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Hossain MT, Hossain MA. Targeting PI3K in cancer treatment: A comprehensive review with insights from clinical outcomes. Eur J Pharmacol 2025; 996:177432. [PMID: 40020984 DOI: 10.1016/j.ejphar.2025.177432] [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: 11/16/2024] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/03/2025]
Abstract
The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cancer, including cell growth, survival, metabolism, and metastasis. Its major role in tumor growth makes it a key target for cancer therapeutics, offering significant potential to slow tumor progression and enhance patient outcomes. Gain-of-function mutations, gene amplifications, and the loss of regulatory proteins like PTEN are frequently observed in malignancies, contributing to tumor development and resistance to conventional treatments such as chemotherapy and hormone therapy. As a result, PI3K inhibitors have received a lot of interest in cancer research. Several kinds of small-molecule PI3K inhibitors have been developed, including pan-PI3K inhibitors, isoform-specific inhibitors, and dual PI3K/mTOR inhibitors, each targeting a distinct component of the pathway. Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and hematologic malignancies. Despite promising results in preclinical and clinical trials, the overall clinical success of PI3K inhibitors has been mixed. While some patients may get substantial advantages, a considerable number of them acquire resistance as a result of feedback activation of alternative pathways, adaptive tumor responses, and treatment-emergent mutations. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.
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Affiliation(s)
- Md Takdir Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
| | - Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
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Xue Y, Chen J, Sun X, Su C, Fan S, Song X, Deng R, Hao J. Exosomes derived from M2 macrophage promote HUVECs proliferation, migration and tube formation in vitro. Sci Rep 2025; 15:17876. [PMID: 40404811 PMCID: PMC12098727 DOI: 10.1038/s41598-025-03113-5] [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] [Received: 10/28/2024] [Accepted: 05/19/2025] [Indexed: 05/24/2025] Open
Abstract
Angiogenesis is one of the hallmarks of solid tumors. Exosomes are extracellular vesicles, which are involved in multiple stages of tumor progression. The role of macrophage-derived exosomes in angiogenesis in oral squamous cell carcinoma (OSCC), where macrophages are crucial components of the tumor microenvironment (TME), remains to be explored. The M2 macrophages and microvessels in OSCC were stained by immunohistochemistry. M2 macrophages were induced in vitro and exosomes were extracted by gradient centrifugation using ultracentrifugation. Fluorescence confocal microscopy was used to observe the uptake of M2 macrophage-derived exosomes by human umbilical vein endothelial cells (HUVECs). CCK-8 proliferation assay, TRANSWELL migration assay and tube formation assay were used to detect the effects of M2 macrophage-derived exosomes on the proliferation, migration and tube formation of HUVECs. Immunohistochemical study showed that M2 macrophage infiltration was positively correlated with microvessel density in OSCC. We induced M2 macrophages in vitro and successfully extracted its exosomes. The cellular internalization of fluorescence-labeled exosomes by HUVECs was dynamically monitored via laser scanning confocal microscopy. The M2 macrophage-derived exosomes promoted the proliferation, migration, and tube-forming ability of HUVECs. The results showed that M2 macrophage-derived exosomes could promote the proliferation, migration and tubulation of HUVECs.
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Affiliation(s)
- Yiwen Xue
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, 210008, China
| | - Jingru Chen
- Changsha Medical University, Changsha, 410219, China
| | - Xin Sun
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, 210008, China
| | - Chuanchao Su
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, 210008, China
| | - Siyu Fan
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, 210008, China
| | - Xiao Song
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, 210008, China
| | - Runzhi Deng
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, 210008, China.
| | - Jing Hao
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, 210008, China.
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3
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Hochstadt J, Martínez Pacheco S, Casanova-Acebes M. Embracing diversity: macrophage complexity in cancer. Trends Cancer 2025; 11:351-364. [PMID: 39753470 DOI: 10.1016/j.trecan.2024.12.002] [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: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 04/11/2025]
Abstract
Macrophages are myeloid cells that receive, integrate, and respond to tumoral cues. Tumors evolve and are shaped by macrophages, with tumor-associated macrophage (TAM)-tumor sculpting capacities going beyond an increase in their cellular mass. Longitudinal and local heterogeneity of TAM states is now possible with the use of single-cell and spatial transcriptomics. However, understanding TAM biology and its fundamental functional programs is still challenging, probably because of the lack of models that fully integrate TAM complexity. Here, we aim to review TAM diversity not only at the level of single-cell phenotypes but also by integrating complex physiological signals that determine their complexity and plasticity in tumors.
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Affiliation(s)
- Jan Hochstadt
- Cancer Immunity Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Sarai Martínez Pacheco
- Cancer Immunity Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - María Casanova-Acebes
- Cancer Immunity Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
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Chang TD, Chen YJ, Luo JL, Zhang C, Chen SY, Lin ZQ, Zhang PD, Shen YX, Tang TX, Li H, Dong LM, Tang ZH, Chen D, Wang YM. Adaptation of Natural Killer Cells to Hypoxia: A Review of the Transcriptional, Translational, and Metabolic Processes. Immunotargets Ther 2025; 14:99-121. [PMID: 39990274 PMCID: PMC11846490 DOI: 10.2147/itt.s492334] [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: 08/21/2024] [Accepted: 02/08/2025] [Indexed: 02/25/2025] Open
Abstract
As important innate immune cells, natural killer (NK) cells play an essential role in resisting pathogen invasion and eliminating transformed cells. However, the hypoxic microenvironment caused by disease conditions is an important physicochemical factor that impairs NK cell function. With the increasing prominence of NK cells in immunotherapy, there has been a surge of interest in developing biological means through which NK cells may overcome the inhibition caused by hypoxia in disease conditions. Although the effects of hypoxic conditions in shaping the functions of NK cells have been increasingly recognized and investigated, reviews have been scantly. A comprehensive understanding of how NK cells adapt to hypoxia can provide valuable insights into how the functional capacity of NK cells may be restored. This review focuses on the functional alterations of NK cells in response to hypoxia. It delineates the mechanisms by which NK cells adapt to hypoxia at the transcriptional, metabolic, translational levels. Furthermore, given the complexity of the hypoxic microenvironment, we also elucidated the effects of key hypoxic metabolites on NK cells. Finally, this review discusses the current clinical therapies derived from targeting hypoxic NK cells. The study of NK cell adaptation to hypoxia has yielded new insights into immunotherapy. These insights may lead to development of novel strategies to improve the treatment of infectious diseases and cancer.
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Affiliation(s)
- Te-Ding Chang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yu-Jie Chen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jia-Liu Luo
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Cong Zhang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Shun-Yao Chen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Zhi-Qiang Lin
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Pei-Dong Zhang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - You-Xie Shen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Ting-Xuan Tang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Hui Li
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Li-Ming Dong
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Zhao-Hui Tang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Deng Chen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yu-Man Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
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Yang H, Li J, Niu Y, Zhou T, Zhang P, Liu Y, Li Y. Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment. Front Immunol 2025; 16:1494788. [PMID: 40028341 PMCID: PMC11868052 DOI: 10.3389/fimmu.2025.1494788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/29/2025] [Indexed: 03/05/2025] Open
Abstract
Metabolic reprogramming is one of the major biological features of malignant tumors, playing a crucial role in the initiation and progression of cancer. The tumor microenvironment consists of various non-cancer cells, such as hepatic stellate cells, cancer-associated fibroblasts (CAFs), immune cells, as well as extracellular matrix and soluble substances. In liver cancer, metabolic reprogramming not only affects its own growth and survival but also interacts with other non-cancer cells by influencing the expression and release of metabolites and cytokines (such as lactate, PGE2, arginine). This interaction leads to acidification of the microenvironment and restricts the uptake of nutrients by other non-cancer cells, resulting in metabolic competition and symbiosis. At the same time, metabolic reprogramming in neighboring cells during proliferation and differentiation processes also impacts tumor immunity. This article provides a comprehensive overview of the metabolic crosstalk between liver cancer cells and their tumor microenvironment, deepening our understanding of relevant findings and pathways. This contributes to further understanding the regulation of cancer development and immune evasion mechanisms while providing assistance in advancing personalized therapies targeting metabolic pathways for anti-cancer treatment.
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Affiliation(s)
- Haoqiang Yang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Jinghui Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yiting Niu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Tao Zhou
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Pengyu Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yang Liu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yanjun Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, TongjiShanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Dong R, Ji Z, Wang M, Ma G. Role of macrophages in vascular calcification: From the perspective of homeostasis. Int Immunopharmacol 2025; 144:113635. [PMID: 39566391 DOI: 10.1016/j.intimp.2024.113635] [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: 09/28/2024] [Revised: 11/04/2024] [Accepted: 11/11/2024] [Indexed: 11/22/2024]
Abstract
Vascular calcification (VC) is a crucial risk factor for the high morbidity and mortality associated with cardiovascular and cerebrovascular diseases. With the global population aging, the incidence of VC is escalating annually. However, due to its silent clinical process, VC often results in irreversible clinical outcomes. Inflammation is a core element in the VC process, and macrophages are the major inflammatory cells. Due to their diverse origins, microenvironments, and polarization states, macrophages exhibit significant heterogeneity, exerting strong effects on the occurrence, development, and even the regression of VC. In this review, we summarize the origin, distribution, classification, and surface markers of macrophages. Simultaneously, we explore the mechanisms by which macrophages maintain homeostasis or regulate inflammation, including the macrophage-mediated regulation of VC through the release of inflammatory factors, osteogenic genes, extracellular vesicles, and alterations in efferocytosis. Finally, we discuss research targeting inflammation and macrophages to develop novel therapeutic regimens for preventing and treating VC.
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Affiliation(s)
- Rong Dong
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87, Dingjiaqiao, Nanjing 210009, China; Department of Cardiology, Yancheng No. 1 People's Hospital, No. 66 South Renmin Road, Yancheng 224000, China
| | - Zhenjun Ji
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87, Dingjiaqiao, Nanjing 210009, China
| | - Mi Wang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87, Dingjiaqiao, Nanjing 210009, China
| | - Genshan Ma
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87, Dingjiaqiao, Nanjing 210009, China.
