. Notably, this study is the first design to utilize hydrogel for thermoradiotherapy. Both in vitro and in vivo experiments, the PRC demonstrated excellent effects of PTT-RT, good stability and biocompatibility, indicating our nanoplatform promote the development of anti-cancer combination thermoradiotherapy with greater clinical significance.
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28
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Sieck GC. Physiology in Perspective: Harnessing Homeostasis. Physiology (Bethesda) 2021; 36:71-72. [PMID: 33595383 DOI: 10.1152/physiol.00003.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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