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Li F, Jin C, Pan Y, Zhang Z, Wang L, Deng J, Zhou Y, Guo B, Zhang S. Construction of a stromal cell-related prognostic signature based on a 101-combination machine learning framework for predicting prognosis and immunotherapy response in triple-negative breast cancer. Front Immunol 2025; 16:1544348. [PMID: 40438115 PMCID: PMC12116347 DOI: 10.3389/fimmu.2025.1544348] [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: 12/12/2024] [Accepted: 04/21/2025] [Indexed: 06/01/2025] Open
Abstract
Background Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic targets and poor immunotherapy outcomes. The tumor microenvironment (TME) plays a key role in cancer progression. Advances in single-cell transcriptomics have highlighted the impact of stromal cells on tumor progression, immune suppression, and immunotherapy. This study aims to identify stromal cell marker genes and develop a prognostic signature for predicting TNBC survival outcomes and immunotherapy response. Methods Single-cell RNA sequencing (scRNA-seq) datasets were retrieved from the Gene Expression Omnibus (GEO) database and annotated using known marker genes. Cell types preferentially distributed in TNBC were identified using odds ratios (OR). Bulk transcriptome data were analyzed using Weighted correlation network analysis (WGCNA) to identify myCAF-, VSMC-, and Pericyte-related genes (MVPRGs). A consensus MVP cell-related signature (MVPRS) was developed using 10 machine learning algorithms and 101 model combinations and validated in training and validation cohorts. Immune infiltration and immunotherapy response were assessed using CIBERSORT, ssGSEA, TIDE, IPS scores, and an independent cohort (GSE91061). FN1, a key gene in the model, was validated through qRT-PCR, immunohistochemistry, RNA interference, CCK-8 assay, apoptosis assay and wound-healing assay. Results In TNBC, three stromal cell subpopulations-myofibroblastic cancer-associated fibroblasts (myCAF), vascular smooth muscle cells (VSMCs), and pericytes-were enriched, exhibiting high interaction frequencies and strong associations with poor prognosis. A nine-gene prognostic model (MVPRS), developed from 23 prognostically significant genes among the 259 MVPRGs, demonstrated excellent predictive performance and was validated as an independent prognostic factor. A nomogram integrating MVPRS, age, stage, and tumor grade offered clinical utility. High-risk group showed reduced immune infiltration and increased activity in tumor-related pathways like ANGIOGENESIS and HYPOXIA, while low-risk groups responded better to immunotherapy based on TIDE and IPS scores. FN1, identified as a key oncogene, was highly expressed in TNBC tissues and cell lines, promoting proliferation and migration while inhibiting apoptosis. Conclusion This study reveals TNBC microenvironment heterogeneity and introduces a prognostic signature based on myCAF, VSMC, and Pericyte marker genes. MVPRS effectively predicts TNBC prognosis and immunotherapy response, providing guidance for personalized treatment. FN1 was validated as a key oncogene impacting TNBC progression and malignant phenotype, with potential as a therapeutic target.
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Affiliation(s)
- Fanrong Li
- Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
| | - Congnan Jin
- Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yacheng Pan
- Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
| | - Zheng Zhang
- Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
| | - Liying Wang
- Jiangsu Clinical Medicine Research Institute, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jieqiong Deng
- Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yifeng Zhou
- Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
- Jiangsu Clinical Medicine Research Institute, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Binbin Guo
- Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
| | - Shenghua Zhang
- Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
- Jiangsu Clinical Medicine Research Institute, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Liu Y, Chen Y, Shu J, Zhang Z, You Y, Yue S, Ji Q, Chen K, Liu Y, Duan B, Yu B, Kou S, Pang X, Wang W, Yang L, Zhao Z, Gao J. Dual-energy CT for predicting progression-free survival of locally advanced gastric cancer after gastrectomy: Insights into tumor angiogenesis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:110017. [PMID: 40222263 DOI: 10.1016/j.ejso.2025.110017] [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: 12/11/2024] [Revised: 03/12/2025] [Accepted: 04/03/2025] [Indexed: 04/15/2025]
Abstract
OBJECTIVES To investigate preoperative dual-energy CT (DECT)-derived independent risk factors affecting progression-free survival (PFS) in patients with locally advanced gastric cancer (LAGC) undergoing gastrectomy, and to reveal the underlying histopathologic changes. METHODS This prospective study included patients who underwent preoperative DECT scan and gastrectomy. Clinical data, DECT-derived morphological characteristics and iodine-related parameters were comprehensively collected. Univariate and multivariate analyses were carried out to identify independent risk factors associated with PFS. The prognostic performance of various parameters was evaluated using the bootstrap-based consistency index (C-index) and time-dependent receiver operating characteristic (ROC) analysis. Kaplan-Meier curves were used to assess the differences in survival analysis. The histopathologic underpinnings of the DECT-based combined parameter for evaluating PFS were explored. RESULTS 120 LAGC patients (63.3 ± 10.9 years; 94 men) were analyzed. Age, arterial enhancement fraction (AEF), serosal invasion, and tumor thickness were identified as preoperative independent risk factors affecting PFS (all p < 0.05). The combined parameters based on these risk factors achieved a C-index of 0.75, significantly or slightly superior to that of any single risk factor (all p < 0.05) or postoperative pathological staging (C-index, 0.67; p > 0.05). For predicting the 0.5-, 1- and 2-year PFS, the combined parameter had an area-under-the-curve (AUC) of 0.72, 0.77, and 0.74, respectively. PFS significantly differed between patients of high- and low-risks assessed with the combined parameter (p < 0.001). Histopathologically, the combined parameter was associated with tumor microvessel density (r = 0.31, p < 0.001). CONCLUSION The combination of DECT-derived morphological characteristics, iodine-related parameters, and clinical data helped accurately stratify PFS in LAGC before surgery and is associated with tumor angiogenesis. CLINICAL RELEVANCE STATEMENT Dual-energy CT was promising in the preoperative evaluation of the progression-free survival in LAGC patients after gastrectomy.
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Affiliation(s)
- Yiyang Liu
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Henan International Joint Laboratory of Medical Imaging, Zhengzhou, China; Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor, Zhengzhou, China; Henan Key Laboratory of CT Imaging, Zhengzhou, China; The First Clinical School of Medicine, Zhengzhou University, Zhengzhou, 450052, China
| | - Yusong Chen
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Henan International Joint Laboratory of Medical Imaging, Zhengzhou, China; Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor, Zhengzhou, China; Henan Key Laboratory of CT Imaging, Zhengzhou, China; The First Clinical School of Medicine, Zhengzhou University, Zhengzhou, 450052, China
| | - Jiao Shu
- The First Clinical School of Medicine, Zhengzhou University, Zhengzhou, 450052, China; Department of Pathology, The First Affiliated Hospital of Zhengzhou University, China
| | - Zhe Zhang
- The First Clinical School of Medicine, Zhengzhou University, Zhengzhou, 450052, China; Department of Pathology, The First Affiliated Hospital of Zhengzhou University, China
| | - Yaru You
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Henan International Joint Laboratory of Medical Imaging, Zhengzhou, China; Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor, Zhengzhou, China; Henan Key Laboratory of CT Imaging, Zhengzhou, China; The First Clinical School of Medicine, Zhengzhou University, Zhengzhou, 450052, China
| | - Songwei Yue
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Henan International Joint Laboratory of Medical Imaging, Zhengzhou, China; Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor, Zhengzhou, China; Henan Key Laboratory of CT Imaging, Zhengzhou, China
| | - Qingyu Ji
- Department of Radiology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 014030, China
| | - Kuisheng Chen
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, China
| | - Yao Liu
- Department of Pathology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, China
| | - Bo Duan
- Department of Radiology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 014030, China
| | - Baiqing Yu
- Department of Medical Oncology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, China
| | - Songzi Kou
- The First Clinical School of Medicine, Zhengzhou University, Zhengzhou, 450052, China; Department of Pathology, The First Affiliated Hospital of Zhengzhou University, China
| | - Xia Pang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, China
| | - Weitao Wang
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Li Yang
- Department of Pathology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, China.
| | - Zihao Zhao
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Henan International Joint Laboratory of Medical Imaging, Zhengzhou, China; Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor, Zhengzhou, China; Henan Key Laboratory of CT Imaging, Zhengzhou, China.
| | - Jianbo Gao
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Henan International Joint Laboratory of Medical Imaging, Zhengzhou, China; Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor, Zhengzhou, China; Henan Key Laboratory of CT Imaging, Zhengzhou, China; The First Clinical School of Medicine, Zhengzhou University, Zhengzhou, 450052, China.
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Sharma N, Panigrahi R, Pradhan P, Parida S, Sahoo SR. Expression of CD68+ Tumor associated macrophages in relation to β-catenin in carcinoma stomach. INDIAN J PATHOL MICR 2024; 67:15-20. [PMID: 38358183 DOI: 10.4103/ijpm.ijpm_535_22] [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] [Indexed: 02/16/2024] Open
Abstract
Background With no unified system for tumor associated macrophages (TAMs) density assessment, limited information is available on their relationship with β-catenin expression. Aim To evaluate the density of CD68+ TAMs in gastric adenocarcinoma samples by immunohistochemistry and correlate it with grade, stage, invasion, and beta-catenin. Designs and Settings Formalin fixed paraffin embedded (FFPE) blocks from gastrectomy specimens of proven gastric adenocarcinoma were prospectively and retrospectively were studied over a period of two years. Materials and Methods Immunohistochemistry with CD68 and β-catenin was performed. TAM density was qualitatively compared in "tumor" versus "stroma" and "tumor" versus "non-tumor" regions. Quantitative CD68+ TAM density was assessed using different methods and compared. Cases were classified as high and low TAM based on the median value and correlated with histologic type, location, grade, stage and β-catenin expression pattern. Statistical Analysis Spearman's rank correlation test was used to compare the different methods of TAM density evaluation. The categorical variables were studied using Pearson's Chi-square or Fisher's exact test. CD68+ TAM density and β-catenin expression were correlated by analysis of variance. A P value ≤ 0.05 was taken as statistically significant. Results The CD68+ TAMs in the "tumor" versus "non-tumor" area (p = 0.34) and "tumor" versus "stroma distribution" (p = 0.81) did not show any statistical significance. All methods of TAM density were found to be comparable. High TAM group is significantly associated with lymphovascular invasion, tumor depth, lymph node metastasis, and abnormal β-catenin expression. Conclusion TAMs density plays an important role in the tumor stage. Macrophages may possibly induce gastric cancer invasiveness by activating β-catenin pathway.
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Affiliation(s)
- Nikhil Sharma
- Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Ranjita Panigrahi
- Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Prita Pradhan
- Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Sabyasachi Parida
- Department of Surgical Oncology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Saroj R Sahoo
- Department of Surgical Oncology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
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Zheng J, Jiang J, Pu Y, Xu T, Sun J, Zhang Q, He L, Liang X. Tumor-associated macrophages in nanomaterial-based anti-tumor therapy: as target spots or delivery platforms. Front Bioeng Biotechnol 2023; 11:1248421. [PMID: 37654704 PMCID: PMC10466823 DOI: 10.3389/fbioe.2023.1248421] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/03/2023] [Indexed: 09/02/2023] Open
Abstract
Targeting tumor-associated macrophages (TAMs) has emerged as a promising approach in cancer therapy. This article provides a comprehensive review of recent advancements in the field of nanomedicines targeting TAMs. According to the crucial role of TAMs in tumor progression, strategies to inhibit macrophage recruitment, suppress TAM survival, and transform TAM phenotypes are discussed as potential therapeutic avenues. To enhance the targeting capacity of nanomedicines, various approaches such as the use of ligands, immunoglobulins, and short peptides are explored. The utilization of live programmed macrophages, macrophage cell membrane-coated nanoparticles and macrophage-derived extracellular vesicles as drug delivery platforms is also highlighted, offering improved biocompatibility and prolonged circulation time. However, challenges remain in achieving precise targeting and controlled drug release. The heterogeneity of TAMs and the variability of surface markers pose hurdles in achieving specific recognition. Furthermore, the safety and clinical applicability of these nanomedicines requires further investigation. In conclusion, nanomedicines targeting TAMs hold great promise in cancer therapy, offering enhanced specificity and reduced side effects. Addressing the existing limitations and expanding our understanding of TAM biology will pave the way for the successful translation of these nano-therapies into clinical practice.