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Ruditsky A, Fisher K, Tighe K, B'lanton J, Ma X, Jiang K, Byrne K, Carter-Cooper B, Casildo A, Passaniti A, Carrier F, Lapidus R, Richard K, Kallen ME, Ng VY. A Novel Approach to Potentially Improving Soft-Tissue Sarcoma Survival: Prophylactic Lung Radiotherapy Inhibits Growth of Lung Metastases and Prolongs Survival in a Murine Soft-Tissue Sarcoma Model. Cureus 2024; 16:e76334. [PMID: 39867071 PMCID: PMC11757009 DOI: 10.7759/cureus.76334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/24/2024] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND Circulating tumor cells and clusters (CTC) from soft-tissue sarcoma (STS) that become entrapped in the lung can form micro-metastases and lead to pulmonary metastatic disease. Many patients with localized high-risk STS later develop metastases. Radiation is effective at reducing local recurrence by eradicating microscopic infiltration and satellites in the reactive zone surrounding the primary tumor. Prophylactic lung irradiation for patients with high-risk STS is a novel concept to potentially reduce the appearance of macroscopic metastases and improve survival. A proof-of-principle study was performed based on a novel approach: prophylactic lung radiation after resection of the primary tumor to address microscopic pulmonary deposits from CTC. METHODS Immunocompromised mice and luciferase-expressing human fibrosarcoma (HT-1080-Luc) cell lines were used. In phase 1, HT-1080-Luc cells were injected into the tail vein to simulate CTC for the development of pulmonary metastases. Whole-lung irradiation (WLI) was then performed in the treated mice prior to the appearance of macroscopic metastases. In phase 2, a flank tumor was established to simulate a primary STS, followed by a tail-vein injection of HT-1080-Luc cells. Treatment groups included surgical removal of the primary STS and hemithoracic irradiation (HTI). Body weight and bioluminescence data were obtained and the mice were euthanized on Day 31 (phase 1) and Day 15 (phase 2) or when they reached 20% weight loss. RESULTS In phase 1, prophylactic WLI increased survival and decreased pulmonary metastases. In phase 2, prophylactic HTI (left lung) decreased pulmonary metastases compared to controls. Lung histology showed dramatically decreased growth and number of established metastases with HTI. Resection of the primary tumor did not affect the growth of metastases. CONCLUSION Prophylactic WLI after resection of the primary tumor to inhibit the growth of pulmonary metastases from previously entrapped CTCs may be a promising approach to improve survival for patients with localized high-risk STS.
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Affiliation(s)
| | - Kalin Fisher
- Department of Orthopaedics, University of Maryland, Baltimore, USA
| | - Kayla Tighe
- Translational Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | - Jasmine B'lanton
- Cancer, National Cancer Institutes, Frederick, USA
- Translational Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | - Xinrong Ma
- Translational Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | - Kai Jiang
- Department of Radiation Oncology, University of Maryland, Baltimore, USA
| | - Kevin Byrne
- Department of Radiation Oncology, University of Maryland, Baltimore, USA
| | - Brandon Carter-Cooper
- Translational Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | - Andrea Casildo
- Translational Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | - Antonino Passaniti
- Translational Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | - France Carrier
- Translational Radiation Sciences, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | - Rena Lapidus
- Translational Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | - Katharina Richard
- Translational Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
| | | | - Vincent Y Ng
- Department of Orthopaedics, University of Maryland, Baltimore, USA
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Drüeke TB, Alhenc-Gelas F. A new mechanism in adrenal control of aldosterone secretion involving the macrophage and VEGF. Kidney Int 2024; 106:1011-1014. [PMID: 39299499 DOI: 10.1016/j.kint.2024.08.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/21/2024] [Indexed: 09/22/2024]
Affiliation(s)
- Tilman B Drüeke
- Inserm Unit 1018, Team 5, CESP, Hôpital Paul Brousse, Paris-Sud University (UPS) and Versailles Saint-Quentin-en-Yvelines University (Paris-Ile-de-France-Ouest University, UVSQ), Villejuif, France.
| | - François Alhenc-Gelas
- Inserm U 1038, Centre de recherche des Cordeliers, Paris-Cité University, Sorbonne-University, Paris, France
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Zhang J, Yang L, Xu B, Ji H, Liu S, Wang X, Li X, Wang Q, Song Z. The role of ATP6V0D2 in breast cancer: associations with prognosis, immune characteristics, and TNBC progression. Front Oncol 2024; 14:1511810. [PMID: 39678496 PMCID: PMC11638046 DOI: 10.3389/fonc.2024.1511810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 11/11/2024] [Indexed: 12/17/2024] Open
Abstract
Objective Researches have identified ATPase H+ transporting V0 subunit d2 (ATP6V0D2) as a significant factor in various cancers. However, its prognostic value in breast cancer (BRCA) and its biological role in BRCA cells remain unclear. Methods In this research, we examined the varying expression levels of ATP6V0D2 in both BRCA and normal breast tissue by utilizing information derived from databases including the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), along with clinical samples. Survival studies were carried out to investigate the link between ATP6V0D2 levels and prognosis in BRCA patients. A series of enrichment analyses identified possible pathways associated with the differentially expressed genes in BRCA. The relationships among ATP6V0D2 expression, immune characteristics, and gene mutation were evaluated using Spearman's test. Finally, the expression of ATP6V0D2 was identified by quantitative real-time polymerase chain reaction (RT-qPCR) alongside western blot analysis. Additionally, Cell Counting kit-8 (CCK-8), Colony formation, Transwell, Scratch healing, and Mouse xenograft tumor assays were conducted to assessed the impact of ATP6V0D2 knockdown on the biological functions in TNBC. Results ATP6V0D2 exhibited high expression in a range of cancers and correlated with unfavorable prognosis in BRCA. Functional enrichment analyses revealed enrichment of extracellular matrix-receptor interaction, focal adhesion, and the signaling pathway of tumor growth factor-beta in the high ATP6V0D2 expression group. Additionally, ATP6V0D2 was closely associated with immune checkpoints. Its expression positively associated with the infiltration levels of macrophage and neutrophil, but inversely with CD8+ T and plasmacytoid dendritic cells. Mutation analysis revealed that PIK3CA, linked to decreased OS, exhibited a higher mutation rate in the ATP6V0D2 high expression group. Furthermore, ATP6V0D2 knockdown inhibited TNBC cells invasion, migration, and proliferation abilities. Conclusion ATP6V0D2 acts as a promising indicator for both diagnosis and prediction of outcomes in breast cancer and could potentially be a novel therapeutic target for BRCA.
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Affiliation(s)
- Jingyu Zhang
- Department of Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Lixian Yang
- Department of Breast Surgery, Xingtai People’s Hospital, Xingtai, Hebei, China
| | - Bin Xu
- Department of Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Haibo Ji
- Department of Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shuo Liu
- Department of Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaohan Wang
- Department of Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaolong Li
- Department of Breast Surgery, Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, China
| | - Quanle Wang
- Department of Breast Surgery, Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, China
| | - Zhenchuan Song
- Department of Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Key Laboratory for Breast Cancer Molecular Medicine of Hebei Province, Shijiazhuang, Hebei, China
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Lorenc P, Sikorska A, Molenda S, Guzniczak N, Dams-Kozlowska H, Florczak A. Physiological and tumor-associated angiogenesis: Key factors and therapy targeting VEGF/VEGFR pathway. Biomed Pharmacother 2024; 180:117585. [PMID: 39442237 DOI: 10.1016/j.biopha.2024.117585] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/03/2024] [Accepted: 10/14/2024] [Indexed: 10/25/2024] Open
Abstract
Cancer remains one of the leading causes of death worldwide and poses a significant challenge to effective treatment due to its complexity. Angiogenesis, the formation of new blood vessels, is one of the cancer hallmarks and is a critical process in tumor growth and metastasis. The pivotal role of angiogenesis in cancer development has made antiangiogenic treatment a promising strategy for cancer therapy. To develop an effective therapy, it is essential to understand the basics of the physiological and tumor angiogenesis process. This review presents the primary factors related to physiological and tumor angiogenesis and the mechanisms of angiogenesis in tumors. We summarize potential molecular targets for cancer treatment by focusing on the vasculature, with the VEGF/VEGFR pathway being one of the most important and well-studied. Additionally, we present the advantages and limitations of currently used clinical protocols for cancer treatment targeting the VEGF/VEGFR pathway.
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Affiliation(s)
- Patryk Lorenc
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland; Doctoral School, Poznan University of Medical Sciences, 70 Bukowska St, Poznan 60-812, Poland
| | - Agata Sikorska
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland
| | - Sara Molenda
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland; Doctoral School, Poznan University of Medical Sciences, 70 Bukowska St, Poznan 60-812, Poland
| | - Natalia Guzniczak
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland
| | - Hanna Dams-Kozlowska
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland
| | - Anna Florczak
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland.
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11
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Zhou Y, Lou J, Tian Y, Ding J, Wang X, Tang B. How lactate affects immune strategies in lymphoma. Front Mol Biosci 2024; 11:1480884. [PMID: 39464313 PMCID: PMC11502318 DOI: 10.3389/fmolb.2024.1480884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/30/2024] [Indexed: 10/29/2024] Open
Abstract
Tumor cells undergo metabolic reprogramming through shared pathways, resulting in a hypoxic, acidic, and highly permeable internal tumor microenvironment (TME). Lactate, once only regarded as a waste product of glycolysis, has an inseparable dual role with tumor immunity. It can not only provide a carbon source for immune cells to enhance immunity but also help the immune escape through a variety of ways. Lymphoma also depends on the proliferation signal of TME. This review focuses on the dynamic process of lactate metabolism and immune function changes in lymphoma and aims to comprehensively summarize and explore which genes, transcription factors, and pathways affect the biological changes and functions of immune cells. To deeply understand the complex and multifaceted role of lactate metabolism and immunity in lymphoma, the combination of lactate targeted therapy and classical immunotherapy will be a promising development direction in the future.
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Affiliation(s)
- Yuehan Zhou
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinzhan Lou
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuqin Tian
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinlei Ding
- Department of Thoracic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaobo Wang
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bo Tang
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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12
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Liu Y, Liang J, Zhang Y, Guo Q. Drug resistance and tumor immune microenvironment: An overview of current understandings (Review). Int J Oncol 2024; 65:96. [PMID: 39219258 PMCID: PMC11387120 DOI: 10.3892/ijo.2024.5684] [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: 05/29/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
The use of antitumor drugs represents a reliable strategy for cancer therapy. Unfortunately, drug resistance has become increasingly common and contributes to tumor metastasis and local recurrence. The tumor immune microenvironment (TME) consists of immune cells, cytokines and immunomodulators, and collectively they influence the response to treatment. Epigenetic changes including DNA methylation and histone modification, as well as increased drug exportation have been reported to contribute to the development of drug resistance in cancers. In the past few years, the majority of studies on tumors have only focused on the development and progression of a tumor from a mechanistic standpoint; few studies have examined whether the changes in the TME can also affect tumor growth and drug resistance. Recently, emerging evidence have raised more concerns regarding the role of TME in the development of drug resistance. In the present review, it was discussed how the suppressive TME adapts to drug resistance characterized by the cooperation of immune cells, cytokines, immunomodulators, stromal cells and extracellular matrix. Furthermore, it was reviewed how these immunological or metabolic changes alter immuno‑surveillance and thus facilitate tumor drug resistance. In addition, potential targets present in the TME for developing novel therapeutic strategies to improve individualized therapy for cancer treatment were revealed.