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Affiliation(s)
- Jixuan Zheng
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, West China School of Medicine, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jinting Jiang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, West China School of Medicine, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Yicheng Pu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, West China School of Medicine, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Tingrui Xu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, West China School of Medicine, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jiantong Sun
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, West China School of Medicine, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Qiang Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ling He
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Liang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, West China School of Medicine, West China School of Pharmacy, Sichuan University, Chengdu, China
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2023:321-326. [DOI: 10.1007/978-981-97-0013-4_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Xue L, Chu W, Wan F, Wu P, Zhao X, Ma L, She Y, Li C, Li Y. YKL-39 is an independent prognostic factor in gastric adenocarcinoma and is associated with tumor-associated macrophage infiltration and angiogenesis. World J Surg Oncol 2022; 20:362. [DOI: 10.1186/s12957-022-02830-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 11/04/2022] [Indexed: 11/15/2022] Open
Abstract
Abstract
Background
Gastric cancer has a high incidence and mortality rate. Angiogenesis is necessary for tumor infiltration and metastasis and affects patient prognosis. YKL-39 has monocyte chemotactic activity and pro-angiogenic activity in some tumors. In this study, we investigated the relationship between YKL-39 and tumor-associated macrophages and microangiogenesis in gastric cancer to determine its potential as a prognostic biomarker.
Materials and methods
A total of 119 patients with gastric cancer who had undergone gastrectomy at the 940th Hospital of the Joint Security Force between 2014 and 2018 were included in this study. We assayed the protein expression of YKL-39, CD68, and CD34 by immunohistochemistry in tissues of 119 patients with gastric cancer, as well as the intracellular expression of YKL-39 and CD68 by immunofluorescence. Data were analyzed with SPSS Statistics 25.0 to explore the impact of expression of YKL-39, CD68, and CD34 in gastric cancer patients and the relationship among them.
Results
Our results show that YKL-39 was expressed in both the nucleus and cytoplasm of gastric cancer cells and tumor mesenchyme. YKL-39 protein expression was associated with the depth of tumor infiltration, lymph node metastasis, and TNM stage; CD68 protein expression was associated with lymph node metastasis and TNM stage; CD34 protein expression was not associated with clinicopathological characteristics. Expression of YKL-39 was positively correlated with CD68 and CD34 (p < 0.001), and high expression of YKL-39 was associated with poor prognosis (p < 0.05).
Conclusion
In gastric cancer, YKL-39 expression is positively correlated with the degree of tumor-associated macrophage infiltration and angiogenesis, and is a potential prognostic marker for gastric cancer.
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Ucaryilmaz Metin C, Ozcan G. The HIF-1α as a Potent Inducer of the Hallmarks in Gastric Cancer. Cancers (Basel) 2022; 14:2711. [PMID: 35681691 PMCID: PMC9179860 DOI: 10.3390/cancers14112711] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/01/2023] Open
Abstract
Hypoxia is the principal architect of the topographic heterogeneity in tumors. Hypoxia-inducible factor-1α (HIF-1α) reinforces all hallmarks of cancer and donates cancer cells with more aggressive characteristics at hypoxic niches. HIF-1α potently induces sustained growth factor signaling, angiogenesis, epithelial-mesenchymal transition, and replicative immortality. Hypoxia leads to the selection of cancer cells that evade growth suppressors or apoptotic triggers and deregulates cellular energetics. HIF-1α is also associated with genetic instability, tumor-promoting inflammation, and escape from immunity. Therefore, HIF-1α may be an important therapeutic target in cancer. Despite that, the drug market lacks safe and efficacious anti-HIF-1α molecules, raising the quest for fully unveiling the complex interactome of HIF-1α in cancer to discover more effective strategies. The knowledge gap is even wider in gastric cancer, where the number of studies on hypoxia is relatively low compared to other well-dissected cancers. A comprehensive review of the molecular mechanisms by which HIF-1α induces gastric cancer hallmarks could provide a broad perspective to the investigators and reveal missing links to explore in future studies. Thus, here we review the impact of HIF-1α on the cancer hallmarks with a specific focus on gastric cancer.
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Affiliation(s)
| | - Gulnihal Ozcan
- Department of Medical Pharmacology, School of Medicine, Koç University, 34450 Istanbul, Turkey
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Senchukova MA. Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer. World J Gastroenterol 2021; 27:8262-8282. [PMID: 35068869 PMCID: PMC8717017 DOI: 10.3748/wjg.v27.i48.8262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/02/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460021, Russia
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Na HY, Park Y, Nam SK, Koh J, Kwak Y, Ahn SH, Park DJ, Kim HH, Lee KS, Lee HS. Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry. J Transl Med 2021; 19:529. [PMID: 34952595 PMCID: PMC8710020 DOI: 10.1186/s12967-021-03203-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/16/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). METHODS We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. RESULTS Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. CONCLUSIONS Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.
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Affiliation(s)
- Hee Young Na
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yujun Park
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Kyu Sang Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea.
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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Zhao Y, Zhang B, Zhang Q, Ma X, Feng H. Tumor-associated macrophages in osteosarcoma. J Zhejiang Univ Sci B 2021; 22:885-892. [PMID: 34783219 DOI: 10.1631/jzus.b2100029] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. It is an aggressive tumor with a tendency to spread to the lung, which is the most common site of metastasis. Patients with advanced OS with metastases have poor prognoses despite the application of chemotherapy, thus highlighting the need for novel therapeutic targets. The tumor microenvironment (TME) of OS is confirmed to be essential for and supportive of tumor growth and dissemination. The immune component of the OS microenvironment is mainly composed of tumor-associated macrophages (TAMs). In OS, TAMs promote tumor growth and angiogenesis and upregulate the cancer stem cell-like phenotype. However, TAMs inhibit the metastasis of OS. Therefore, much attention has been paid to investigating the mechanism of TAMs in OS development and the progression of immunotherapy for OS. In this article, we aim to summarize the roles of TAMs in OS and the major findings on the application of TAMs in OS treatment.
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Affiliation(s)
- Yi Zhao
- Department of Orthopedics, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Benzheng Zhang
- Department of Ophthalmology, the Second Hospital of Hebei Medical University, Shijiazhuang 050061, China
| | - Qianqian Zhang
- Department of Gynecology, the Second Hospital of Hebei Medical University, Shijiazhuang 050061, China
| | - Xiaowei Ma
- Department of Orthopedics, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Helin Feng
- Department of Orthopedics, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
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11
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Cheng Y, Song S, Wu P, Lyu B, Qin M, Sun Y, Sun A, Mu L, Xu F, Zhang L, Wang J, Zhang Q. Tumor Associated Macrophages and TAMs-Based Anti-Tumor Nanomedicines. Adv Healthc Mater 2021; 10:e2100590. [PMID: 34292673 DOI: 10.1002/adhm.202100590] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/08/2021] [Indexed: 12/14/2022]
Abstract
As an important part of tumor microenvironment, tumor associated macrophages (TAMs) play a vital role in the occurrence, development, invasion, and metastasis of many malignant tumors and can significantly promote the formation of tumor blood vessels and lymphatic vessels, hence TAMs are greatly associated with poor prognosis. The research on nanomedicine has achieved huge progress, and nano-drugs have been widely utilized to treat various diseases through different mechanisms. Therefore, developing nano-drugs that are based on TAMs-associated anti-tumor mechanisms to effectively suppress tumor growth is expected to be a promising research filed. This paper introduces relevant information about TAMs in terms of their origin, and their roles in tumor genesis, development and metastasis. Furthermore, TAMs-related anti-tumor nano-drugs are summarized. Specifically, a wide range of nano-drugs targeting at TAMs are introduced, and categorized according to their therapeutic mechanisms toward tumors. Additionally, various nano delivery platforms using TAMs as cell carriers which aim at inhibiting tumor growth are reviewed. These two parts elucidate that the exploration of nanomedicine is essential to the study on TAMs-related anti-tumor strategies. This review is also intended to provide novel ideas for in-depth investigation on anti-tumor molecular mechanisms and nano-drug delivery systems based on TAMs.
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Affiliation(s)
- Yuxi Cheng
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Siyang Song
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Peiyao Wu
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
- School of Pharmacy Shenyang Pharmaceutical University Shenyang 110016 China
| | - Bochen Lyu
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Mengmeng Qin
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Yanan Sun
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Aning Sun
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Limin Mu
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Fei Xu
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Lu Zhang
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Jiancheng Wang
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
| | - Qiang Zhang
- State Key Laboratory of Natural and Biomimetic Drugs Peking University Beijing 100191 China
- School of Pharmacy Shenyang Pharmaceutical University Shenyang 110016 China
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12
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Liu J, Geng X, Hou J, Wu G. New insights into M1/M2 macrophages: key modulators in cancer progression. Cancer Cell Int 2021; 21:389. [PMID: 34289846 PMCID: PMC8296555 DOI: 10.1186/s12935-021-02089-2] [Citation(s) in RCA: 289] [Impact Index Per Article: 72.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/13/2021] [Indexed: 12/11/2022] Open
Abstract
Infiltration of macrophages in and around tumor nest represents one of the most crucial hallmarks during tumor progression. The mutual interactions with tumor cells and stromal microenvironment contribute to phenotypically polarization of tumor associated macrophages. Macrophages consist of at least two subgroups, M1 and M2. M1 phenotype macrophages are tumor-resistant due to intrinsic phagocytosis and enhanced antitumor inflammatory reactions. Contrastingly, M2 are endowed with a repertoire of tumor-promoting capabilities involving immuno-suppression, angiogenesis and neovascularization, as well as stromal activation and remodeling. The functional signature of M2 incorporates location-related, mutually connected, and cascade-like reactions, thereby accelerating paces of tumor aggressiveness and metastasis. In this review, mechanisms underlying the distinct functional characterization of M1 and M2 macrophages are demonstrated to make sense of M1 and M2 as key regulators during cancer progression.