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Affiliation(s)
- Yan Liu
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jun Liang
- Department of Radiology, Qingdao Haici Hospital, Qingdao, Shandong 266000, P.R. China
| | - Yanping Zhang
- Department of Radiology, Qingdao Haici Hospital, Qingdao, Shandong 266000, P.R. China
| | - Qie Guo
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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13
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Lecoultre M, Walker PR, El Helali A. Oncolytic virus and tumor-associated macrophage interactions in cancer immunotherapy. Clin Exp Med 2024; 24:202. [PMID: 39196415 PMCID: PMC11358230 DOI: 10.1007/s10238-024-01443-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024]
Abstract
Oncolytic viruses (OV) are a promising strategy in cancer immunotherapy. Their capacity to promote anti-tumoral immunity locally raises hope that cancers unresponsive to current immunotherapy approaches could be tackled more efficiently. In this context, tumor-associated macrophages (TAM) must be considered because of their pivotal role in cancer immunity. Even though TAM tend to inhibit anti-tumoral responses, their ability to secrete pro-inflammatory cytokines and phagocytose cancer cells can be harnessed to promote therapeutic cancer immunity. OVs have the potential to promote TAM pro-inflammatory functions that favor anti-tumoral immunity. But in parallel, TAM pro-inflammatory functions induce OV clearance in the tumor, thereby limiting OV efficacy and highlighting that the interaction between OV and TAM is a double edge sword. Moreover, engineered OVs were recently developed to modulate specific TAM functions such as phagocytic activity. The potential of circulating monocytes to deliver OV into the tumor after intravenous administration is also emerging. In this review, we will present the interaction between OV and TAM, the potential of engineered OV to modulate specific TAM functions, and the promising role of circulating monocytes in OV delivery to the tumor.
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Affiliation(s)
- Marc Lecoultre
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, China
- Division of General Internal Medicine, Geneva University Hospital, Geneva, Switzerland
| | - Paul R Walker
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Immunobiology of Brain Tumours Laboratory, Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland
| | - Aya El Helali
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, China.
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14
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Yang F, Lee G, Fan Y. Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism. Angiogenesis 2024; 27:333-349. [PMID: 38580870 PMCID: PMC11303583 DOI: 10.1007/s10456-024-09913-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 03/04/2024] [Indexed: 04/07/2024]
Abstract
Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.
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Affiliation(s)
- Fan Yang
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Obstetrics and Gynecology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Gloria Lee
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Yi Fan
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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15
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Fan Z, Karakone M, Nagarajan S, Nagy N, Mildenberger W, Petrova E, Hinte LC, Bijnen M, Häne P, Nelius E, Chen J, Ferapontova I, von Meyenn F, Trepiccione F, Berber M, Ribas DP, Eichmann A, Zennaro MC, Takeda N, Fischer JW, Spyroglou A, Reincke M, Beuschlein F, Loffing J, Greter M, Stockmann C. Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure. Cell Rep 2024; 43:114395. [PMID: 38941187 DOI: 10.1016/j.celrep.2024.114395] [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: 02/09/2023] [Revised: 04/22/2024] [Accepted: 06/07/2024] [Indexed: 06/30/2024] Open
Abstract
Macrophages play crucial roles in organ-specific functions and homeostasis. In the adrenal gland, macrophages closely associate with sinusoidal capillaries in the aldosterone-producing zona glomerulosa. We demonstrate that macrophages preserve capillary specialization and modulate aldosterone secretion. Using macrophage-specific deletion of VEGF-A, single-cell transcriptomics, and functional phenotyping, we found that the loss of VEGF-A depletes PLVAP+ fenestrated endothelial cells in the zona glomerulosa, leading to increased basement membrane collagen IV deposition and subendothelial fibrosis. This results in increased aldosterone secretion, called "haptosecretagogue" signaling. Human aldosterone-producing adenomas also show capillary rarefaction and basement membrane thickening. Mice with myeloid cell-specific VEGF-A deletion exhibit elevated serum aldosterone, hypokalemia, and hypertension, mimicking primary aldosteronism. These findings underscore macrophage-to-endothelial cell signaling as essential for endothelial cell specialization, adrenal gland function, and blood pressure regulation, with broader implications for other endocrine organs.
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Affiliation(s)
- Zheng Fan
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland.
| | - Mara Karakone
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
| | | | - Nadine Nagy
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wiebke Mildenberger
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
| | - Ekaterina Petrova
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
| | - Laura Catharina Hinte
- Laboratory of Nutrition and Metabolic Epigenetics, Institute for Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Mitchell Bijnen
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
| | - Philipp Häne
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
| | - Eric Nelius
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
| | - Jing Chen
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
| | - Irina Ferapontova
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
| | - Ferdinand von Meyenn
- Laboratory of Nutrition and Metabolic Epigenetics, Institute for Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Francesco Trepiccione
- Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Mesut Berber
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
| | - David Penton Ribas
- Electrophysiology Facility (e-phac), Department of Molecular Life Sciences, University of Zurich (UZH), 8057 Zürich, Switzerland
| | - Anne Eichmann
- Cardiovascular Research Center and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
| | | | - Norihiko Takeda
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan
| | - Jens W Fischer
- Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Ariadni Spyroglou
- Klinik für Endokrinologie, Diabetologie, und Klinische Ernährung, UniversitätsSpital Zürich (USZ) and UZH, Raemistrasse 100, 8091 Zurich, Switzerland; Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Martin Reincke
- Klinik für Endokrinologie, Diabetologie, und Klinische Ernährung, UniversitätsSpital Zürich (USZ) and UZH, Raemistrasse 100, 8091 Zurich, Switzerland
| | - Felix Beuschlein
- Klinik für Endokrinologie, Diabetologie, und Klinische Ernährung, UniversitätsSpital Zürich (USZ) and UZH, Raemistrasse 100, 8091 Zurich, Switzerland; Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Johannes Loffing
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
| | - Melanie Greter
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
| | - Christian Stockmann
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland; INSERM U970, Paris Cardiovascular Research Center, Paris, France.
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16
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Su P, Li O, Ke K, Jiang Z, Wu J, Wang Y, Mou Y, Jin W. Targeting tumor‑associated macrophages: Critical players in tumor progression and therapeutic strategies (Review). Int J Oncol 2024; 64:60. [PMID: 38695252 PMCID: PMC11087038 DOI: 10.3892/ijo.2024.5648] [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: 03/01/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024] Open
Abstract
Tumor‑associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor‑promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage‑based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM‑targeting therapeutic strategies and discussed the obstacles and perspectives of TAM‑targeting therapies for cancers.
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Affiliation(s)
- Pengfei Su
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Ou Li
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Kun Ke
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Zhichen Jiang
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Jianzhang Wu
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Yuanyu Wang
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Yiping Mou
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Weiwei Jin
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
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17
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De Palma M, Hanahan D. Milestones in tumor vascularization and its therapeutic targeting. NATURE CANCER 2024; 5:827-843. [PMID: 38918437 DOI: 10.1038/s43018-024-00780-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 04/22/2024] [Indexed: 06/27/2024]
Abstract
Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future.
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Affiliation(s)
- Michele De Palma
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
| | - Douglas Hanahan
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
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18
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Wang S, Wang J, Chen Z, Luo J, Guo W, Sun L, Lin L. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. NPJ Precis Oncol 2024; 8:31. [PMID: 38341519 DOI: 10.1038/s41698-024-00522-z] [Citation(s) in RCA: 147] [Impact Index Per Article: 147.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Tumor drug resistance emerges from the interaction of two critical factors: tumor cellular heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute essential components of the TME. M2-like TAMs are essential in facilitating tumor metastasis as well as augmenting the drug resistance of tumors. This review encapsulates the mechanisms that M2-like TAMs use to promote tumor drug resistance. We also describe the emerging therapeutic strategies that are currently targeting M2-like TAMs in combination with other antitumor drugs, with some still undergoing clinical trial evaluation. Furthermore, we summarize and analyze various existing approaches for developing novel drugs that target M2-like TAMs to overcome tumor resistance, highlighting how targeting M2-like TAMs can effectively stop tumor growth, metastasis, and overcome tumor drug resistance.
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Affiliation(s)
- Shujing Wang
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingrui Wang
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiqiang Chen
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiamin Luo
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Guo
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lingling Sun
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lizhu Lin
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China.
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
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19
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Vanhaver C, Aboubakar Nana F, Delhez N, Luyckx M, Hirsch T, Bayard A, Houbion C, Dauguet N, Brochier A, van der Bruggen P, Bruger AM. Immunosuppressive low-density neutrophils in the blood of cancer patients display a mature phenotype. Life Sci Alliance 2024; 7:e202302332. [PMID: 37931958 PMCID: PMC10628041 DOI: 10.26508/lsa.202302332] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/26/2023] [Accepted: 10/27/2023] [Indexed: 11/08/2023] Open
Abstract
The presence of human neutrophils in the tumor microenvironment is strongly correlated to poor overall survival. Most previous studies have focused on the immunosuppressive capacities of low-density neutrophils (LDN), also referred to as granulocytic myeloid-derived suppressor cells, which are elevated in number in the blood of many cancer patients. We observed two types of LDN in the blood of lung cancer and ovarian carcinoma patients: CD45high LDN, which suppressed T-cell proliferation and displayed mature morphology, and CD45low LDN, which were immature and non-suppressive. We simultaneously evaluated the classical normal-density neutrophils (NDN) and, when available, tumor-associated neutrophils. We observed that NDN from cancer patients suppressed T-cell proliferation, and NDN from healthy donors did not, despite few transcriptomic differences. Hence, the immunosuppression mediated by neutrophils in the blood of cancer patients is not dependent on the cells' density but rather on their maturity.
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Affiliation(s)
| | - Frank Aboubakar Nana
- Institut de Duve, Université Catholique de Louvain, Brussels, Belgium
- Service de Pneumologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- Institut de Recherche Expérimentale et Clinique (IREC)/Pôle de Pneumologie, Université Catholique de Louvain, Brussels, Belgium
| | - Nicolas Delhez
- Institut de Duve, Université Catholique de Louvain, Brussels, Belgium
| | - Mathieu Luyckx
- Institut de Duve, Université Catholique de Louvain, Brussels, Belgium
- Service de Gynécologie et Andrologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- Centre de Chirurgie Oncologique, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Thibault Hirsch
- Institut de Duve, Université Catholique de Louvain, Brussels, Belgium
| | - Alexandre Bayard
- Institut de Duve, Université Catholique de Louvain, Brussels, Belgium
| | - Camille Houbion
- Institut de Duve, Université Catholique de Louvain, Brussels, Belgium
| | - Nicolas Dauguet
- Institut de Duve, Université Catholique de Louvain, Brussels, Belgium
| | - Alice Brochier
- Hematology Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | | | - Annika M Bruger
- Institut de Duve, Université Catholique de Louvain, Brussels, Belgium
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20
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Tang B, Ma W, Lin Y. Emerging applications of anti-angiogenic nanomaterials in oncotherapy. J Control Release 2023; 364:61-78. [PMID: 37871753 DOI: 10.1016/j.jconrel.2023.10.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/08/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023]
Abstract
Angiogenesis is the process of generating new blood vessels from pre-existing vasculature. Under normal conditions, this process is delicately controlled by pro-angiogenic and anti-angiogenic factors. Tumor cells can produce plentiful pro-angiogenic molecules promoting pathological angiogenesis for uncontrollable growth. Therefore, anti-angiogenic therapy, which aims to inhibit tumor angiogenesis, has become an attractive approach for oncotherapy. However, classic anti-angiogenic agents have several limitations in clinical use, such as lack of specific targeting, low bioavailability, and poor therapeutic outcomes. Hence, alternative angiogenic inhibitors are highly desired. With the emergence of nanotechnology, various nanomaterials have been designed for anti-angiogenesis purposes, offering promising features like excellent targeting capabilities, reduced side effects, and enhanced therapeutic efficacy. In this review, we describe tumor vascular features, discuss current dilemma of traditional anti-angiogenic medicines in oncotherapy, and underline the potential of nanomaterials in tumor anti-angiogenic therapy. Moreover, we discuss the current challenges of anti-angiogenic cancer treatment. We expect that this summary of anti-angiogenic nanomaterials in oncotherapy will offer valuable insights, facilitating their extensive applications in the future.
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Affiliation(s)
- Bicai Tang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, Sichuan 610041, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Wenjuan Ma
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, Sichuan 610041, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, Sichuan 610041, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
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21
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Tajaldini M, Poorkhani A, Amiriani T, Amiriani A, Javid H, Aref P, Ahmadi F, Sadani S, Khori V. Strategy of targeting the tumor microenvironment via inhibition of fibroblast/fibrosis remodeling new era to cancer chemo-immunotherapy resistance. Eur J Pharmacol 2023; 957:175991. [PMID: 37619785 DOI: 10.1016/j.ejphar.2023.175991] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 08/02/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023]
Abstract
The use of repurposing drugs that may have neoplastic and anticancer effects increases the efficiency and decrease resistance to chemotherapy drugs through a biochemical and mechanical transduction mechanisms through modulation of fibroblast/fibrosis remodeling in tumor microenvironment (TME). Interestingly, fibroblast/fibrosis remodeling plays a vital role in mediating cancer metastasis and drug resistance after immune chemotherapy. The most essential hypothesis for induction of chemo-immunotherapy resistance is via activation of fibroblast/fibrosis remodeling and preventing the infiltration of T cells after is mainly due to the interference between cytoskeleton, mechanical, biochemical, metabolic, vascular, and remodeling signaling pathways in TME. The structural components of the tumor that can be targeted in the fibroblast/fibrosis remodeling include the depletion of the TME components, targeting the cancer-associated fibroblasts and tumor associated macrophages, alleviating the mechanical stress within the ECM, and normalizing the blood vessels. It has also been found that during immune-chemotherapy, TME injury and fibroblast/fibrosis remodeling causes the up-regulation of inhibitory signals and down-regulation of activated signals, which results in immune escape or chemo-resistance of the tumor. In this regard, repurposing or neo-adjuvant drugs with various transduction signaling mechanisms, including anti-fibrotic effects, are used to target the TME and fibroblast/fibrosis signaling pathway such as angiotensin 2, transforming growth factor-beta, physical barriers of the TME, cytokines and metabolic factors which finally led to the reverse of the chemo-resistance. Consistent to many repurposing drugs such as pirfenidone, metformin, losartan, tranilast, dexamethasone and pentoxifylline are used to decrease immune-suppression by abrogation of TME inhibitory signal that stimulates the immune system and increases efficiency and reduces resistance to chemotherapy drugs. To overcome immunosuppression based on fibroblast/fibrosis remodeling, in this review, we focus on inhibitory signal transduction, which is the physical barrier, alleviates mechanical stress and prevents mechano-metabolic activation.
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Affiliation(s)
- Mahboubeh Tajaldini
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amirhoushang Poorkhani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Taghi Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amirhossein Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciencess, Catastega Institue of Medical Sciences, Mashhad, Iran
| | - Parham Aref
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Farahnazsadat Ahmadi
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Somayeh Sadani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Vahid Khori
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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22
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Kasurinen JH, Hagström J, Kaprio T, Jalkanen S, Salmi M, Böckelman C, Haglund C. Prognostic Values of Tissue and Serum Angiogenic Growth Factors Depend on the Phenotypic Subtypes of Colorectal Cancer. Cancers (Basel) 2023; 15:3871. [PMID: 37568687 PMCID: PMC10417397 DOI: 10.3390/cancers15153871] [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: 06/10/2023] [Revised: 07/24/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
We classified colorectal cancer (CRC) patients into four phenotypic subgroups and investigated the prognostic value of angiogenic growth factors across subgroups. Preoperative serum concentrations and tissue expressions of VEGF, bFGF, and PDGF-bb were determined among 322 CRC patients. We classified patients into phenotypic subgroups (immune, canonical, metabolic, and mesenchymal) according to a method described in our earlier work. Among the metabolic subgroup, patients with high serum concentrations of VEGF, bFGF, or PDGF-bb exhibited a significantly improved prognosis. Moreover, those with high VEGF tissue expressions exhibited a significantly improved prognosis among patients in the metabolic subgroup. Among immune patients, a high VEGF serum expression is associated with a worse prognosis. A high serum bFGF concentration is associated with a favorable prognostic factor among patients with a canonical tumor phenotype. A high PDGF-bb tissue expression is associated with non-metastasized disease and with the immune, canonical, and metabolic subtypes. To our knowledge, this is the first study to show that the prognostic value of angiogenic growth factors differs between phenotypic subtypes.
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Affiliation(s)
- Jussi Herman Kasurinen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00100 Helsinki, Finland (C.B.); (C.H.)
| | - Jaana Hagström
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00100 Helsinki, Finland (C.B.); (C.H.)
- Department of Pathology, University of Helsinki and Helsinki University Hospital, 00100 Helsinki, Finland
- Department of Oral Pathology and Radiology, University of Turku, 20014 Turku, Finland
| | - Tuomas Kaprio
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00100 Helsinki, Finland (C.B.); (C.H.)
- Department of Surgery, University of Helsinki and Helsinki University Hospital, 00100 Helsinki, Finland
| | - Sirpa Jalkanen
- MediCity Research Laboratory and Institute of Biomedicine, University of Turku, 20014 Turku, Finland
| | - Marko Salmi
- MediCity Research Laboratory and Institute of Biomedicine, University of Turku, 20014 Turku, Finland
| | - Camilla Böckelman
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00100 Helsinki, Finland (C.B.); (C.H.)
- Department of Surgery, University of Helsinki and Helsinki University Hospital, 00100 Helsinki, Finland
| | - Caj Haglund
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00100 Helsinki, Finland (C.B.); (C.H.)
- Department of Pathology, University of Helsinki and Helsinki University Hospital, 00100 Helsinki, Finland
- Department of Surgery, University of Helsinki and Helsinki University Hospital, 00100 Helsinki, Finland
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23
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Geraldo LH, Garcia C, Xu Y, Leser FS, Grimaldi I, de Camargo Magalhães ES, Dejaegher J, Solie L, Pereira CM, Correia AH, De Vleeschouwer S, Tavitian B, Canedo NHS, Mathivet T, Thomas JL, Eichmann A, Lima FRS. CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma. Cell Mol Life Sci 2023; 80:179. [PMID: 37314567 DOI: 10.1007/s00018-023-04788-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 04/06/2023] [Accepted: 04/21/2023] [Indexed: 06/15/2023]
Abstract
Glioblastoma (GBM) is the most common and fatal primary tumor of the central nervous system (CNS) and current treatments have limited success. Chemokine signaling regulates both malignant cells and stromal cells of the tumor microenvironment (TME), constituting a potential therapeutic target against brain cancers. Here, we investigated the C-C chemokine receptor type 7 (CCR7) and the chemokine (C-C-motif) ligand 21 (CCL21) for their expression and function in human GBM and then assessed their therapeutic potential in preclinical mouse GBM models. In GBM patients, CCR7 expression positively associated with a poor survival. CCL21-CCR7 signaling was shown to regulate tumor cell migration and proliferation while also controlling tumor associated microglia/macrophage recruitment and VEGF-A production, thereby controlling vascular dysmorphia. Inhibition of CCL21-CCR7 signaling led to an increased sensitivity to temozolomide-induced tumor cell death. Collectively, our data indicate that drug targeting of CCL21-CCR7 signaling in tumor and TME cells is a therapeutic option against GBM.
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Affiliation(s)
- Luiz Henrique Geraldo
- Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro (UFRJ), Rua César Pernetta, 1.766, Cidade Universitária da UFRJ, Rio de Janeiro, RJ, 21949-590, Brazil.
- Université de Paris, PARCC, INSERM, 75015, Paris, France.
- Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06510-3221, USA.
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06510-3221, USA.
| | - Celina Garcia
- Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro (UFRJ), Rua César Pernetta, 1.766, Cidade Universitária da UFRJ, Rio de Janeiro, RJ, 21949-590, Brazil
| | - Yunling Xu
- Université de Paris, PARCC, INSERM, 75015, Paris, France
| | - Felipe Saceanu Leser
- Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro (UFRJ), Rua César Pernetta, 1.766, Cidade Universitária da UFRJ, Rio de Janeiro, RJ, 21949-590, Brazil
| | - Izabella Grimaldi
- Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro (UFRJ), Rua César Pernetta, 1.766, Cidade Universitária da UFRJ, Rio de Janeiro, RJ, 21949-590, Brazil
| | - Eduardo Sabino de Camargo Magalhães
- Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro (UFRJ), Rua César Pernetta, 1.766, Cidade Universitária da UFRJ, Rio de Janeiro, RJ, 21949-590, Brazil
| | - Joost Dejaegher
- Laboratory of Experimental Neurosurgery and Neuroanatomy, Department of Neurosciences, KU Leuven, Leuven, Belgium
- Department of Neurosurgery, KU Leuven, Leuven, Belgium
| | - Lien Solie
- Laboratory of Experimental Neurosurgery and Neuroanatomy, Department of Neurosciences, KU Leuven, Leuven, Belgium
- Department of Neurosurgery, KU Leuven, Leuven, Belgium
| | - Cláudia Maria Pereira
- Faculdade de Odontologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21949-590, Brazil
| | - Ana Helena Correia
- Departmento de Patologia, Faculdade de Medicina, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Steven De Vleeschouwer
- Laboratory of Experimental Neurosurgery and Neuroanatomy, Department of Neurosciences, KU Leuven, Leuven, Belgium
- Department of Neurosurgery, KU Leuven, Leuven, Belgium
| | | | - Nathalie Henriques Silva Canedo
- Departmento de Patologia, Faculdade de Medicina, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Jean-Leon Thomas
- Université Pierre et Marie Curie Paris 06 UMRS1127, Sorbonne Université, Paris, France.
- Department of Neurology, Yale University School of Medicine, New Haven, CT, 06510-3221, USA.
| | - Anne Eichmann
- Université de Paris, PARCC, INSERM, 75015, Paris, France
- Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06510-3221, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06510-3221, USA
| | - Flavia Regina Souza Lima
- Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro (UFRJ), Rua César Pernetta, 1.766, Cidade Universitária da UFRJ, Rio de Janeiro, RJ, 21949-590, Brazil.