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Affiliation(s)
- Jiuyang Liu
- Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiafei Geng
- Department of Ultrasound Imaging, Hubei Cancer Hospital, Wuhan, China
| | - Jinxuan Hou
- Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
| | - Gaosong Wu
- Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
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13
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Zhang S, Li D, Zhao M, Yang F, Sang C, Yan C, Wang Z, Li Y. Exosomal miR-183-5p Shuttled by M2 Polarized Tumor-Associated Macrophage Promotes the Development of Colon Cancer via Targeting THEM4 Mediated PI3K/AKT and NF-κB Pathways. Front Oncol 2021; 11:672684. [PMID: 34249713 PMCID: PMC8267908 DOI: 10.3389/fonc.2021.672684] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/10/2021] [Indexed: 12/24/2022] Open
Abstract
Background Abnormal accumulation of macrophages in the colon cancer (CC) contribute to its progression. miR-183-5p has been confirmed as an oncogene in CC and this article explores the effect and mechanism of exosomal miR-183-5p enriched by M2-polarized tumor-associated macrophages (TAM) on CC cells. Methods The human macrophage THP1 was induced to M2 polarization through IL-4 and IL-13 treatment. Exosomes in THP1 were isolated through ultracentrifugation, and the miR-183-5p expression in macrophages and exosomes was verified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The miR-183-5p inhibitors and mimics were applied to down-regulate and upregulate miR-183-5p in macrophages, respectively. Meanwhile, CC cell lines LoVo and SW480 were treated with the macrophage conditioned medium and exosomes, respectively. CC cells’ proliferation, invasion, and apoptosis were tested by the cell counting kit-8 (CCK-8) assay, colony formation assay, flow cytometry (FCM), Transwell assay, and xenograft assay, respectively. The profiles of thioesterase superfamily member 4 (THEM4), Akt, and NF-κB were compared by Western blotting (WB). Results The miR-183-5p level in M2-TAM and M2-TAM-derived exosomes was significantly increased. Meanwhile, M2-TAM and M2-TAM-derived exosomes significantly facilitated CC cell proliferation and invasion and dampened apoptosis. Overexpression of miR-183-5p in M2-TAM aggravated M2-TAM-mediated promotive effects on CC cells, with down-regulating miR-183-5p reversed M2-TAM-mediated tumor-promotive effects. Mechanically, miR-183-5p targeted THEM4 and inhibited its mRNA and protein expression. Overexpressing THEM4 abated miR-183-5p-mediated carcinogenic effects and inactivates Akt and NF-κB pathways in CC cells. Overall, this article elaborated that exosomal miR-183-5p shuttled by M2-TAM mediated Akt/NF-κB pathway to accelerate CC progression through targeting THEM4.
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Affiliation(s)
- Shangxin Zhang
- Department of Gastrointestinal Surgery & Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Deguan Li
- Department of Gastrointestinal Surgery & Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Min Zhao
- Department of General Surgery, Yanqing District Hospital (Peking University Third Hospital Yanqing Hospital), Beijing, China
| | - Fei Yang
- Department of Orthopedics, Beijing Yanqing District Hospital (Peking University Third Hospital Yanqing Hospital), Beijing, China
| | - Changye Sang
- Department of General Surgery, Yanqing District Hospital (Peking University Third Hospital Yanqing Hospital), Beijing, China
| | - Changhong Yan
- Department of General Surgery, Yanqing District Hospital (Peking University Third Hospital Yanqing Hospital), Beijing, China
| | - Zhenjun Wang
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yongxiang Li
- Department of Gastrointestinal Surgery & Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
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14
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King R, Hayes C, Donohoe CL, Dunne MR, Davern M, Donlon NE. Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers. World J Gastrointest Oncol 2021; 13:312-331. [PMID: 34040696 PMCID: PMC8131902 DOI: 10.4251/wjgo.v13.i5.312] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/24/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The malfeasant role of the hypoxic tumour microenvironment (TME) in cancer progression was recognized decades ago but the exact mechanisms that augment the hallmarks of cancer and promote treatment resistance continue to be elucidated. Gastroesophageal cancers (GOCs) represent a major burden of worldwide disease, responsible for the deaths of over 1 million people annually. Disentangling the impact of hypoxia in GOCs enables a better overall understanding of the disease pathogenesis while shining a light on novel therapeutic strategies and facilitating precision treatment approaches with the ultimate goal of improving outcomes for patients with these diseases. This review discusses the underlying principles and processes of the hypoxic response and the effect of hypoxia in promoting the hallmarks of cancer in the context of GOCs. We focus on its bidirectional influence on inflammation and how it drives angiogenesis, innate and adaptive immune evasion, metastasis, and the reprogramming of cellular bioenergetics. The contribution of the hypoxic GOC TME to treatment resistance is examined and a brief overview of the pharmacodynamics of hypoxia-targeted therapeutics is given. The principal methods that are used in measuring hypoxia and how they may enhance prognostication or provide rationale for individually tailored management in the case of tumours with significant hypoxic regions are also discussed.
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Affiliation(s)
- Ross King
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Conall Hayes
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Claire L Donohoe
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Margaret R Dunne
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Maria Davern
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Noel E Donlon
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
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15
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Jian Y, Yang K, Sun X, Zhao J, Huang K, Aldanakh A, Xu Z, Wu H, Xu Q, Zhang L, Xu C, Yang D, Wang S. Current Advance of Immune Evasion Mechanisms and Emerging Immunotherapies in Renal Cell Carcinoma. Front Immunol 2021; 12:639636. [PMID: 33767709 PMCID: PMC7985340 DOI: 10.3389/fimmu.2021.639636] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/08/2021] [Indexed: 12/16/2022] Open
Abstract
Renal cell carcinoma is a highly heterogeneous cancer group, and the complex microenvironment of the tumor provides appropriate immune evasion opportunities. The molecular mechanism of immune escape in renal cell carcinoma is currently a hot issue, focusing primarily on the major complex of histocompatibility, immunosuppressive cells, their secreted immunosuppressive cytokines, and apoptosis molecule signal transduction. Immunotherapy is the best treatment option for patients with metastatic or advanced renal cell carcinoma and combination immunotherapy based on a variety of principles has shown promising prospects. Comprehensive and in-depth knowledge of the molecular mechanism of immune escape in renal cell carcinoma is of vital importance for the clinical implementation of effective therapies. The goal of this review is to address research into the mechanisms of immune escape in renal cell carcinoma and the use of the latest immunotherapy. In addition, we are all looking forward to the latest frontiers of experimental combination immunotherapy.
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Affiliation(s)
- Yuli Jian
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Kangkang Yang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Xiaoxin Sun
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Jun Zhao
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Kai Huang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Abdullah Aldanakh
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhongyang Xu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Haotian Wu
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qiwei Xu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Lin Zhang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Chunyan Xu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Deyong Yang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shujing Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
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16
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Senchukova MA, Makarova EV, Shurygina EI, Volchenko NN. Morphological Characteristics and Clinical Significance of Different Types of Tumor Vessels in Patients with Stages I-IIA of Squamous Cervical Cancer. JOURNAL OF ONCOLOGY 2020; 2020:3818051. [PMID: 32849870 PMCID: PMC7441445 DOI: 10.1155/2020/3818051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/02/2020] [Accepted: 07/11/2020] [Indexed: 02/05/2023]
Abstract
The determination of factors associated with progression of cervical cancer is important, both for a recurrence risk assessment and for determining optimal treatment tactics. Previously, we showed the prognostic value of different types of tumor microvessels (MVs) in gastric and breast cancer. The object of this research was to study the morphology and clinical significance of different tumor microvessels in early cervical cancer. A total of 65 archived paraffin blocks of patients with I-IIA stages of squamous cervical cancer were investigated. Samples were stained with Mayer hematoxylin and immunohistochemically using antibodies to CD34, podoplanin, HIF-1a, and Snail. The eight types of tumor MVs differed in morphology were identified. It was established that only the dilated capillaries (DСs) with weak expression of CD34, the contact type DCs, the capillaries in tumor solid component, and the lymphatic vessels in the lymphoid and polymorphic cell infiltrates of tumor stroma are associated with clinical and pathological characteristics of early cervical cancer. Preliminary results also suggest that a combination of fragmentation in tumor solid component and the contact type DCs may predict a recurrence of early cervical cancer. Given the small number of cervical cancer recurrences, the predictive significance of the described markers requires a more thorough examination.
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Affiliation(s)
- Marina A. Senchukova
- Department of Oncology, Orenburg State Medical University, 460000 Orenburg, Russia
| | - Elena V. Makarova
- Department of Oncology, Orenburg State Medical University, 460000 Orenburg, Russia
| | - Elena I. Shurygina
- Department of Pathology, Orenburg State Medical University, 460000 Orenburg, Russia
| | - Nadezhda N. Volchenko
- Department of Pathology, P. A. Hertzen Moscow Oncology Research Center, National Medical Research Center of Radiology, 125284 Moscow, Russia
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17
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Wu K, Lin K, Li X, Yuan X, Xu P, Ni P, Xu D. Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment. Front Immunol 2020; 11:1731. [PMID: 32849616 PMCID: PMC7417513 DOI: 10.3389/fimmu.2020.01731] [Citation(s) in RCA: 452] [Impact Index Per Article: 90.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 06/29/2020] [Indexed: 12/25/2022] Open
Abstract
The immunosuppressive status of the tumor microenvironment (TME) remains poorly defined due to a lack of understanding regarding the function of tumor-associated macrophages (TAMs), which are abundant in the TME. TAMs are crucial drivers of tumor progression, metastasis, and resistance to therapy. Intra- and inter-tumoral spatial heterogeneities are potential keys to understanding the relationships between subpopulations of TAMs and their functions. Antitumor M1-like and pro-tumor M2-like TAMs coexist within tumors, and the opposing effects of these M1/M2 subpopulations on tumors directly impact current strategies to improve antitumor immune responses. Recent studies have found significant differences among monocytes or macrophages from distinct tumors, and other investigations have explored the existence of diverse TAM subsets at the molecular level. In this review, we discuss emerging evidence highlighting the redefinition of TAM subpopulations and functions in the TME and the possibility of separating macrophage subsets with distinct functions into antitumor M1-like and pro-tumor M2-like TAMs during the development of tumors. Such redefinition may relate to the differential cellular origin and monocyte and macrophage plasticity or heterogeneity of TAMs, which all potentially impact macrophage biomarkers and our understanding of how the phenotypes of TAMs are dictated by their ontogeny, activation status, and localization. Therefore, the detailed landscape of TAMs must be deciphered with the integration of new technologies, such as multiplexed immunohistochemistry (mIHC), mass cytometry by time-of-flight (CyTOF), single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and systems biology approaches, for analyses of the TME.
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Affiliation(s)
| | | | | | | | | | | | - Dakang Xu
- Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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18
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Chang WH, Lai AG. The hypoxic tumour microenvironment: A safe haven for immunosuppressive cells and a therapeutic barrier to overcome. Cancer Lett 2020; 487:34-44. [PMID: 32470490 DOI: 10.1016/j.canlet.2020.05.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/28/2020] [Accepted: 05/12/2020] [Indexed: 12/14/2022]
Abstract
Dating back to the seminal work of Paul Ehrlich, the idea of harnessing our immune system to eliminate cancerous cells is now over a century old. In the presence of a functional immune system that so efficiently guards the host against developing neoplasms, tumour cells must evolve sophisticated strategies to escape immune destruction in order to give rise to clinically detectable cancers. A new way of treating cancer would thus be to target the immune system itself rather than the tumour, and extensive studies in randomised trials have cemented the possibility of using immunotherapy for treating advanced-stage cancers. Immunotherapy, however, is only tolerated in a minority of patients and in many cases, patients suffer from adverse immune-related reactions when the immune system goes into overdrive. A primary barrier thwarting the development of effective immunotherapy seems to coalesce into the peculiarities of the tumour microenvironment for which hypoxia is a key feature. Here, we review emerging themes on how hypoxia contributes to immune suppression and obstructs anti-tumour effector cell functions. We discuss the challenges and opportunities relating to the potential for dually targeting hypoxia and the immune system to promote durable and favourable responses in cancer patients.
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Affiliation(s)
- Wai Hoong Chang
- Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, United Kingdom
| | - Alvina G Lai
- Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, United Kingdom.
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19
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Su P, Wang Q, Bi E, Ma X, Liu L, Yang M, Qian J, Yi Q. Enhanced Lipid Accumulation and Metabolism Are Required for the Differentiation and Activation of Tumor-Associated Macrophages. Cancer Res 2020; 80:1438-1450. [PMID: 32015091 DOI: 10.1158/0008-5472.can-19-2994] [Citation(s) in RCA: 310] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/03/2020] [Accepted: 01/29/2020] [Indexed: 12/14/2022]
Abstract
Tumor-associated macrophages (TAM) are important tumor-promoting cells. However, the mechanisms underlying how the tumor and its microenvironment reprogram these cells remain elusive. Here we report that lipids play a crucial role in generating TAMs in the tumor microenvironment (TME). Macrophages from both human and murine tumor tissues were enriched with lipids due to increased lipid uptake by macrophages. TAMs expressed elevated levels of the scavenger receptor CD36, accumulated lipids, and used fatty acid oxidation (FAO) instead of glycolysis for energy. High levels of FAO promoted mitochondrial oxidative phosphorylation, production of reactive oxygen species, phosphorylation of JAK1, and dephosphorylation of SHP1, leading to STAT6 activation and transcription of genes that regulate TAM generation and function. These processes were critical for TAM polarization and activity, both in vitro and in vivo. In summary, we highlight the importance of lipid metabolism in the differentiation and function of protumor TAMs in the TME. SIGNIFICANCE: This study highlights the role of lipid metabolism in the differentiation and function of TAMs and suggests targeting TAM fatty acid oxidation as a potential therapeutic modality for human cancers.
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Affiliation(s)
- Pan Su
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston Methodist, Houston, Texas
| | - Qiang Wang
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston Methodist, Houston, Texas
| | - Enguang Bi
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston Methodist, Houston, Texas
| | - Xingzhe Ma
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston Methodist, Houston, Texas
| | - Lintao Liu
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston Methodist, Houston, Texas
| | - Maojie Yang
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston Methodist, Houston, Texas
| | - Jianfei Qian
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston Methodist, Houston, Texas
| | - Qing Yi
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston Methodist, Houston, Texas.
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20
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Jayasingam SD, Citartan M, Thang TH, Mat Zin AA, Ang KC, Ch'ng ES. Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice. Front Oncol 2020; 9:1512. [PMID: 32039007 PMCID: PMC6992653 DOI: 10.3389/fonc.2019.01512] [Citation(s) in RCA: 426] [Impact Index Per Article: 85.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 12/16/2019] [Indexed: 12/15/2022] Open
Abstract
Tumor-associated macrophages (TAMs) as immune cells within the tumor microenvironment have gained much interests as basic science regarding their roles in tumor progression unfolds. Better understanding of their polarization into pro-tumoral phenotype to promote tumor growth, tumor angiogenesis, immune evasion, and tumor metastasis has prompted various studies to investigate their clinical significance as a biomarker of predictive and prognostic value across different cancer types. Yet, the methodologies to investigate the polarization phenomena in solid tumor tissue vary. Nonetheless, quantifying the ratio of M1 to M2 TAMs has emerged to be a prevailing parameter to evaluate this polarization phenomena for clinical application. This mini-review focuses on recent studies exploring clinical significance of M1/M2 TAM ratio in human cancer tissue and critically evaluates the technicalities and challenges in quantifying this parameter for routine clinical practice. Immunohistochemistry appears to be the preferred methodology for M1/M2 TAM evaluation as it is readily available in clinical laboratories, albeit with certain limitations. Recommendations are made to standardize the quantification of TAMs for better transition into clinical practice and for better comparison among studies in various populations of patients and cancer types.
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Affiliation(s)
- Sharmilla Devi Jayasingam
- Oncological and Radiological Sciences Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Marimuthu Citartan
- Infectious Disease Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Thean Hock Thang
- Infectious Disease Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
- Faculty of Applied Sciences, AIMST University, Kedah, Malaysia
| | - Anani Aila Mat Zin
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
| | - Kai Cheen Ang
- Infectious Disease Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Ewe Seng Ch'ng
- Oncological and Radiological Sciences Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
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21
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Carvalho TM, Cardoso HJ, Figueira MI, Vaz CV, Socorro S. The peculiarities of cancer cell metabolism: A route to metastasization and a target for therapy. Eur J Med Chem 2019; 171:343-363. [PMID: 30928707 DOI: 10.1016/j.ejmech.2019.03.053] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/19/2019] [Accepted: 03/21/2019] [Indexed: 02/06/2023]
Abstract
The last decade has witnessed the peculiarities of metabolic reprogramming in tumour onset and progression, and their relevance in cancer therapy. Also, it has been indicated that the metastatic process may depend on the metabolic rewiring and adaptation of cancer cells to the pressure of tumour microenvironment and limiting nutrient availability. The present review gatherers the existent knowledge on the influence of tumour microenvironment and metabolic routes driving metastasis. A focus will be given to glycolysis, fatty acid metabolism, glutaminolysis, and amino acid handling. In addition, the role of metabolic waste driving metastasization will be explored. Finally, we discuss the status of cancer treatment approaches targeting metabolism. This knowledge revision will highlight the critical metabolic targets in metastasis and the chemicals already used in preclinical studies and clinical trials, providing clues that would be further exploited in medicinal chemistry research.
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Affiliation(s)
- Tiago Ma Carvalho
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Henrique J Cardoso
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Marília I Figueira
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Cátia V Vaz
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Sílvia Socorro
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
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22
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Senchukova MA, Makarova EV, Kalinin EA, Tkachev VV. Modern ideas about the origin, features of morphology, prognostic and predictive significance of tumor vessels. RUSSIAN JOURNAL OF BIOTHERAPY 2019; 18:6-15. [DOI: 10.17650/1726-9784-2019-18-1-6-15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The review presents modern ideas about the origin of tumor vessels and the features of their morphology. The various approaches to the classification of tumor vessel types and to the assessment of their clinical and prognostic significance are described. Also, the main problems associated with the use of angiogenesis blockers in the treatment of malignancies and their possible solutions are reflected in the review.
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Affiliation(s)
- M. A. Senchukova
- Orenburg State Medical University of the Ministry of Health of the Russian Federation; Orenburg Regional Clinical Oncology Dispensary
| | - E. V. Makarova
- Orenburg State Medical University of the Ministry of Health of the Russian Federation; Orenburg Regional Clinical Oncology Dispensary
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Wen ZF, Liu H, Gao R, Zhou M, Ma J, Zhang Y, Zhao J, Chen Y, Zhang T, Huang F, Pan N, Zhang J, Fox BA, Hu HM, Wang LX. Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1. J Immunother Cancer 2018; 6:151. [PMID: 30563569 PMCID: PMC6299637 DOI: 10.1186/s40425-018-0452-5] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 11/16/2018] [Indexed: 12/13/2022] Open
Abstract
Background Tumor-associated macrophages (TAMs) facilitate tumor progression via establishment of an immunosuppressive tumor microenvironment (TME). However, it is poorly understood how tumor cells could functionally modulate TAMs. Our previous work indicated that tumor cell-released autophagosomes (TRAPs), a type of LC3-II+ double-membrane extracellular vesicles (EVs) was sufficient to suppress anti-tumor immune responses by inducing IL-10-producing B cells and immune suppressive neutrophils. Here, we hypothesized that TRAPs may participate in regulating macrophage polarization. Methods TRAPs isolated from multiple murine tumor cell lines and pleural effusions or ascites of cancer patients were incubated with bone marrow-derived macrophages (BMDMs) and monocytes, respectively. Cellular phenotypes were examined by flow cytometry, ELISA and quantitative PCR. TRAPs treated BMDMs were tested for the ability to suppress T-cell proliferation in vitro, and for promotion of tumor growth in vivo. Transwell chamber and neutralization antibodies were added to ascertain the inhibitory molecules expressed on BMDMs exposed to TRAPs. Knockout mice were used to identify the receptors responsible for TRAPs-induced BMDMs polarization and the signaling mechanism was examined by western blot. Autophagy-deficient tumors were profiled for phenotypic changes of TAMs and IFN-γ secretion of T cells by flow cytometry. The phenotype of monocytes from pleural effusions or ascites of cancer patients was assessed by flow cytometry. Results TRAPs converted macrophages into an immunosuppressive M2-like phenotype characterized by the expression of PD-L1 and IL-10. These macrophages inhibited the proliferation of both CD4+ and CD8+ T cells in vitro, and promoted tumor growth mainly through PD-L1 in vivo. TRAPs-induced macrophage polarization was dependent on TLR4-mediated MyD88-p38-STAT3 signaling. In vivo studies indicated that disruption of autophagosome formation in B16F10 cells by silencing the autophagy gene Beclin1 resulted in a remarkable delay in tumor growth, which was associated with reduced autophagosome secretion, TAMs reprogramming and enhanced T cell activation. Moreover, the levels of LC3B+ EVs appeared to correlate significantly with up-regulation of PD-L1 and IL-10 in matched monocytes from effusions or ascites of cancer patients, and TRAPs isolated from these samples could also polarize monocytes to an M2-like phenotype with increased expression of PD-L1, CD163 and IL-10, decreased expression of HLA-DR, and T cell-suppressive function. Conclusions These findings suggest the TRAPs-PD-L1 axis as a major driver of immunosuppression in the TME by eliciting macrophage polarization towards an M2-like phenotype, and highlight the potential novel therapeutic approach of simultaneously targeting autophagy and PD-L1. Electronic supplementary material The online version of this article (10.1186/s40425-018-0452-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zhi-Fa Wen
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Hongxiang Liu
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Rong Gao
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Meng Zhou
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Jie Ma
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Yue Zhang
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Jinjin Zhao
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Yongqiang Chen
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Tianyu Zhang
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Fang Huang
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Ning Pan
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Jinping Zhang
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, People's Republic of China
| | - Bernard A Fox
- Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, 2N81 North Pavilion, 4805 N.E. Glisan St, Portland, OR, 97213, USA
| | - Hong-Ming Hu
- Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, 2N81 North Pavilion, 4805 N.E. Glisan St, Portland, OR, 97213, USA.
| | - Li-Xin Wang
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China.
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Yuan CL, Liang R, Liu ZH, Li YQ, Luo XL, Ye JZ, Lin Y. Bone morphogenetic protein and activin membrane-bound inhibitor overexpression inhibits gastric tumor cell invasion via the transforming growth factor-β/epithelial-mesenchymal transition signaling pathway. Exp Ther Med 2018; 15:5422-5430. [PMID: 29805551 PMCID: PMC5958702 DOI: 10.3892/etm.2018.6083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 01/22/2018] [Indexed: 12/15/2022] Open
Abstract
Gastric carcinoma is one of the most common human malignancies and remains the second leading cause of cancer-associated mortality worldwide. Gastric carcinoma is characterized by early-stage metastasis and is typically diagnosed in the advanced stage. Previous results have indicated that bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) overexpression has been demonstrated to inhibit growth and metastasis of gastric cancer cells. However, the molecular mechanisms of the BAMBI-mediated signaling pathway in the progression of gastric cancer are poorly understood. In the present study, to assess whether BAMBI overexpression inhibited the growth and aggressiveness of gastric carcinoma cells through regulation of transforming growth factor (TGF)-β/epithelial-mesenchymal transition (EMT) signaling pathway, the growth and metastasis of gastric carcinoma cells were analyzed following BAMBI overexpression and knockdown in vitro and in vivo. Molecular changes in the TGF-β/EMT signaling pathway were studied in gastric carcinoma cells following BAMBI overexpression and knockdown. DNA methylation of the gene regions encoding the TGF-β/EMT signaling pathway was investigated in gastric carcinoma cells. Tumor growth in tumor-bearing mice was analyzed after mice were subjected to endogenous overexpression of BAMBI. Results indicated that BAMBI overexpression significantly inhibited gastric carcinoma cell growth and aggressiveness, whereas knockdown of BAMBI significantly promoted its growth and metastasis compared with the control (P<0.01). The TGF-β/EMT signaling pathway was downregulated in BAMBI-overexpressed gastric carcinoma cells; however, signaling was promoted following BAMBI knockdown. In addition, it was observed that BAMBI overexpression significantly downregulated the DNA methylation of the gene regions encoding the TGF-β/EMT signaling pathway (P<0.01). Furthermore, RNA interference-mediated BAMBI overexpression also promoted apoptosis in gastric cancer cells and significantly inhibited growth of gastric tumors in murine xenografts (P<0.01). In conclusion, the present findings suggest that BAMBI overexpression inhibited the TGF-β/EMT signaling pathway and suppressed the invasiveness of gastric tumors, suggesting BAMBI may be a potential target for the treatment of gastric carcinoma via regulation of the TGF-β/EMT signaling pathway.