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24
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Brisson L, Henrique Geraldo L, Bikfalvi A, Mathivet T. The strange Microenvironment of Glioblastoma. Rev Neurol (Paris) 2023; 179:490-501. [PMID: 36964121 PMCID: PMC11195635 DOI: 10.1016/j.neurol.2023.03.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/24/2023] [Accepted: 03/01/2023] [Indexed: 03/26/2023]
Abstract
Glioblastoma (GB) is the most common and aggressive primary brain tumor, with poor patient survival and lack of effective therapies. Late advances trying to decipher the composition of the GB tumor microenvironment (TME) emphasized its role in tumor progression and potentialized it as a therapeutic target. Many components participate critically to tumor development and expansion such as blood vessels, immune cells or components of the nervous system. Dysmorphic tumor vasculature brings challenges to optimal delivery of cytotoxic agents currently used in clinics. Also, massive infiltration of immunosuppressive myeloid cells and limited recruitment of T cells limits the success of conventional immunotherapies. Neuronal input seems also be required for tumor expansion. In this review, we provide a comprehensive report of vascular and immune component of the GB TME and their cross talk during GB progression.
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Affiliation(s)
- L Brisson
- BRIC Inserm U1312, Université de Bordeaux, 33615 Pessac, France
| | - L Henrique Geraldo
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - A Bikfalvi
- BRIC Inserm U1312, Université de Bordeaux, 33615 Pessac, France.
| | - T Mathivet
- BRIC Inserm U1312, Université de Bordeaux, 33615 Pessac, France
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25
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Ebeling S, Kowalczyk A, Perez-Vazquez D, Mattiola I. Regulation of tumor angiogenesis by the crosstalk between innate immunity and endothelial cells. Front Oncol 2023; 13:1171794. [PMID: 37234993 PMCID: PMC10206118 DOI: 10.3389/fonc.2023.1171794] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/10/2023] [Indexed: 05/28/2023] Open
Abstract
Endothelial cells and immune cells are major regulators of cancer progression and prognosis. Endothelial cell proliferation and angiogenesis are required for providing nutrients and oxygen to the nascent tumor and infiltration of immune cells to the tumor is dependent on endothelial cell activation. Myeloid cells and innate lymphocytes have an important role in shaping the tumor microenvironment by crosstalking with cancer cells and structural cells, including endothelial cells. Innate immune cells can modulate the activation and functions of tumor endothelial cells, and, in turn, endothelial cell expression of adhesion molecules can affect immune cell extravasation. However, the mechanisms underlying this bidirectional crosstalk are not fully understood. In this review, we will provide an overview of the current knowledge on the pathways regulating the crosstalk between innate immune cells and endothelial cells during tumor progression and discuss their potential contribution to the development of novel anti-tumor therapeutic approaches.
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Affiliation(s)
- Svenja Ebeling
- Institute of Microbiology, Infectious Diseases and Immunology (I-MIDI), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Berlin, Germany
- Laboratory of Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Anita Kowalczyk
- Institute of Microbiology, Infectious Diseases and Immunology (I-MIDI), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Berlin, Germany
- Laboratory of Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Diego Perez-Vazquez
- Institute of Microbiology, Infectious Diseases and Immunology (I-MIDI), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Berlin, Germany
- Laboratory of Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Irene Mattiola
- Institute of Microbiology, Infectious Diseases and Immunology (I-MIDI), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Berlin, Germany
- Laboratory of Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
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26
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Jiang Y, Liu X, Ye J, Ma Y, Mao J, Feng D, Wang X. Migrasomes, a new mode of intercellular communication. Cell Commun Signal 2023; 21:105. [PMID: 37158915 PMCID: PMC10165304 DOI: 10.1186/s12964-023-01121-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 03/30/2023] [Indexed: 05/10/2023] Open
Abstract
Migrasomes are newly discovered extracellular vesicles (EVs) that are formed in migrating cells and mediate intercellular communication. However, their size, biological generation, cargo packaging, transport, and effects on recipient cells by migrasomes are different from those of other EVs. In addition to mediating organ morphogenesis during zebrafish gastrulation, discarding damaged mitochondria, and lateral transport of mRNA and proteins, growing evidence has demonstrated that migrasomes mediate a variety of pathological processes. In this review, we summarize the discovery, mechanisms of formation, isolation, identification, and mediation of cellular communication in migrasomes. We discuss migrasome-mediated disease processes, such as osteoclast differentiation, proliferative vitreoretinopathy, tumor cell metastasis by PD-L1 transport, immune cell chemotaxis to the site of infection by chemokines, angiogenesis promotion via angiogenic factors by immune cells, and leukemic cells chemotaxis to the site of mesenchymal stromal cells. Moreover, as new EVs, we propose the potential of migrasomes for disease diagnosis and treatment. Video Abstract.
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Affiliation(s)
- Yuyun Jiang
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Xi Liu
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Jixian Ye
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Yongbin Ma
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
- Department of Central Laboratory, Jintan Hospital, Jiangsu University, 500 Avenue Jintan, Jintan, 213200, People's Republic of China.
| | - Jiahui Mao
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Dingqi Feng
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Xuefeng Wang
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
- Department of Nuclear Medicine and Institute of Digestive Diseases, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
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27
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Hänggi K, Ruffell B. Cell death, therapeutics, and the immune response in cancer. Trends Cancer 2023; 9:381-396. [PMID: 36841748 PMCID: PMC10121860 DOI: 10.1016/j.trecan.2023.02.001] [Citation(s) in RCA: 94] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/19/2023] [Accepted: 02/03/2023] [Indexed: 02/27/2023]
Abstract
Induction of cell death is inexorably linked with cancer therapy, but this can also initiate wound-healing processes that have been linked to cancer progression and therapeutic resistance. Here we describe the contribution of apoptosis and the lytic cell death pathways in the response to therapy (including chemotherapy and immunotherapy). We also discuss how necroptosis, pyroptosis, and ferroptosis function to promote tumor immunogenicity, along with emerging findings that these same forms of death can paradoxically contribute to immune suppression and tumor progression. Understanding the duality of cell death in cancer may allow for the development of therapeutics that shift the balance towards regression.
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Affiliation(s)
- Kay Hänggi
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Brian Ruffell
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
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28
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Umakoshi M, Nakamura A, Tsuchie H, Li Z, Kudo-Asabe Y, Miyabe K, Ito Y, Yoshida M, Nagasawa H, Okada K, Nanjo H, Maeda D, Miyakoshi N, Tanaka M, Goto A. Macrophage numbers in the marginal area of sarcomas predict clinical prognosis. Sci Rep 2023; 13:1290. [PMID: 36690825 PMCID: PMC9870999 DOI: 10.1038/s41598-023-28024-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 01/11/2023] [Indexed: 01/25/2023] Open
Abstract
Even when treated comprehensively by surgery, chemotherapy, and radiotherapy, soft-tissue sarcoma has an unfavorable outcome. Because soft-tissue sarcoma is rare, it is the subject of fewer clinicopathological studies, which are important for clarifying pathophysiology. Here, we examined tumor-associated macrophages in the intratumoral and marginal areas of sarcomas to increase our knowledge about the pathophysiology. Seventy-five sarcoma specimens (not limited to a single histological type), resected at our institution, were collected, and the number of CD68-, CD163-, and CD204-positive macrophages in the intratumoral and marginal areas was counted. We then performed statistical analysis to examine links between macrophage numbers, clinical factors, and outcomes. A high number of macrophages positive for all markers in both areas was associated with worse disease-free survival (DFS). Next, we divided cases according to the FNCLCC classification (Grade 1 and Grades 2/3). In the Grade 1 group, there was no significant association between macrophage number and DFS. However, in the Grade 2/3 group, high numbers of CD163- and CD204-positive macrophages in the marginal area were associated with poor DFS. By contrast, there was no significant difference between the groups with respect to high or low numbers of CD68-, CD163-, or CD204-positive macrophages in the intratumoral area. Multivariate analysis identified the number of CD163- and CD204-positive macrophages in the marginal area as an independent prognostic factor. Macrophage numbers in the marginal area of soft-tissue sarcoma may better reflect clinical behavior.
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Affiliation(s)
- Michinobu Umakoshi
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan.
| | - Akiko Nakamura
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Hiroyuki Tsuchie
- Department of Orthopedic Surgery, Graduate School of Medicine, Akita University, Akita, Japan
| | - Zhuo Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, China
| | - Yukitsugu Kudo-Asabe
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Ken Miyabe
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yukinobu Ito
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Makoto Yoshida
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Hiroyuki Nagasawa
- Department of Orthopedic Surgery, Graduate School of Medicine, Akita University, Akita, Japan
| | - Kyoji Okada
- Department of Physical Therapy, Graduate School of Health Science, Akita University, Akita, Japan
| | - Hiroshi Nanjo
- Department of Pathology, Akita University Hospital, Akita, Japan
| | - Daichi Maeda
- Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Graduate School of Medicine, Akita University, Akita, Japan
| | - Masamitsu Tanaka
- Department of Molecular Medicine and Biochemistry, Graduate School of Medicine, Akita University, Akita, Japan
| | - Akiteru Goto
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan
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29
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Li HX, Wang SQ, Lian ZX, Deng SL, Yu K. Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer. Cells 2022; 12:cells12010064. [PMID: 36611857 PMCID: PMC9818185 DOI: 10.3390/cells12010064] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer.
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Affiliation(s)
- Huan-Xiang Li
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shu-Qi Wang
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Zheng-Xing Lian
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shou-Long Deng
- National Health Commission (NHC) of China Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
- Correspondence: (S.-L.D.); (K.Y.)
| | - Kun Yu
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
- Correspondence: (S.-L.D.); (K.Y.)
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30
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Liu M, Liu L, Song Y, Li W, Xu L. Targeting macrophages: a novel treatment strategy in solid tumors. J Transl Med 2022; 20:586. [PMID: 36510315 PMCID: PMC9743606 DOI: 10.1186/s12967-022-03813-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
In the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are the most abundant immune cells, which act as a key regulator in tumorigenesis and progression. Increasing evidence have demonstrated that the TME alters the nature of macrophages to maintain dynamic tissue homeostasis, allowing TAMs to acquire the ability to stimulate angiogenesis, promote tumor metastasis and recurrence, and suppress anti-tumor immune responses. Furthermore, tumors with high TAM infiltration have poor prognoses and are resistant to treatment. In the field of solid tumor, the exploration of tumor-promoting mechanisms of TAMs has attracted much attention and targeting TAMs has emerged as a promising immunotherapeutic strategy. Currently, the most common therapeutic options for targeting TAMs are as follows: the deletion of TAMs, the inhibition of TAMs recruitment, the release of phagocytosis by TAMs, and the reprogramming of macrophages to remodel their anti-tumor capacity. Promisingly, the study of chimeric antigen receptor macrophages (CAR-Ms) may provide even greater benefit for patients with solid tumors. In this review, we discuss how TAMs promote the progression of solid tumors as well as summarize emerging immunotherapeutic strategies that targeting macrophages.