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Affiliation(s)
- Chun-Ling Yuan
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Rong Liang
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhi-Hui Liu
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yong-Qiang Li
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiao-Ling Luo
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jia-Zhou Ye
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yan Lin
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Yuan X, Zhang J, Li D, Mao Y, Mo F, Du W, Ma X. Prognostic significance of tumor-associated macrophages in ovarian cancer: A meta-analysis. Gynecol Oncol 2017; 147:181-187. [PMID: 28698008 DOI: 10.1016/j.ygyno.2017.07.007] [Citation(s) in RCA: 195] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 07/01/2017] [Accepted: 07/04/2017] [Indexed: 02/05/2023]
Abstract
OBJECTIVE The role of tumor-associated macrophages (TAMs) in tumor microenvironment remains controversial due to the two different polarized subsets of TAMs. Here, we performed a meta-analysis to evaluate the correlation between subpopulations of TAMs and clinical outcomes in patients with ovarian cancer. METHODS A comprehensive search in PUBMED/Medline and EMBASE databases was performed. The association between TAMs and patient prognosis of ovarian cancer was estimated with hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) using a random-effect model. Additionally, sensitivity analysis and Begg's test were conducted. RESULTS Nine studies including 794 patients were enrolled in the meta-analysis. The results showed that higher M1/M2 ratio in tumor tissues was associated with a favorable overall survival (OS) (HR=0.449, 95% CI=0.283-0.712, P=0.001). Elevated intra-islet M1/M2 TAMs ratio showed a positive correlation for OS (HR=0.510, 95% CI=0.264-0.986, P=0.045). No significant relation was observed between OS and CD68+ TAMs (HR=0.99, 95% CI=0.88-1.11, P=0.859), CD163+ TAMs (HR=1.04, 95% CI=0.92-1.16, P=0.544) or CD163+/CD68+ TAMs ratio (HR=1.628, 95% CI=0.529-5.008, P=0.395). Worse progression-free survival (PFS) was associated with high density of CD163+ TAMs (HR=2.157, 95% CI=1.406-3.312, P=0.000) and higher ratio of CD163+/CD68+ TAMs (HR=3.223, 95% CI=1.805-5.755, P=0.000). Elevated M1/M2 TAMs ratio predicted better PFS of ovarian cancer (HR=0.490, 95% CI=0.270-0.890, P=0.019). Furthermore, high density of CD163+ and CD68+ TAMs was observed in ovarian cancer with advanced TNM stage. CONCLUSION In our study, it was revealed that CD163+ TAMs infiltration was associated with poor prognosis of ovarian cancer and high M1/M2 macrophages ratio in tumor tissues predicted better prognosis.
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Affiliation(s)
- Xia Yuan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School Sichuan University, Chengdu, PR China.
| | - Jing Zhang
- West China Medical School Sichuan University, Chengdu, PR China
| | - Dan Li
- Department of Respiratory Medicine, West China Hospital, West China Medical School Sichuan University, Chengdu, PR China
| | - Ye Mao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School Sichuan University, Chengdu, PR China
| | - Fei Mo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School Sichuan University, Chengdu, PR China
| | - Wei Du
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School Sichuan University, Chengdu, PR China
| | - Xuelei Ma
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School Sichuan University, Chengdu, PR China.
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Zhou Q, Xian M, Xiang S, Xiang D, Shao X, Wang J, Cao J, Yang X, Yang B, Ying M, He Q. All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages. Cancer Immunol Res 2017; 5:547-559. [PMID: 28515123 DOI: 10.1158/2326-6066.cir-16-0259] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 02/24/2017] [Accepted: 05/12/2017] [Indexed: 12/22/2022]
Abstract
M2-polarized tumor-associated macrophages (TAM) play a critical role in cancer invasion and metastasis. Here, we report that M2 macrophages enhanced metastasis of K7M2 WT osteosarcoma cells to the lungs in mice, thus establishing M2 TAMs as a therapeutic target for blocking osteosarcoma metastasis. We found that all-trans retinoic acid (ATRA) inhibited osteosarcoma metastasis via inhibiting the M2 polarization of TAMs. ATRA suppressed IL13- or IL4-induced M2-type macrophages, and then inhibited migration of osteosarcoma cells as promoted by M2-type macrophages in vitro ATRA reduced the number of pulmonary metastatic nodes of osteosarcoma and decreased expression of M2-type macrophages in metastatic nodes both in intravenous injection and orthotopic transplantation models. ATRA's effect was independent of conventional STAT3/6 or C/EBPβ signaling, which regulate M2-like polarization of macrophages. Quantitative genomic and functional analyses revealed that MMP12, a macrophage-secreted elastase, was elevated in IL13-skewed TAM polarization, whereas ATRA treatment downregulated IL13-induced secretion of MMP12. This downregulation correlates with the antimetastasis effect of ATRA. Our results show the role of TAM polarization in osteosarcoma metastasis, identify a therapeutic opportunity for antimetastasis treatment, and indicate ATRA treatment as an approach for preventing osteosarcoma metastasis via M2-type polarization intervention. Cancer Immunol Res; 5(7); 547-59. ©2017 AACR.
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Affiliation(s)
- Qian Zhou
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Miao Xian
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Senfeng Xiang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Danyan Xiang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xuejing Shao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jincheng Wang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ji Cao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiaochun Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Meidan Ying
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
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Expression of Vav3 protein and its prognostic value in patients with gastric cancer. Pathol Res Pract 2017; 213:435-440. [PMID: 28285969 DOI: 10.1016/j.prp.2017.01.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 01/28/2017] [Accepted: 01/30/2017] [Indexed: 01/08/2023]
Abstract
Vav3 is associated with tumor growth, apoptosis, invasion, metastasis and angiogenesis. In this study, we detected the expression of Vav3 in gastric cancer tissues, and explored its role in invasion, metastasis and prognosis of gastric cancer. Vav3, MMP-2, MMP-9, TIMP-1 and TIMP-2 in primary lesion and pericarcinous tissues were tested with Immunohistochemistry and Western blot. Results showed a higher expression of Vav3 in primary lesion than in pericarcinous tissue, and the expression of Vav3 was significantly correlated with MMP-2, MMP-9 and TIMP-1 in gastric cancer tissues. Overexpression of Vav3 was associated with poorer differentiation, advanced clinical stage, more significant infiltration depth, lymphatic metastasis, and perineural invasion. Results of Kaplan-Meier verified that overexpression of Vav3 was related to poorer prognosis and shorter survival time. Moreover, Cox proportional hazard model revealed that overexpression of Vav3 was an independent risk factor of prognosis for patients with gastric cancer. In all, we conclude that overexpression of Vav3 is an independent risk factor for prognosis of gastric cancer, and can be used as a prognostic indicator. This may be because that Vav3 could regulate genes which associated with the invasion and metastasis.
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28
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Yin S, Huang J, Li Z, Zhang J, Luo J, Lu C, Xu H, Xu H. The Prognostic and Clinicopathological Significance of Tumor-Associated Macrophages in Patients with Gastric Cancer: A Meta-Analysis. PLoS One 2017; 12:e0170042. [PMID: 28081243 PMCID: PMC5230964 DOI: 10.1371/journal.pone.0170042] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 12/26/2016] [Indexed: 12/20/2022] Open
Abstract
Objective Comprehensive studies have investigated the prognostic and clinicopathological value of tumor-associated macrophages (TAMs) in gastric cancer patients, yet results remain controversial. Therefore, we performed a meta-analysis to clarify this issue. Methods PubMed, Embase, and the Cochrane Library databases were searched to identify eligible studies. We extracted hazard ratios (HRs) and odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) to estimate the effect sizes. In addition, subgroup analysis and sensitivity analysis were also conducted. Results A total of 19 studies involving 2242 patients were included. High generalised TAMs density was significantly associated with poor overall survival (OS) (HR 1.49, 95% CI 1.15–1.95). Subgroup analysis revealed that CD68+ TAMs had no significant effect on OS (HR 1.38, 95% CI 1.00–1.91). High M1 TAMs density was correlated with better OS (HR 0.45, 95% CI 0.32–0.65). By contrast, high density of M2 TAMs was correlated with a poor prognosis for OS (HR 1.48, 95% CI 1.25–1.75). Furthermore, high M2 TAMs density was correlated with larger tumor size, diffuse Lauren type, poor histologic differentiation, deeper tumor invasion, lymph node metastasis, and advanced TNM stage. Conclusions Overall, this meta-analysis reveal that although CD68+ TAMs infiltration has the neutral prognostic effects on OS, the M1/M2 polarization of TAMs are predicative factor of prognosis in gastric cancer patients.
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Affiliation(s)
- Songcheng Yin
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jinyu Huang
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhan Li
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Junyan Zhang
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jiazi Luo
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chunyang Lu
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Hao Xu
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Huimian Xu
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
- * E-mail:
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Sundstrom A, Bar-Sagi D, Mishra B. Simulating Heterogeneous Tumor Cell Populations. PLoS One 2016; 11:e0168984. [PMID: 28030620 PMCID: PMC5193460 DOI: 10.1371/journal.pone.0168984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 12/09/2016] [Indexed: 12/12/2022] Open
Abstract
Certain tumor phenomena, like metabolic heterogeneity and local stable regions of chronic hypoxia, signify a tumor's resistance to therapy. Although recent research has shed light on the intracellular mechanisms of cancer metabolic reprogramming, little is known about how tumors become metabolically heterogeneous or chronically hypoxic, namely the initial conditions and spatiotemporal dynamics that drive these cell population conditions. To study these aspects, we developed a minimal, spatially-resolved simulation framework for modeling tissue-scale mixed populations of cells based on diffusible particles the cells consume and release, the concentrations of which determine their behavior in arbitrarily complex ways, and on stochastic reproduction. We simulate cell populations that self-sort to facilitate metabolic symbiosis, that grow according to tumor-stroma signaling patterns, and that give rise to stable local regions of chronic hypoxia near blood vessels. We raise two novel questions in the context of these results: (1) How will two metabolically symbiotic cell subpopulations self-sort in the presence of glucose, oxygen, and lactate gradients? We observe a robust pattern of alternating striations. (2) What is the proper time scale to observe stable local regions of chronic hypoxia? We observe the stability is a function of the balance of three factors related to O2-diffusion rate, local vessel release rate, and viable and hypoxic tumor cell consumption rate. We anticipate our simulation framework will help researchers design better experiments and generate novel hypotheses to better understand dynamic, emergent whole-tumor behavior.
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Affiliation(s)
- Andrew Sundstrom
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Department of Computer Science, Courant Institute of Mathematical Sciences, New York, NY, United States of America
| | - Dafna Bar-Sagi
- Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, United States of America
| | - Bud Mishra
- Department of Computer Science, Courant Institute of Mathematical Sciences, New York, NY, United States of America
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The Fate of the Tumor in the Hands of Microenvironment: Role of TAMs and mTOR Pathway. Mediators Inflamm 2016; 2016:8910520. [PMID: 28074082 PMCID: PMC5198177 DOI: 10.1155/2016/8910520] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 11/19/2016] [Accepted: 11/24/2016] [Indexed: 11/17/2022] Open
Abstract
Since 2000, written with elegance and accuracy, Hanahan and Weinberg have proposed six major hallmarks of cancer and, together, they provide great advances to the understanding of tumoral biology. Our knowledge about tumor behavior has improved and the investigators have now recognized that inflammatory microenvironment may be a new feature for the tumor entities. Macrophages are considered as an important component of tumoral microenvironment. Biologically, two forms of activated macrophages can be observed: classically activated macrophages (M1) and alternative activated macrophages (M2). Despite the canonical pathways that control this puzzle of macrophages polarization, recently, mTOR signaling pathway has been implicated as an important piece in determining the metabolic and functional differentiation of M1 and M2 profiles. Currently, it is believed that macrophages related to tumoral microenvironment present an “M2-like” feature promoting an immunosuppressive microenvironment enhancing tumoral angiogenesis, growth, and metastasis. In the present review we discuss the role of macrophages in the tumor microenvironment and the role of mTOR pathway in M1 and M2 differentiation. We also discuss the recent findings in M1 and M2 polarization as a possible target in the cancer therapy.
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31
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Fuchs CS, Tabernero J, Tomášek J, Chau I, Melichar B, Safran H, Tehfe MA, Filip D, Topuzov E, Schlittler L, Udrea AA, Campbell W, Brincat S, Emig M, Melemed SA, Hozak RR, Ferry D, Caldwell CW, Ajani JA. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br J Cancer 2016; 115:974-982. [PMID: 27623234 PMCID: PMC5061911 DOI: 10.1038/bjc.2016.293] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 08/12/2016] [Accepted: 08/16/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma. METHODS A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had ⩾1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3. RESULTS None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI=0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI=0.38, 1.22) and low (HR=0.73, 95% CI=0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression. CONCLUSIONS REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited.
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Affiliation(s)
- Charles S Fuchs
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Jiří Tomášek
- Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno 656 53, Czech Republic
| | - Ian Chau
- Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
| | - Bohuslav Melichar
- Onkologicka klinika, Lekarska fakulta Univerzity Palackeho a Fakultni nemocnice, I.P. Pavlova, 6, Olomouc 779 00, Czech Republic
| | - Howard Safran
- Brown University Oncology Research Group, 164 Summit Avenue, Fain 3, Providence, Rhode Island 02906, USA
| | - Mustapha A Tehfe
- Centre Hospitalier de Montréal, 1560 Sherbrooke East St, Montreal, Quebec H2L4M1, Canada
| | - Dumitru Filip
- Spitalul Judetean de Urgenta, Strada George Coşbuc 31, Baia Mare 430031, Romania
| | - Eldar Topuzov
- State Budgetary Educational Institution of Higher Professional Education (SBEIHPE), Northwest State Medical University na II Mechnikov, Ministry of Healthcare of the Russian Federation, Russia
| | - Luis Schlittler
- Hospital da Cida de Passo Fundo, Rua Tiradentes, 295 Centro, Passo Fundo, 99010-260, Brazil
| | | | | | | | - Michael Emig
- Lilly Deutschland GmbH, Werner-Reimers-Straße 2, Bad Homburg vor der Höhe 61352, Germany
| | - Symantha A Melemed
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - Rebecca R Hozak
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - David Ferry
- Eli Lilly and Company, 440 Route 22 East, Bridgewater, New Jersey 08807, USA
| | - C William Caldwell
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - Jaffer A Ajani
- The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, Texas 77030, USA
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Okła K, Wertel I, Polak G, Surówka J, Wawruszak A, Kotarski J. Tumor-Associated Macrophages and Myeloid-Derived Suppressor Cells as Immunosuppressive Mechanism in Ovarian Cancer Patients: Progress and Challenges. Int Rev Immunol 2016; 35:372-385. [PMID: 27644763 DOI: 10.1080/08830185.2016.1206097] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancers are complex masses of malignant cells and nonmalignant cells that create the tumor microenvironment (TME). Non-transformed cells of the TME such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) have been observed in the TME of ovarian cancer (OC) patients. Although these subsets may contribute to each step of carcinogenesis and are commonly associated with poor prognosis, still little is known about creation of the protumor microenvironment in OC. In this review, we focused on the nature and prognostic significance of TAMs and MDSCs in OC patients. Moreover, we discuss the main problems and challenges that must be overcome by researchers and clinicians to enrich our knowledge about the immunosuppressive microenvironment of cancers.
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Affiliation(s)
- Karolina Okła
- a Department of Oncological Gynaecology and Gynaecology , Medical University , Lublin , Poland
| | - Iwona Wertel
- a Department of Oncological Gynaecology and Gynaecology , Medical University , Lublin , Poland
| | - Grzegorz Polak
- a Department of Oncological Gynaecology and Gynaecology , Medical University , Lublin , Poland
| | - Justyna Surówka
- a Department of Oncological Gynaecology and Gynaecology , Medical University , Lublin , Poland
| | - Anna Wawruszak
- b Department of Biochemistry and Molecular Biology , Medical University , Lublin , Poland
| | - Jan Kotarski
- a Department of Oncological Gynaecology and Gynaecology , Medical University , Lublin , Poland
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Sundstrom A, Grabocka E, Bar-Sagi D, Mishra B. Histological Image Processing Features Induce a Quantitative Characterization of Chronic Tumor Hypoxia. PLoS One 2016; 11:e0153623. [PMID: 27093539 PMCID: PMC4836667 DOI: 10.1371/journal.pone.0153623] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 04/02/2016] [Indexed: 11/17/2022] Open
Abstract
Hypoxia in tumors signifies resistance to therapy. Despite a wealth of tumor histology data, including anti-pimonidazole staining, no current methods use these data to induce a quantitative characterization of chronic tumor hypoxia in time and space. We use image-processing algorithms to develop a set of candidate image features that can formulate just such a quantitative description of xenographed colorectal chronic tumor hypoxia. Two features in particular give low-variance measures of chronic hypoxia near a vessel: intensity sampling that extends radially away from approximated blood vessel centroids, and multithresholding to segment tumor tissue into normal, hypoxic, and necrotic regions. From these features we derive a spatiotemporal logical expression whose truth value depends on its predicate clauses that are grounded in this histological evidence. As an alternative to the spatiotemporal logical formulation, we also propose a way to formulate a linear regression function that uses all of the image features to learn what chronic hypoxia looks like, and then gives a quantitative similarity score once it is trained on a set of histology images.
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Affiliation(s)
- Andrew Sundstrom
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.,Department of Computer Science, Courant Institute of Mathematical Sciences, New York, NY, United States of America
| | - Elda Grabocka
- Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, United States of America
| | - Dafna Bar-Sagi
- Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, United States of America
| | - Bud Mishra
- Department of Computer Science, Courant Institute of Mathematical Sciences, New York, NY, United States of America
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2016:269-274. [DOI: 10.1007/978-981-287-706-2_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Senchukova MA, Ryabov АB. Modern concepts of factors for gastric cancer progression. ONKOLOGIYA. ZHURNAL IMENI P.A.GERTSENA 2016; 5:82. [DOI: 10.17116/onkolog20165182-87] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
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Becht E, Giraldo NA, Germain C, de Reyniès A, Laurent-Puig P, Zucman-Rossi J, Dieu-Nosjean MC, Sautès-Fridman C, Fridman WH. Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers. Adv Immunol 2016; 130:95-190. [DOI: 10.1016/bs.ai.2015.12.002] [Citation(s) in RCA: 153] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Wu MH, Lee WJ, Hua KT, Kuo ML, Lin MT. Macrophage Infiltration Induces Gastric Cancer Invasiveness by Activating the β-Catenin Pathway. PLoS One 2015; 10:e0134122. [PMID: 26226629 PMCID: PMC4520459 DOI: 10.1371/journal.pone.0134122] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 07/06/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Despite evidence that activated macrophages act in an inflammatory microenvironment to promote gastric tumorigenesis via β-catenin signaling, the effects of β-catenin signaling on gastric cancer cell metastasis and the relationship of these cells with surrounding tumor associated macrophages have not been directly studied. METHODS Immunohistochemical staining was employed to analyze 103 patients. An invasion assay was used to evaluate the relationship between macrophages and gastric cancer cells. β-catenin gain-of-function and loss-of-function approaches were performed. To assess the β-catenin regulation mechanism in gastric cancer cells, Western blotting and reverse-transcription polymerase chain reaction were used. RESULTS Increased density of macrophages was associated with advanced stage and poor survival. Gastric cancer cell lines co-cultured with macrophages conditioned medium showed increased nuclear accumulation of β-catenin and increased invading ability. AKT but not ERK regulated β-catenin translocation. MMP7 and CD44, both β-catenin downstream genes, were involved in macrophage-activated gastric cancer cell invasion. CONCLUSION(S) Collectively, the clinical data suggest that macrophage infiltration is correlated with increased grade and poor prognosis for gastric cancer patients who underwent radical resection. Macrophages may induce invasiveness by activating the β-catenin pathway.
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Affiliation(s)
- Ming-Hsun Wu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Jiunn Lee
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Tai Hua
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Min-Liang Kuo
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Tsan Lin
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Education & Bioethics, Graduate Institute of Medical Education & Bioethics, National Taiwan University College of Medicine, Taiwan
- * E-mail:
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Signaling Circuits and Regulation of Immune Suppression by Ovarian Tumor-Associated Macrophages. Vaccines (Basel) 2015; 3:448-66. [PMID: 26343197 PMCID: PMC4494355 DOI: 10.3390/vaccines3020448] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 05/24/2015] [Accepted: 05/26/2015] [Indexed: 12/25/2022] Open
Abstract
The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.
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Guo J, Wang B, Fu Z, Wei J, Lu W. Hypoxic Microenvironment Induces EMT and Upgrades Stem-Like Properties of Gastric Cancer Cells. Technol Cancer Res Treat 2015; 15:60-8. [PMID: 25601854 DOI: 10.1177/1533034614566413] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 12/08/2014] [Indexed: 12/18/2022] Open
Abstract
Hypoxia microenvironment, as a major feature of solid tumors, increases tumors progression and metastasis. To research whether hypoxia influences the epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) of gastric cancer cells and their cell biological behaviors. Human gastric cancer cell lines BGC823 and SGC7901 were cultivated in different oxygen tensions for proliferation, colony formation, soft agar formation, migration, and invasion analyses. Markers of EMT (E-cadherin, N-cadherin, Vimentin, and Snail) and markers of CSCs (Sox2, Oct4, and Bmi1) were investigated by real-time polymerase chain reaction, Western blotting, and immunofluorescent analysis. Cultivated at hypoxic condition, BGC823 and SGC7901 cells morphology began to change significantly. The cells pretreated under hypoxia grew faster than those cells always cultivated in normoxia. Meanwhile, hypoxia pretreatment dramatically promoted cell proliferation, migration and invasion, and increased capability of colony and soft agar colony formation. Furthermore, under hypoxia, E-cadherin decreased and N-cadherin, Vimentin, Snail, Sox2, Oct4, and Bmi1 increased both on the level of messenger RNA and protein. We drew a conclusion that the hypoxic microenvironment induced EMT, upgraded stem-like properties of gastric cancer cells, promoted invasion and metastasis, and behaved more malignantly.