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Affiliation(s)
- Mengmeng Liu
- grid.414008.90000 0004 1799 4638Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008 China ,grid.207374.50000 0001 2189 3846Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450052 China
| | - Lina Liu
- grid.414008.90000 0004 1799 4638Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Yongping Song
- grid.412633.10000 0004 1799 0733Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Wei Li
- grid.412633.10000 0004 1799 0733Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Linping Xu
- grid.414008.90000 0004 1799 4638Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008 China
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Zhang C, Li T, Yin S, Gao M, He H, Li Y, Jiang D, Shi M, Wang J, Yu L. Monocytes deposit migrasomes to promote embryonic angiogenesis. Nat Cell Biol 2022; 24:1726-1738. [PMID: 36443426 DOI: 10.1038/s41556-022-01026-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/12/2022] [Indexed: 11/30/2022]
Abstract
Pro-angiogenic factors are key regulators of angiogenesis. Here we report that highly migratory cells patrol the area of capillary formation in chick embryo chorioallantoic membrane. These cells deposit migrasomes on their migration tracks, creating migrasome-enriched areas. Single-cell sequencing identified these cells as monocytes. Depletion of monocytes impairs capillary formation. Quantitative mass spectrometry analysis reveals that monocyte migrasomes are enriched with pro-angiogenic factors. Purified migrasomes promote capillary formation and monocyte recruitment in vivo, and endothelial cell tube formation and monocyte chemotaxis in vitro. Knockdown or knockout of TSPAN4 reduces migrasome formation and impairs capillary formation and monocyte recruitment. Mechanistically, monocytes promote angiogenesis via VEGFA and CXCL12 in migrasomes. In summary, monocytes deposit migrasomes enriched in pro-angiogenic factors to promote angiogenesis.
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Affiliation(s)
- Cuifang Zhang
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China
| | - Tianqi Li
- School of Life Science, Tsinghua University, Beijing, China
| | - Shuyao Yin
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China
| | - Mingyi Gao
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China
| | - Helen He
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China
| | - Ying Li
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China
| | - Dong Jiang
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China
| | - Minghui Shi
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China
| | - Jianbin Wang
- School of Life Science, Tsinghua University, Beijing, China
| | - Li Yu
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China.
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Zheng W, Qian C, Tang Y, Yang C, Zhou Y, Shen P, Chen W, Yu S, Wei Z, Wang A, Lu Y, Zhao Y. Manipulation of the crosstalk between tumor angiogenesis and immunosuppression in the tumor microenvironment: Insight into the combination therapy of anti-angiogenesis and immune checkpoint blockade. Front Immunol 2022; 13:1035323. [PMID: 36439137 PMCID: PMC9684196 DOI: 10.3389/fimmu.2022.1035323] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/26/2022] [Indexed: 09/23/2023] Open
Abstract
Immunotherapy has been recognized as an effective and important therapeutic modality for multiple types of cancer. Nevertheless, it has been increasing recognized that clinical benefits of immunotherapy are less than expected as evidenced by the fact that only a small population of cancer patients respond favorably to immunotherapy. The structurally and functionally abnormal tumor vasculature is a hallmark of most solid tumors and contributes to an immunosuppressive microenvironment, which poses a major challenge to immunotherapy. In turn, multiple immune cell subsets have profound consequences on promoting neovascularization. Vascular normalization, a promising anti-angiogenic strategy, can enhance vascular perfusion and promote the infiltration of immune effector cells into tumors via correcting aberrant tumor blood vessels, resulting in the potentiation of immunotherapy. More interestingly, immunotherapies are prone to boost the efficacy of various anti-angiogenic therapies and/or promote the morphological and functional alterations in tumor vasculature. Therefore, immune reprograming and vascular normalization appear to be reciprocally regulated. In this review, we mainly summarize how tumor vasculature propels an immunosuppressive phenotype and how innate and adaptive immune cells modulate angiogenesis during tumor progression. We further highlight recent advances of anti-angiogenic immunotherapies in preclinical and clinical settings to solidify the concept that targeting both tumor blood vessels and immune suppressive cells provides an efficacious approach for the treatment of cancer.
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Affiliation(s)
- Weiwei Zheng
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Cheng Qian
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu Tang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chunmei Yang
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yueke Zhou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peiliang Shen
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenxing Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Suyun Yu
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhonghong Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhao
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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Beach C, MacLean D, Majorova D, Arnold JN, Olcina MM. The effects of radiation therapy on the macrophage response in cancer. Front Oncol 2022; 12:1020606. [PMID: 36249052 PMCID: PMC9559862 DOI: 10.3389/fonc.2022.1020606] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 09/12/2022] [Indexed: 11/27/2022] Open
Abstract
The efficacy of radiotherapy, a mainstay of cancer treatment, is strongly influenced by both cellular and non-cellular features of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are a heterogeneous population within the TME and their prevalence significantly correlates with patient prognosis in a range of cancers. Macrophages display intrinsic radio-resistance and radiotherapy can influence TAM recruitment and phenotype. However, whether radiotherapy alone can effectively "reprogram" TAMs to display anti-tumor phenotypes appears conflicting. Here, we discuss the effect of radiation on macrophage recruitment and plasticity in cancer, while emphasizing the role of specific TME components which may compromise the tumor response to radiation and influence macrophage function. In particular, this review will focus on soluble factors (cytokines, chemokines and components of the complement system) as well as physical changes to the TME. Since the macrophage response has the potential to influence radiotherapy outcomes this population may represent a drug target for improving treatment. An enhanced understanding of components of the TME impacting radiation-induced TAM recruitment and function may help consider the scope for future therapeutic avenues to target this plastic and pervasive population.
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Affiliation(s)
- Callum Beach
- Department of Oncology, Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - David MacLean
- Department of Oncology, Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Dominika Majorova
- Department of Oncology, Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - James N. Arnold
- School of Cancer and Pharmaceutical Sciences, King’s College London, London, United Kingdom
| | - Monica M. Olcina
- Department of Oncology, Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom,*Correspondence: Monica M. Olcina,
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Terrassoux L, Claux H, Bacari S, Meignan S, Furlan A. A Bloody Conspiracy. Blood Vessels and Immune Cells in the Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14194581. [PMID: 36230504 PMCID: PMC9558972 DOI: 10.3390/cancers14194581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/10/2022] [Accepted: 09/15/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary The tumor microenvironment has risen over the last years as a significant contributor to the failure of antitumoral strategies due to its numerous pro-tumorigenic activities. In this review, we focused on two features of this microenvironment, namely angiogenesis and immunity, which have been the targets of therapies to tackle tumors via its microenvironmental part over the last decade. Increasing our knowledge of the complex interactions within this ecosystem is mandatory to optimize these therapeutic approaches. The development of innovative experimental models is of great help in reaching this goal. Abstract Cancer progression occurs in concomitance with a profound remodeling of the cellular microenvironment. Far from being a mere passive event, the re-orchestration of interactions between the various cell types surrounding tumors highly contributes to the progression of the latter. Tumors notably recruit and stimulate the sprouting of new blood vessels through a process called neo-angiogenesis. Beyond helping the tumor cope with an increased metabolic demand associated with rapid growth, this also controls the metastatic dissemination of cancer cells and the infiltration of immune cells in the tumor microenvironment. To decipher this critical interplay for the clinical progression of tumors, the research community has developed several valuable models in the last decades. This review offers an overview of the various instrumental solutions currently available, including microfluidic chips, co-culture models, and the recent rise of organoids. We highlight the advantages of each technique and the specific questions they can address to better understand the tumor immuno-angiogenic ecosystem. Finally, we discuss this development field’s fundamental and applied perspectives.
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Affiliation(s)
- Lisa Terrassoux
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Hugo Claux
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Salimata Bacari
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Samuel Meignan
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Alessandro Furlan
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
- Correspondence:
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Baci D, Cekani E, Imperatori A, Ribatti D, Mortara L. Host-Related Factors as Targetable Drivers of Immunotherapy Response in Non-Small Cell Lung Cancer Patients. Front Immunol 2022; 13:914890. [PMID: 35874749 PMCID: PMC9298844 DOI: 10.3389/fimmu.2022.914890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/13/2022] [Indexed: 11/13/2022] Open
Abstract
Despite some significant therapeutic breakthroughs leading to immunotherapy, a high percentage of patients with non-small cell lung cancer (NSCLC) do not respond to treatment on relapse, thus experiencing poor prognosis and survival. The unsatisfying results could be related to the features of the tumor immune microenvironment and the dynamic interactions between a tumor and immune infiltrate. Host-tumor interactions strongly influence the course of disease and response to therapies. Thus, targeting host-associated factors by restoring their physiologic functions altered by the presence of a tumor represents a new therapeutic approach to control tumor development and progression. In NSCLC, the immunogenic tumor balance is shifted negatively toward immunosuppression due to the release of inhibitory factors as well as the presence of immunosuppressive cells. Among these cells, there are myeloid-derived suppressor cells, regulatory T cells that can generate a tumor-permissive milieu by reprogramming the cells of the hosts such as tumor-associated macrophages, tumor-associated neutrophils, natural killer cells, dendritic cells, and mast cells that acquire tumor-supporting phenotypes and functions. This review highlights the current knowledge of the involvement of host-related factors, including innate and adaptive immunity in orchestrating the tumor cell fate and the primary resistance mechanisms to immunotherapy in NSCLC. Finally, we discuss combinational therapeutic strategies targeting different aspects of the tumor immune microenvironment (TIME) to prime the host response. Further research dissecting the characteristics and dynamic interactions within the interface host-tumor is necessary to improve a patient fitness immune response and provide answers regarding the immunotherapy efficacy, with the aim to develop more successful treatments for NSCLC.
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Affiliation(s)
- Denisa Baci
- Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, Milan, Italy.,Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Elona Cekani
- Medical Oncology Clinic, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Andrea Imperatori
- Center for Thoracic Surgery, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Lorenzo Mortara
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
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Zheng X, Xu H, Lin T, Tan P, Xiong Q, Yi X, Qiu S, Yang L, Shen B, Ai J, Wei Q. CD93 orchestrates the tumor microenvironment and predicts the molecular subtype and therapy response of bladder cancer. Comput Biol Med 2022; 147:105727. [PMID: 35785664 DOI: 10.1016/j.compbiomed.2022.105727] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/25/2022] [Accepted: 06/11/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND CD93 is newly reported to normalize vasculature and attenuate pancreatic cancer therapy response, but its role in bladder cancer (BLCA) is unknown. METHOD The immunologic role of CD93 is analyzed across TCGA pan-cancers. The correlation between CD93 and BLCA clinical and tumor microenvironment features, predicted immunotherapy pathways, molecular subtypes, therapeutic signatures and mutation status was evaluated in TCGA-BLCA and other two BLCA cohorts. The impact of CD93 on immunotherapy response was validated by five real-world cohorts, and chemotherapy response was assessed with IC50. CD93-based risk model was constructed with LASSO regression and validated by seven independent cohorts. RESULT CD93 is positively correlated with immunomodulators, tumor-infiltrating lymphocytes (TILs) and immune checkpoints across pan-cancers. In BLCA, CD93 leads to higher T cell inflamed score and expression of immune checkpoints. However, CD93 is indicative of more aggressive clinical features, worse survival, more tumor-associated macrophages and regulatory T cells recruitment, less recognition and killing of cancer cells by T cells, lower predicted chemotherapy and immunotherapy response, which is further validated by immunotherapy cohorts (IMvigor210: 16.11% vs 29.53%; GSE176307: 15.56% vs 20.93%). Notably, CD93 correlates with enriched neuroendocrine subtype and epithelial-mesenchymal transition differentiation, while CD93-low group has enriched luminal subtype. Pathways including hypoxia and Wnt-β-catenin are enriched along with CD93 expression, and more frequent FGFR3 mutation is also observed. Lastly, the CD93-based risk model, validated by seven independent cohorts, is powerful in distinguishing the survival probability of BLCA (3-year AUC 0.808). CONCLUSION CD93 plays a critical role in tumor immune regulation. CD93 expression indicates more aggressive clinicopathological status and molecular subtypes of BLCA and worse therapy response, which implies that combing anti-CD93 therapy with immunotherapy (or chemotherapy) may be potentially beneficial for BLCA in clinical practice.