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Affiliation(s)
- Jinbao Guo
- Department of Gastrointestinal Surgery, the First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Bin Wang
- Department of Cardiothoracic Surgery, the First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zhongxue Fu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jinlai Wei
- Department of Gastrointestinal Surgery, the First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Weidong Lu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Yan L, Ba N, Wu M, Zheng XK, Zhang J, Xing X, Zhang ZS. Effect of hyperthermic perfusion chemotherapy on vascular endothelial growth factor receptor 1 and matrix metalloproteinase-9 in patients with gastric cancer. Shijie Huaren Xiaohua Zazhi 2014; 22:3654-3659. [DOI: 10.11569/wcjd.v22.i24.3654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effect of hyperthermic perfusion chemotherapy on vascular endothelial growth factor receptor 1 (VEGFR-1) and matrix metalloproteinase 9 (MMP-9) in patients with gastric cancer.
METHODS: Eighty-six gastric cancer patients treated at our hospital from March 2010 to April 2013 were randomly divided into either a treatment group or a control group, with 43 cases in each group. The control group was given conventional chemotherapy, and the treatment group was given hyperthermic perfusion chemotherapy. Carbohydrate antigen 72-4 (CA72-4), VEGFR-1 and MMP-9, changes in clinical symptoms and adverse reactions were compared between before and after treatment.
RESULTS: There were no significant differences in CA72-4 value, the percentages of VEGFR-1 or MMP-9 positive cases, or the number of cases with ascites between the two groups before treatment (P > 0.05). CA72-4 value, the percentages of VEGFR-1 and MMP-9 positive cases, and the number of cases with ascites were significantly lower in the treatment group than in the control group (5.43 kU/L ± 2.07 kU/L vs 7.08 kU/L ± 3.19 kU/L, 18.60% vs 41.86%, 23.26% vs 41.86%, 7 vs 15, P < 0.05). The recurrence rates at 6 mo and 1 yr were significantly lower in the treatment group than in the control group (2.33% vs 18.6%, 13.95% vs 32.56%, P < 0.05), while the survival rates at 6 mo and 1 yr were significantly higher in the treatment group (88.37% vs 69.77%, 44.19% vs 67.44%, P < 0.05). The numbers of cases with gastrointestinal bleeding, abdominal pain, leukopenia and diarrhea were significantly less in the treatment group than in the control group (2 vs 9, 5 vs 13, 1 vs 9, 2 vs 9, P < 0.05).
CONCLUSION: Hyperthermic perfusion chemotherapy can achieve better effects than conventional chemotherapy in patients with gastric cancer, and it can reduce the levels of VEGFR-1and MMP-9, relieve clinical symptoms and decrease the relapse rate.
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Disseminated tumor cells in bone marrow of gastric cancer patients: correlation with tumor hypoxia and clinical relevance. JOURNAL OF ONCOLOGY 2014; 2014:582140. [PMID: 24669218 PMCID: PMC3942335 DOI: 10.1155/2014/582140] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 12/21/2013] [Accepted: 01/02/2014] [Indexed: 01/14/2023]
Abstract
Aim. The evaluation of the clinical relevance of disseminated tumor cells (DTCs) in bone marrow (BM) of patients with gastric cancer (GC) and their association with primary tumor hypoxia. Patients and Methods. 89 resected specimens were used. DTCs were detected using immunocytochemistry, the level of tumor hypoxia using NMR spectroscopy, CD68, CD34, VEGF, and VEGFR-1 (Flt-1) expression using immunohistochemistry, and MMP-2 and MMP-9 activity using zymography. Results. DTCs were detected in 51.4% of GC patients with M0. There was significant correlation between frequency of DTCs in BM and level of tumor hypoxia (P < 0.024). DTCs presence was accompanied with Flt-1 positivity of BM. The correlation between DTCs and tumor VEGF expression in patients with M0 was shown (P < 0.0248). Activity of MMP-2 and MMP-9 in BM was linked with DTCs in patients with M0 (P < 0.05). Overall survival (OS) of patients with M0 and DTCs was shorter than that of patients without DTCs (patients in both groups were operated only) (P = 0.0497). Conclusion. Appearance of DTCs correlates with hypoxia level in primary tumors. Detection of DTCs in GC patients may be relevant indicator for adjuvant chemotherapy using.
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Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, Movahedi K, Houbracken I, Schouppe E, Elkrim Y, Karroum O, Jordan B, Carmeliet P, Gysemans C, De Baetselier P, Mazzone M, Van Ginderachter JA. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 2013; 74:24-30. [PMID: 24220244 DOI: 10.1158/0008-5472.can-13-1196] [Citation(s) in RCA: 329] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors. However, to what extent tumor hypoxia regulates the TAM phenotype in vivo is unknown. Here, we show that the myeloid infiltrate in mouse lung carcinoma tumors encompasses two morphologically distinct CD11b(hi)F4/80(hi)Ly6C(lo) TAM subsets, designated as MHC-II(lo) and MHC-II(hi) TAM, both of which were derived from tumor-infiltrating Ly6C(hi) monocytes. MHC-II(lo) TAM express higher levels of prototypical M2 markers and reside in more hypoxic regions. Consequently, MHC-II(lo) TAM contain higher mRNA levels for hypoxia-regulated genes than their MHC-II(hi) counterparts. To assess the in vivo role of hypoxia on these TAM features, cancer cells were inoculated in prolyl hydroxylase domain 2 (PHD2)-haplodeficient mice, resulting in better-oxygenated tumors. Interestingly, reduced tumor hypoxia did not alter the relative abundance of TAM subsets nor their M2 marker expression, but specifically lowered hypoxia-sensitive gene expression and angiogenic activity in the MHC-II(lo) TAM subset. The same observation in PHD2(+/+) → PHD2(+/-) bone marrow chimeras also suggests organization of a better-oxygenized microenvironment. Together, our results show that hypoxia is not a major driver of TAM subset differentiation, but rather specifically fine-tunes the phenotype of M2-like MHC-II(lo) TAM.
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Affiliation(s)
- Damya Laoui
- Authors' Affiliations: Laboratory of Myeloid Cell Immunology, VIB; Laboratory of Cellular and Molecular Immunology; Cell Differentiation Unit, Diabetes Research Centre, Vrije Universiteit Brussel; Biomedical Magnetic Resonance Unit, U.C. Louvain, Brussels; Laboratory of Molecular Oncology and Angiogenesis; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB; and Experimental Medicine and Endocrinology, Department of Experimental Medicine, K.U. Leuven, Leuven, Belgium
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Shi Q, Pisani LJ, Lee YK, Messing S, Ansari C, Bhaumik S, Lowery L, Lee BD, Meyer DE, Daldrup-Link HE. Evaluation of the novel USPIO GEH121333 for MR imaging of cancer immune responses. CONTRAST MEDIA & MOLECULAR IMAGING 2013; 8:281-8. [PMID: 23606432 PMCID: PMC3662997 DOI: 10.1002/cmmi.1526] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 11/06/2012] [Accepted: 12/11/2012] [Indexed: 02/06/2023]
Abstract
Tumor-associated macrophages (TAM) maintain a chronic inflammation in cancers, which is associated with tumor aggressiveness and poor prognosis. The purpose of this study was to: (1) evaluate the pharmacokinetics and tolerability of the novel ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) compound GEH121333; (2) assess whether GEH121333 can serve as a MR imaging biomarker for TAM; and (3) compare tumor MR enhancement profiles between GEH121333 and ferumoxytol. Blood half-lives of GEH121333 and ferumoxytol were measured by relaxometry (n = 4 each). Tolerance was assessed in healthy rats injected with high dose GEH121333, vehicle or saline (n = 4 each). Animals were monitored for 7 days regarding body weight, complete blood counts and serum chemistry, followed by histological evaluation of visceral organs. MR imaging was performed on mice harboring MMTV-PyMT-derived breast adenocarcinomas using a 7 T scanner before and up to 72 h post-injection (p.i.) of GEH121333 (n = 10) or ferumoxytol (n = 9). Tumor R1, R2* relaxation rates were compared between different experimental groups and time points, using a linear mixed effects model with a random effect for each animal. MR data were correlated with histopathology. GEH121333 showed a longer circulation half-life than ferumoxytol. Intravenous GEH121333 did not produce significant adverse effects in rats. All tumors demonstrated significant enhancement on T1, T2 and T2*-weighted images at 1, 24, 48 and 72 h p.i. GEH121333 generated stronger tumor T2* enhancement than ferumoxytol. Histological analysis verified intracellular compartmentalization of GEH121333 by TAM at 24, 48 and 72 h p.i. MR imaging with GEH121333 nanoparticles represents a novel biomarker for TAM assessment. This new USPIO MR contrast agent provides a longer blood half-life and better TAM enhancement compared with the iron supplement ferumoxytol.
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Affiliation(s)
- Qiaoyun Shi
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA
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Raposo TP, Pires I, Carvalho MI, Prada J, Argyle DJ, Queiroga FL. Tumour-associated macrophages are associated with vascular endothelial growth factor expression in canine mammary tumours. Vet Comp Oncol 2013; 13:464-74. [PMID: 24119241 DOI: 10.1111/vco.12067] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 08/19/2013] [Accepted: 08/19/2013] [Indexed: 12/16/2022]
Abstract
Tumour-associated macrophages (TAMs) have been implicated in carcinogenesis including an important role in angiogenesis. In this study, we describe the relationship between TAMs and angiogenesis in canine mammary tumours (CMT). Formalin-fixed paraffin-embedded CMT samples [(n = 128: malignant (n = 97) and benign (n = 31)] were submitted to immunohistochemical staining to detect MAC387, vascular endothelial growth factor VEGF and CD31 expression. A statistical analysis was carried out to assess possible associations with clinicopathological variables and biological markers of tumour angiogenesis. TAMs, detected by MAC387 expression, were significantly associated with malignant CMT (P < 0.001) and VEGF positive tumours (P = 0.002) and also associated with VEGF expression within malignant CMT (P = 0.043). Associations with clinicopathological variables were found between TAMs and the presence of infiltrative growth (P = 0.031), low tubule formation (P = 0.040) and lymph node metastasis (P = 0.016). The results support the hypothesis that TAMs influence angiogenesis in CMT suggesting TAMs may represent a therapeutic target in this disease.
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Affiliation(s)
- T P Raposo
- Department of Veterinary Sciences, Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - I Pires
- CECAV, Department of Veterinary Sciences, Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - M I Carvalho
- Department of Veterinary Sciences, Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - J Prada
- CECAV, Department of Veterinary Sciences, Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - D J Argyle
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of Edinburgh, Scotland, UK
| | - F L Queiroga
- Department of Veterinary Sciences, Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal.,CECA-ICETA, University of Porto, Porto, Portugal
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Tan B, Li Y, Zhao Q, Fan L, Wang D, Liu Y. Inhibition of gastric cancer cell growth and invasion through siRNA-mediated knockdown of guanine nucleotide exchange factor Vav3. Tumour Biol 2013; 35:1481-8. [PMID: 24072493 DOI: 10.1007/s13277-013-1204-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2013] [Accepted: 09/16/2013] [Indexed: 01/21/2023] Open
Abstract
Vav3, a Rho GTPase guanine nucleotide exchange factor, is associated with tumor growth, apoptosis, invasion and metastasis, and angiogenesis. However, the role of Vav3 in gastric cancer remains unclear. In this study, Vav3 expression was blocked by specific siRNA in gastric cancer cell line MGC803. MTT was used to assay cell proliferation activity; wound healing assay and transwell assay were applied to detect cell migration and invasion ability; and qRT-PCR and Western blot were employed to detect expression levels of Vav3 as well as proliferation, migration, and invasion-related genes. The results showed that Vav3 expression in gastric cancer tissues and cell lines was significantly upregulated and was higher than that in adjacent tissues of cancer and normal gastric mucosal cell lines. Vav3 knockdown inhibited proliferation, migration, and invasion of MGC803 gastric cancer cells. The expression of P21, P27, TIMP-1, and TIMP-2 was upregulated, while proliferating cell nuclear antigen, cyclin E1, matrix metalloproteinase (MMP)-2, and MMP-7 were downregulated by Vav3 knockdown in MGC803 gastric cells. In conclusion, Vav3 is involved in the proliferation, migration, and invasion of gastric cancer cell as a tumor oncogene.