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Affiliation(s)
- Xiaonan Zheng
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Systems Genetics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hang Xu
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tianhai Lin
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ping Tan
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qiao Xiong
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xianyanling Yi
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Shi Qiu
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lu Yang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bairong Shen
- Institute of Systems Genetics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jianzhong Ai
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qiang Wei
- Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Lin Y, Liao X, Zhang Y, Wu G, Ye J, Luo S, He X, Luo M, Xie M, Zhang J, Li Q, Huang Y, Liao S, Li Y, Liang R. Homologous Recombination Pathway Alternation Predicts Prognosis of Colorectal Cancer With Chemotherapy. Front Pharmacol 2022; 13:920939. [PMID: 35734400 PMCID: PMC9207269 DOI: 10.3389/fphar.2022.920939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022] Open
Abstract
Background: Chemotherapy is the basic treatment for colorectal cancer (CRC). However, colorectal cancer cells often develop resistance to chemotherapy drugs, leading to recurrence and poor prognosis. More and more studies have shown that the Homologous recombination (HR) pathway plays an important role in chemotherapy treatment for tumors. However, the relationship between HR pathway, chemotherapy sensitivity, and the prognosis of CRC patients is still unclear. Methods: We collected 35 samples of CRC patients after chemotherapy treatment from Guangxi Medical University Cancer Hospital, then collected mutation data and clinical prognosis data from the group. We also downloaded Mondaca-CRC, TCGA-CRC cohorts for chemotherapy treatment. Result: We found that HR mutant-type (HR-MUT) patients are less likely to experience tumor metastasis after receiving chemotherapy. Additionally, our univariate and multivariate cox regression models showed that HR-MUT can be used as an independent predictor of the prognosis of chemotherapy for CRC patients. The KM curve showed that patients with HR-MUT CRC had significantly prolonged overall survival (OS) time (log-rank p = 0.017; hazard ratio (HR) = 0.69). Compared to HR mutant-type (HR-WT), HR-MUT has a significantly lower IC50 value with several chemotherapeutic drugs. Pathway enrichment analysis further revealed that the HR-MUT displayed a significantly lower rate of DNA damage repair ability, tumor growth, metastasis activity, and tumor fatty acid metabolism activity than HR-WT, though its immune response activity was notably higher. Conclusion: These findings indicate that HR-MUT may be a relevant marker for CRC patients receiving chemotherapy, as it is closely related to improving OS time and reducing chemotherapy resistance.
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Affiliation(s)
- Yan Lin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiaoli Liao
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yumei Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Guobin Wu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Shanshan Luo
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xinxin He
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min Luo
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Mingzhi Xie
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jinyan Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qian Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yu Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Sina Liao
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yongqiang Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
- *Correspondence: Rong Liang, ; Yongqiang Li,
| | - Rong Liang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
- *Correspondence: Rong Liang, ; Yongqiang Li,
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Schiffmann LM, Bruns CJ, Schmidt T. Resistance Mechanisms of the Metastatic Tumor Microenvironment to Anti-Angiogenic Therapy. Front Oncol 2022; 12:897927. [PMID: 35664794 PMCID: PMC9162757 DOI: 10.3389/fonc.2022.897927] [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: 03/16/2022] [Accepted: 04/21/2022] [Indexed: 11/23/2022] Open
Abstract
Angiogenesis describes the formation of blood vessels from an existing vascular network. Anti-angiogenic drugs that target tumor blood vessels have become standard of care in many cancer entities. Though very promising results in preclinical evaluation, anti-angiogenic treatments fell short of expectations in clinical trials. Patients develop resistance over time or are primarily refractory to anti-angiogenic therapies similar to conventional chemotherapy. To further improve efficacy and outcome to these therapies, a deeper understanding of mechanisms that mediate resistance to anti-angiogenic therapies is needed. The field has done tremendous efforts to gain knowledge about how tumors engage tumor cell and microenvironmental mechanisms to do so. This review highlights the current state of knowledge with special focus on the metastatic tumor site and potential therapeutic relevance of this understanding from a translational and clinical perspective.
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Affiliation(s)
- Lars M. Schiffmann
- Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | | | - Thomas Schmidt
- Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Russo M, Nastasi C. Targeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils. Front Oncol 2022; 12:871513. [PMID: 35664746 PMCID: PMC9160747 DOI: 10.3389/fonc.2022.871513] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/11/2022] [Indexed: 12/15/2022] Open
Abstract
The importance of the tumor microenvironment (TME) in dynamically regulating cancer progression and influencing the therapeutic outcome is widely accepted and appreciated. Several therapeutic strategies to modify or modulate the TME, like angiogenesis or immune checkpoint inhibitors, showed clinical efficacy and received approval from regulatory authorities. Within recent decades, new promising strategies targeting myeloid cells have been implemented in preclinical cancer models. The predominance of specific cell phenotypes in the TME has been attributed to pro- or anti-tumoral. Hence, their modulation can, in turn, alter the responses to standard-of-care treatments, making them more or less effective. Here, we summarize and discuss the current knowledge and the correlated challenges about the tumor-associated macrophages and neutrophils targeting strategies, current treatments, and future developments.
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Affiliation(s)
- Massimo Russo
- Laboratory of Cancer Metastasis Therapeutics, Department of Oncology, Mario Negri Pharmacological Research Institute (IRCCS), Milan, Italy
| | - Claudia Nastasi
- Laboratory of Cancer Pharmacology, Department of Oncology, Mario Negri Pharmacological Research Institute (IRCCS), Milan, Italy
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40
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Zhang Q, Guo YX, Zhang WL, Lian HY, Iranzad N, Wang E, Li YC, Tong HC, Li LY, Dong LY, Yang LH, Ma S. Intra-tumoral angiogenesis correlates with immune features and prognosis in glioma. Aging (Albany NY) 2022; 14:4402-4424. [PMID: 35579998 PMCID: PMC9186765 DOI: 10.18632/aging.204079] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 04/22/2022] [Indexed: 11/25/2022]
Abstract
Gliomas are the most common malignant tumor in the brain. As with other tumors, the progression of glioma depends on intra-tumoral angiogenesis. However, the effect of angiogenesis on gliomas is still not fully understood. In this study, we developed an angiogenesis pathway score using Gene Set Variation Analysis (GSAV) in R to assess the status of intra-glioma angiogenesis in The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA mRNAseq_325, CGGA mRNA-array), and GSE16011 datasets. We found that the angiogenesis pathway score not only accurately predicted the prognosis of glioma patients, but also accurately distinguished the malignant phenotype and immune characteristics of gliomas. In addition, as an independent prognostic factor, the score could predict glioma sensitivity to radiotherapy and chemotherapy. In summary, we used the angiogenesis pathway score to reveal the relationship between glioma angiogenesis and the malignant phenotype, immune characteristics, and prognosis of glioma.
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Affiliation(s)
- Qing Zhang
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.,Department of Neurology, Sheng Jing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yao-Xing Guo
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.,Department of Neurology, Sheng Jing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wan-Lin Zhang
- Department of Pathology, Hebei Petro China Central Hospital, Langfang, Hebei, China
| | - Hai-Yan Lian
- Department of Ophthalmology, Jili Hospital of Liuyang (Liuyang Eye Hospital), Changsha, Hunan, China
| | - Natasha Iranzad
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
| | - Endi Wang
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
| | - Ying-Chun Li
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China
| | - Hai-Chao Tong
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China
| | - Le-Yao Li
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China
| | - Ling-Yun Dong
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China
| | - Lian-He Yang
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.,Department of Neurology, Sheng Jing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shuang Ma
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.,Department of Neurology, Sheng Jing Hospital of China Medical University, Shenyang, Liaoning, China
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41
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Zhang Y, Brekken RA. Direct and indirect regulation of the tumor immune microenvironment by VEGF. J Leukoc Biol 2022; 111:1269-1286. [DOI: 10.1002/jlb.5ru0222-082r] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/19/2022] Open
Affiliation(s)
- Yuqing Zhang
- Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center Dallas Texas USA
- Department of Surgery UT Southwestern Medical Center Dallas Texas USA
- Cancer Biology Graduate Program UT Southwestern Medical Center Dallas Texas USA
- Current affiliation: Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
| | - Rolf A. Brekken
- Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center Dallas Texas USA
- Department of Surgery UT Southwestern Medical Center Dallas Texas USA
- Cancer Biology Graduate Program UT Southwestern Medical Center Dallas Texas USA
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42
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Li J, DeNicola GM, Ruffell B. Metabolism in tumor-associated macrophages. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 367:65-100. [PMID: 35461660 PMCID: PMC9094395 DOI: 10.1016/bs.ircmb.2022.01.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Macrophages functionally adapt to a diverse set of signals, a process that is critical for their role in maintaining or restoring tissue homeostasis. This process extends to cancer, where macrophages respond to a series of inflammatory and metabolic cues that direct a maladaptive healing response. Tumor-associated macrophages (TAMs) have altered glucose, amino acid, and lipid metabolic profiles, and interfering with this metabolic shift can blunt the ability of macrophages to promote tumor growth, metastasis, and the creation of an immunosuppressive microenvironment. Here we will review changes in metabolites and metabolic pathways in TAMs and link these with the phenotypic and functional properties of the cells. We will also discuss current strategies targeting TAM metabolism as a therapeutic intervention in cancer.
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Affiliation(s)
- Jie Li
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States; Cancer Biology PhD Program, University of South Florida, Tampa, FL, United States
| | - Gina M DeNicola
- Department of Cancer Physiology, Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Brian Ruffell
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.
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43
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Habanjar O, Diab-Assaf M, Caldefie-Chezet F, Delort L. The Impact of Obesity, Adipose Tissue, and Tumor Microenvironment on Macrophage Polarization and Metastasis. BIOLOGY 2022; 11:339. [PMID: 35205204 PMCID: PMC8869089 DOI: 10.3390/biology11020339] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/19/2022] [Accepted: 02/15/2022] [Indexed: 12/11/2022]
Abstract
Tumor metastasis is a major cause of death in cancer patients. It involves not only the intrinsic alterations within tumor cells, but also crosstalk between these cells and components of the tumor microenvironment (TME). Tumorigenesis is a complex and dynamic process, involving the following three main stages: initiation, progression, and metastasis. The transition between these stages depends on the changes within the extracellular matrix (ECM), in which tumor and stromal cells reside. This matrix, under the effect of growth factors, cytokines, and adipokines, can be morphologically altered, degraded, or reorganized. Many cancers evolve to form an immunosuppressive TME locally and create a pre-metastatic niche in other tissue sites. TME and pre-metastatic niches include myofibroblasts, immuno-inflammatory cells (macrophages), adipocytes, blood, and lymphatic vascular networks. Several studies have highlighted the adipocyte-macrophage interaction as a key driver of cancer progression and dissemination. The following two main classes of macrophages are distinguished: M1 (pro-inflammatory/anti-tumor) and M2 (anti-inflammatory/pro-tumor). These cells exhibit distinct microenvironment-dependent phenotypes that can promote or inhibit metastasis. On the other hand, obesity in cancer patients has been linked to a poor prognosis. In this regard, tumor-associated adipocytes modulate TME through the secretion of inflammatory mediators, which modulate and recruit tumor-associated macrophages (TAM). Hereby, this review describes the cellular and molecular mechanisms that link inflammation, obesity, and cancer. It provides a comprehensive overview of adipocytes and macrophages in the ECM as they control cancer initiation, progression, and invasion. In addition, it addresses the mechanisms of tumor anchoring and recruitment for M1, M2, and TAM macrophages, specifically highlighting their origin, classification, polarization, and regulatory networks, as well as their roles in the regulation of angiogenesis, invasion, metastasis, and immunosuppression, specifically highlighting the role of adipocytes in this process.
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Affiliation(s)
- Ola Habanjar
- Université Clermont-Auvergne, INRAE, UNH, ECREIN, f-63000 Clermont-Ferrand, France; (O.H.); (F.C.-C.)
| | - Mona Diab-Assaf
- Equipe Tumorigénèse Pharmacologie moléculaire et anticancéreuse, Faculté des Sciences II, Université libanaise Fanar, Beyrouth 1500, Liban;
| | - Florence Caldefie-Chezet
- Université Clermont-Auvergne, INRAE, UNH, ECREIN, f-63000 Clermont-Ferrand, France; (O.H.); (F.C.-C.)
| | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH, ECREIN, f-63000 Clermont-Ferrand, France; (O.H.); (F.C.-C.)
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A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression. Nat Cell Biol 2022; 24:940-953. [PMID: 35654839 PMCID: PMC9203279 DOI: 10.1038/s41556-022-00918-8] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 04/20/2022] [Indexed: 12/13/2022]
Abstract
Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced growth delay of syngeneic melanoma and pancreatic tumours. Single-cell transcriptomics of tumours grown in Atf4Δ/Δ mice uncovered a reduction in activation markers in perivascular cancer-associated fibroblasts (CAFs). Atf4Δ/Δ fibroblasts displayed significant defects in collagen biosynthesis and deposition and a reduced ability to support angiogenesis. Mechanistically, ATF4 regulates the expression of the Col1a1 gene and levels of glycine and proline, the major amino acids of collagen. Analyses of human melanoma and pancreatic tumours revealed a strong correlation between ATF4 and collagen levels. Our findings establish stromal ATF4 as a key driver of CAF functionality, malignant progression and metastasis.
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Chen Y, Zheng X, Wu C. The Role of the Tumor Microenvironment and Treatment Strategies in Colorectal Cancer. Front Immunol 2021; 12:792691. [PMID: 34925375 PMCID: PMC8674693 DOI: 10.3389/fimmu.2021.792691] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/15/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) has the second highest mortality rate among all cancers worldwide. Surgery, chemotherapy, radiotherapy, molecular targeting and other treatment methods have significantly prolonged the survival of patients with CRC. Recently, the emergence of tumor immunotherapy represented by immune checkpoint inhibitors (ICIs) has brought new immunotherapy options for the treatment of advanced CRC. As the efficacy of ICIs is closely related to the tumor immune microenvironment (TME), it is necessary to clarify the relationship between the immune microenvironment of CRC and the efficacy of immunotherapy to ensure that the appropriate drugs are selected. We herein review the latest research progress in the immune microenvironment and strategies related to immunotherapy for CRC. We hope that this review helps in the selection of appropriate treatment strategies for CRC patients.
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Affiliation(s)
- Yaping Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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46
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Conte E. Targeting monocytes/macrophages in fibrosis and cancer diseases: Therapeutic approaches. Pharmacol Ther 2021; 234:108031. [PMID: 34774879 DOI: 10.1016/j.pharmthera.2021.108031] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/19/2021] [Accepted: 11/02/2021] [Indexed: 02/08/2023]
Abstract
Over almost 140 years since their identification, the knowledge about macrophages has unbelievably evolved. The 'big eaters' from being thought of as simple phagocytic cells have been recognized as master regulators in immunity, homeostasis, healing/repair and organ development. Long considered to originate exclusively from bone marrow-derived circulating monocytes, macrophages have been also demonstrated to be the first immune cells colonizing tissues in the developing embryo and persisting in adult life by self-renewal, as long-lived tissue resident macrophages. Therefore, heterogeneous populations of macrophages with different ontogeny and functions co-exist in tissues. Macrophages act as sentinels of homeostasis and are intrinsically programmed to lead the wound healing and repair processes that occur after injury. However, in certain pathological circumstances macrophages get dysfunctional, and impaired or aberrant macrophage activities become key features of diseases. For instance, in both fibrosis and cancer, that have been defined 'wounds that do not heal', dysfunctional monocyte-derived macrophages overall play a key detrimental role. On the other hand, due to their plasticity these cells can be 're-educated' and exert anti-fibrotic and anti-cancer functions. Therefore macrophages represent an important therapeutic target in both fibrosis and cancer diseases. The current review will illustrate new insights into the role of monocytes/macrophages in these devastating diseases and summarize new therapeutic strategies and applications of macrophage-targeted drug development in their clinical setting.
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Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma. Bioorg Med Chem 2021; 49:116427. [PMID: 34600240 DOI: 10.1016/j.bmc.2021.116427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 12/29/2022]
Abstract
Glioma, especially the most aggressive type glioblastoma multiforme, is a malignant cancer of the central nervous system with a poor prognosis. Traditional treatments are mainly surgery combined with radiotherapy and chemotherapy, which is still far from satisfactory. Therefore, it is of great clinical significance to find new therapeutic agents. Serving as an inhibitor of differentiation, protein ID2 (inhibitor of DNA binding 2) plays an important role in neurogenesis, neovascularization and malignant development of gliomas. It has been shown that ID2 affects the malignant progression of gliomas through different mechanisms. In this study, a pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations on their ID2 inhibitory activities. Based on the cytotoxicity of these small-molecule compounds, two compounds were shown to effectively inhibit the viability of glioma cells in the micromolar range. Among them, AK-778-XXMU was chosen for further study due to its better solubility in water. A SPR (Surface Plasma Resonance) assay proved the high affinity between AK-778-XXMU and ID2 protein with the KD value as 129 nM. The plausible binding mode of ID2 was studied by molecular docking and it was found to match AGX51 very well in the same binding site. Subsequently, the cancer-suppressing potency of the compound was characterized both in vitro and in vivo. The data demonstrated that compound AK-778-XXMU is a potent ID2 antagonist which has the potential to be developed as a therapeutic agent against glioma.
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48
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Liu X, Ye N, Xiao C, Wang X, Li S, Deng Y, Yang X, Li Z, Yang X. Hyperbaric oxygen regulates tumor microenvironment and boosts commercialized nanomedicine delivery for potent eradication of cancer stem-like cells. NANO TODAY 2021; 40:101248. [DOI: 10.1016/j.nantod.2021.101248] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
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49
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Jones JO, Moody WM, Shields JD. Microenvironmental modulation of the developing tumour: an immune-stromal dialogue. Mol Oncol 2021; 15:2600-2633. [PMID: 32741067 PMCID: PMC8486574 DOI: 10.1002/1878-0261.12773] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/03/2020] [Accepted: 07/27/2020] [Indexed: 12/17/2022] Open
Abstract
Successful establishment of a tumour relies on a cascade of interactions between cancer cells and stromal cells within an evolving microenvironment. Both immune and nonimmune cellular components are key factors in this process, and the individual players may change their role from tumour elimination to tumour promotion as the microenvironment develops. While the tumour-stroma crosstalk present in an established tumour is well-studied, aspects in the early tumour or premalignant microenvironment have received less attention. This is in part due to the challenges in studying this process in the clinic or in mouse models. Here, we review the key anti- and pro-tumour factors in the early microenvironment and discuss how understanding this process may be exploited in the clinic.
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Affiliation(s)
- James O. Jones
- MRC Cancer UnitHutchison/MRC Research CentreUniversity of CambridgeCambridgeUK
- Department of OncologyCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - William M. Moody
- MRC Cancer UnitHutchison/MRC Research CentreUniversity of CambridgeCambridgeUK
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Dik B, Coskun D, Er A. Protective Effect of Nerium Oleander Distillate and Tarantula Cubensis Alcoholic Extract on Cancer Biomarkers on Colon and Liver Tissues of Rats with Experimental Colon Cancer. Anticancer Agents Med Chem 2021; 22:1962-1969. [PMID: 34477527 DOI: 10.2174/1871520621666210903120253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 07/29/2021] [Accepted: 08/11/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Colon cancers are among the three major cancer types that result in death. The research for effective treatment continues. OBJECTIVE The aim of this study is to determine the effects of Tarantula cubensis alcoholic extract (TCAE) and Nerium oleander (NO) distillate on the levels of midkine, TGF-β, VEGF, AFP, COX-2, IGF and caspase 3 in liver and colon tissues of experimentally induced colon cancer in rats. METHOD The liver and colon tissues of the rats were divided into Control, Colon Cancer (AZM), AZM+TCAE and AZM+NO groups and they were homogenized. The levels of midkine, TGF-β, VEGF, AFP, COX-2, IGF and caspase 3 in the colon and liver tissues were measured by ELISA kits. RESULTS All parameters levels of colon and liver tissues in the AZM group were generally higher (p<0.05) than the Control group. TCAE and NO prevented (p<0.05) the increases in midkine, TGF-β, VEGF, AFP, COX-2, IGF and caspase-3 levels in the colon. NO prevented increase of all parameters except for IGF level, while TCAE prevented (p<0.05) the increase of all values apart from COX-2 and IGF levels in the liver. CONCLUSION NO and TCAE may prevented at the specified marker levels of colon in the AZM induced colon cancer. The increases the level of parameters in the liver are not as severe as in the colon, due to the 18-week study period may not be sufficient for liver metastasis formationIn the future molecular studies should be done to determine the mechanisms and pathways of them more clearly.
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Affiliation(s)
- Burak Dik
- Selcuk University, Veterinary Faculty, Department of Pharmacology and Toxicology, Konya, Turkey
| | - Devran Coskun
- Siirt University, Veterinary Faculty, Department of Pharmacology and Toxicology, Siirt, Turkey
| | - Ayşe Er
- Selcuk University, Veterinary Faculty, Department of Pharmacology and Toxicology, Konya, Turkey
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