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Affiliation(s)
- Bibo Tan
- Department of General Surgery, The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, 050011, China,
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Overexpression of the HIF hydroxylase PHD3 is a favorable prognosticator for gastric cancer. Med Oncol 2013; 29:2710-5. [PMID: 22290580 DOI: 10.1007/s12032-012-0171-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2012] [Accepted: 01/17/2012] [Indexed: 10/14/2022]
Abstract
Hypoxia-induced factors (HIFs) play a central role in the adaptive mechanisms of cancer cells to survive under conditions of hypoxia. HIFs are regulated by prolyl hydroxylases (PHDs) among which PHD3 is implicated as a tumor suppressor. We aimed to correlate PHD3 expression with clinicopathologic parameters and to evaluate its prognostic significance in gastric cancer. The 101 tissue samples were collected from 83 resected stages I–IV gastric cancer patients, which were grouped as non-cancerous mucosa (n=18) and primary carcinoma (n=83). PHD3 expression was evaluated by immunohistochemistry. We adopted Pearson chi-square test, univariate analysis, multivariate analysis and Kaplan–Meier method. The positive frequency of PHD3 in cancer cells was 42.2%, whereas non-cancerous mucosa had no detectable PHD3. The expression of PHD3 increased significantly from non-cancerous mucosa to cancer. A significant difference was observed between PHD3 expression and tumor differentiation (P=0.007). The overexpression of PHD3 was associated with well differentiation. In univariate analyses, American Joint Committee on Cancer (AJCC) stage (P<0.0001), pT classification (P<0.0001), pN classification (P<0.0001), differentiation (P=0.0121), peritoneal metastasis (P=0.0006) and gross features (P=0.0104) were significantly associated with survival except PHD3 (P=0.2228) (Table 3). In multivariate analysis, AJCC stage was prognostically independent [hazard ratio (HR), 3.078; 95% confidence interval (CI), 2.228–4.252; P<0.0001]. Overexpression of PHD3 is a favorable prognosticator for gastric cancer. AJCC stage is an independent prognostic factor of gastric cancer.
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Abbondati E, Del-Pozo J, Hoather TM, Constantino-Casas F, Dobson JM. An immunohistochemical study of the expression of the hypoxia markers Glut-1 and Ca-IX in canine sarcomas. Vet Pathol 2013; 50:1063-9. [PMID: 23628694 DOI: 10.1177/0300985813486810] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Tumor hypoxia has been associated with increased malignancy, likelihood of metastasis, and increased resistance to radiotherapy and chemotherapy in human medicine. Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor that is induced by tumor hypoxia and regulates the pathways involved in cellular response and adaptation to the hostile tumor microenvironment. HIF-1 induces transcription of different proteins, including Ca-IX and Glut-1, which are considered endogenous markers of chronic hypoxia in solid tumors in humans. In this study, sections from 40 canine sarcomas (20 histiocytic sarcomas and 20 low-grade soft-tissue sarcomas) were immunostained for these markers. Expression of Glut-1 was scored based on percentage of positive staining cells (0 = <1%; 1 = 1%-50%; 2 = >50%) and intensity of cellular staining (1 = weak; 2 = strong); Ca-IX was scored based on percentage of positive cells (0 = <1%; 1 = 1%-30%; 2 = >30%). Intratumoral microvessel density was measured using CD31 to assess intratumoral neoangiogenesis. Histiocytic sarcomas showed statistically significant higher Glut-1 immunoreactivity and angiogenesis than did low-grade soft-tissue sarcomas. Intratumoral microvessel density in histiocytic sarcomas was positively associated with Glut-1 immunoreactivity score. These findings suggest a potential role of hypoxia in the biology of these tumors and may provide a base for investigation of the potential prognostic use of these markers in naturally occurring canine tumors.
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Affiliation(s)
- E Abbondati
- School of Veterinary Medicine, University of Glasgow, Bearsden, Glasgow, G611QH, UK.
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Villarejo-Campos P, Padilla-Valverde D, Martin RM, Menéndez-Sánchez P, Cubo-Cintas T, Bondia-Navarro JA, Fernández JM. Serum VEGF and VEGF-C values before surgery and after postoperative treatment in gastric cancer. Clin Transl Oncol 2013; 15:265-270. [PMID: 22855190 DOI: 10.1007/s12094-012-0908-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 06/28/2012] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Angiogenesis and lymphangiogenesis are essential processes for the formation of blood and lymphatic vessels that allow tumour growth and spread. The binding of VEGF and VEGF-C factors with their receptors (VEGFR2, VEGFR3) in endothelial cells triggers signals that regulate these processes. We compared preoperative serum VEGF and VEGF-C levels with samples obtained after completion of surgery and adjuvant treatment in patients with gastric cancer. In addition, we determined the prognostic value and relationship to survival of serum VEGF and VEGF-C levels. METHODS We used a prospective cohort study of 59 gastric cancer patients who underwent surgery. Serum VEGF and VEGF-C were measured by enzyme-linked immunosorbent assay (ELISA) the day before surgery and 6 months later, after completion of adjuvant treatment. RESULTS Serum VEGF values decreased after treatment in patients with resectable tumours (mean ± SD) (405.42 ± 298.38 vs. 306.38 ± 212.47 pg/ml; p < 0.01), poorly differentiated and undifferentiated tumours (G3, G4) (438 ± 339.71 vs. 322.47 ± 210.71 pg/ml; p = 0.01), locally advanced gastric tumours (T4 stage) (424.27 ± 323.08 vs. 333.62 ± 221.72 pg/ml; p = 0.03) and tumours with a greater number of involved regional lymph nodes (N3) (442.38 ± 311.52 vs. 337.4 ± 203.64 pg/ml; p = 0.04). Serum preoperative VEGF values over 761 pg/ml were associated with shorter patient survival. The mean overall survival time for patients with serum VEGF levels higher than 761 pg/ml was 7 ± 2.99 months (95 % CI 1.14-12.86) while for patients with serum VEGF levels of less than 761 pg/ml was 21.18 ± 2.88 (95 % CI 15.54-26.83) The mean disease-specific survival time for patients with serum VEGF levels higher than 761 pg/ml was 6.25 ± 2.53 months (95 % CI 1.29-11.21) while for patients with serum VEGF levels of less than 761 pg/ml was 27.57 ± 3.45 (95 % CI 20.80-34.35). Multivariate analysis identified preoperative serum VEGF levels as an independent prognostic factor (HR = 0.144; p = 0.03). CONCLUSIONS Serum VEGF levels decreased after the completion of treatment in patients with resected tumours, suggesting VEGF tracking may be useful in monitoring progression. Preoperative measurement of serum VEGF may help us identify patients with a poor prognosis.
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Affiliation(s)
- Pedro Villarejo-Campos
- Hospital Universitario de Ciudad Real, Carretera Piedrabuena, 20/26-A, Ciudad Real 13005, Spain.
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Chimal-Ramírez GK, Espinoza-Sánchez NA, Fuentes-Pananá EM. Protumor activities of the immune response: insights in the mechanisms of immunological shift, oncotraining, and oncopromotion. JOURNAL OF ONCOLOGY 2013; 2013:835956. [PMID: 23577028 PMCID: PMC3612474 DOI: 10.1155/2013/835956] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 01/25/2013] [Indexed: 12/15/2022]
Abstract
Experimental and clinical studies indicate that cells of the innate and adaptive immune system have both anti- and pro-tumor activities. This dual role of the immune system has led to a conceptual shift in the role of the immune system's regulation of cancer, in which immune-tumor cell interactions are understood as a dynamic process that comprises at least five phases: immunosurveillance, immunoselection, immunoescape, oncotraining, and oncopromotion. The tumor microenvironment shifts immune cells to perform functions more in tune with the tumor needs (oncotraining); these functions are related to chronic inflammation and tissue remodeling activities. Among them are increased proliferation and survival, increased angiogenesis and vessel permeability, protease secretion, acquisition of migratory mesenchymal characteristics, and self-renewal properties that altogether promote tumor growth and metastasis (oncopromotion). Important populations in all these pro-tumor processes are M2 macrophages, N2 neutrophils, regulatory T cells, and myeloid derived suppressor cells; the main effectors molecules are CSF-1, IL-6, metalloproteases, VEGF, PGE-2, TGF- β , and IL-10. Cancer prognosis correlates with densities and concentrations of protumoral populations and molecules, providing ideal targets for the intelligent design of directed preventive or anticancer therapies.
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Affiliation(s)
- G. K. Chimal-Ramírez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Colonia Doctores, 06725 Delegación Cuauhtémoc, DF, Mexico
- Programa de Doctorado en Ciencias Quimicobiológicas del Instituto Politécnico Nacional (IPN), Mexico
| | - N. A. Espinoza-Sánchez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Colonia Doctores, 06725 Delegación Cuauhtémoc, DF, Mexico
- Programa de Doctorado en Ciencias Biomédicas de la Universidad Autónoma de México (UNAM), Mexico
| | - E. M. Fuentes-Pananá
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Colonia Doctores, 06725 Delegación Cuauhtémoc, DF, Mexico
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Li JY, Zhang Y, Zhang WH, Jia S, Kang Y, Zhu XY. Differential distribution of miR-20a and miR-20b may underly metastatic heterogeneity of breast cancers. Asian Pac J Cancer Prev 2013; 13:1901-6. [PMID: 22901144 DOI: 10.7314/apjcp.2012.13.5.1901] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The discovery that microRNA (miRNA) regulates metastasis provide a principal molecular basis for tumor heterogeneity. A characteristic of solid tumors is their heterogenous distribution of blood vessels, with significant hypoxia occurring in regions (centers of tumor) of low blood flow. It is necessary to discover the mechanism of breast cancer metastasis in relation to the fact that there is a differential distribution of crucial microRNA in tumors from centers to edges. METHODS Breast tissues from 48 patients (32 patients with breast cancer) were classified into the high invasive and metastatic group (HIMG), low invasive and metastatic group (LIMG), and normal group. Samples were collected from both the centers and edges of all tumors. The first six specimens were detected by microRNA array, and the second ten specimens were detected by real-time qRT- PCR and Western blot analyses. Correlation analysis was performed between the miRNAs and target proteins. RESULTS The relative content of miR-20a and miR-20b was lower in the center of the tumor than at the edge in the LIMG, lower at the edge of the tumor than in the center in the HIMG, and lower in breast cancer tissues than in normal tissues. VEGF-A and HIF-1alpha mRNA levels were higher in the HIMG than in the LIMG, and levels were higher in both groups than in the normal group; there was no difference in mRNA levels between the edge and center of the tumor. VEGF-A and HIF-1alpha protein levels were higher in the HIMG than in the LIMG, and protein levels in both groups were higher than in the normal group; there was a significant difference in protein expression between the edge and center of the tumor. Correlation analysis showed that the key miRNAs (miR-20a and miR-20b) negatively correlated with the target proteins (VEGF-A and HIF-1alpha). CONCLUSIONS Our data suggest that miR-20a and miR-20b are differentially distributed in breast cancer, while VEGF-A and HIF-1alpha mRNA had coincident distributions, and VEGF-A and HIF-1alpha proteins had uneven and opposing distributions to the miRNAs. It appears that one of the most important facets underlying metastatic heterogeneity is the differential distribution of miR-20a and miR-20b and their regulation of target proteins.
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Affiliation(s)
- Jian-Yi Li
- Department of Breast Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
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