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Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
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Majid U, Bergsland CH, Sveen A, Bruun J, Eilertsen IA, Bækkevold ES, Nesbakken A, Yaqub S, Jahnsen FL, Lothe RA. The prognostic effect of tumor-associated macrophages in stage I-III colorectal cancer depends on T cell infiltration. Cell Oncol (Dordr) 2024; 47:1267-1276. [PMID: 38407700 PMCID: PMC11322253 DOI: 10.1007/s13402-024-00926-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are associated with unfavorable patient prognosis in many cancer types. However, TAMs are a heterogeneous cell population and subsets have been shown to activate tumor-infiltrating T cells and confer a good patient prognosis. Data on the prognostic value of TAMs in colorectal cancer are conflicting. We investigated the prognostic effect of TAMs in relation to tumor-infiltrating T cells in colorectal cancers. METHODS The TAM markers CD68 and CD163 were analyzed by multiplex fluorescence immunohistochemistry and digital image analysis on tissue microarrays of 1720 primary colorectal cancers. TAM density in the tumor stroma was scored in relation to T cell density (stromal CD3+ and epithelial CD8+ cells) and analyzed in Cox proportional hazards models of 5-year relapse-free survival. Multivariable survival models included clinicopathological factors, MSI status and BRAFV600E mutation status. RESULTS High TAM density was associated with a favorable 5-year relapse-free survival in a multivariable model of patients with stage I-III tumors (p = 0.004, hazard ratio 0.94, 95% confidence interval 0.90-0.98). However, the prognostic effect was dependent on tumoral T-cell density. High TAM density was associated with a good prognosis in patients who also had high T-cell levels in their tumors, while high TAM density was associated with poorer prognosis in patients with low T-cell levels (pinteraction = 0.0006). This prognostic heterogeneity was found for microsatellite stable tumors separately. CONCLUSIONS This study supported a phenotypic heterogeneity of TAMs in colorectal cancer, and showed that combined tumor immunophenotyping of multiple immune cell types improved the prediction of patient prognosis.
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Affiliation(s)
- Umair Majid
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Christian Holst Bergsland
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jarle Bruun
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Ina Andrassy Eilertsen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Espen S Bækkevold
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
- Institute of Oral Biology, University of Oslo, Oslo, Norway
| | - Arild Nesbakken
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Sheraz Yaqub
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Hepatobiliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Frode L Jahnsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
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Weng J, Chen J. Comprehensive bioinformatics analysis of the role of VWF in the tumor microenvironment of malignant mesothelioma. Medicine (Baltimore) 2023; 102:e35579. [PMID: 37832118 PMCID: PMC10578691 DOI: 10.1097/md.0000000000035579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
To explore the influence and effect of tumor microenvironment on the development of malignant mesothelioma using machine learning methods. 87 open cases were downloaded from the Cancer Genome Atlas database including transcriptome data, clinical data, and mutation data. The immune, stromal, and estimate scores were calculated for each case by using the ESTIMATE algorithm, and then the cases were grouped according to high and low stromal scores to predict all-cause survival in malignant mesothelioma cases. Their mutation data were analyzed to reveal the differences in mutated genes between the 2 groups, and then the von Willebrand factor (VWF) and FCRL3 genes were identified according to the intersection of DEGs and high-frequency mutated genes. Lastly, the correlation between VWF and the immune checkpoint of 22 kinds of immune cells was analyzed by using the CIBERSORT package of R software. A significant difference was found in the survival time of patients between the high and low stromal score groups. High expression of the VWF gene was negatively correlated with the prognosis of malignant mesothelioma, and the expression of VWF was positively correlated with naive B cells and activated CD4 memory T cells and negatively correlated with NK cells. The results revealed that high expression of VWF may involve in the development of malignant mesothelioma, and the anti-CTLA4 immune checkpoint treatment may have certain efficacy.
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Affiliation(s)
- Jiren Weng
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jing Chen
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
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4
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Zhang L, Qian Y. An epithelial-mesenchymal transition-related prognostic model for colorectal cancer based on weighted gene co-expression network analysis. J Int Med Res 2022; 50:3000605221140683. [PMID: 36510452 DOI: 10.1177/03000605221140683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE To identify susceptibility modules and genes for colorectal cancer (CRC) using weighted gene co-expression network analysis (WGCNA). METHODS Four microarray datasets were downloaded from the Gene Expression Omnibus database. We divided the tumor samples into three subgroups based on consensus clustering of gene expression, and analyzed the correlations between the subgroups and clinical features. The genetic features of the subgroups were investigated by gene set enrichment analysis (GSEA). A gene expression network was constructed using WGCNA, and a protein-protein interaction (PPI) network was used to identify the key genes. Gene modules were annotated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. RESULTS We divided the cancer cases into three subgroups based on consensus clustering (subgroups I, II, III). The green module identified by WGCNA was correlated with clinical characteristics. Ten key genes were identified according to their degree of connectivity in the protein-protein interaction network: FYN, SEMA3A, AP2M1, L1CAM, NRP1, TLN1, VWF, ITGB3, ILK, and ACTN1. CONCLUSION We identified 10 hub genes as candidate biomarkers for CRC. These key genes may provide a theoretical basis for targeted therapy against CRC.
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Affiliation(s)
- Lina Zhang
- Department of General Surgery, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang, China
| | - Yucheng Qian
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
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Stage I-IV Colorectal Cancer Prognosis Can Be Predicted by Type and Number of Intratumoral Macrophages and CLEVER-1 + Vessel Density. Cancers (Basel) 2021; 13:cancers13235988. [PMID: 34885098 PMCID: PMC8656733 DOI: 10.3390/cancers13235988] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Tumor-associated macrophages can either promote or prevent cancer growth depending on factors such as macrophage polarization status, tumor type, and disease stage. Macrophages and vessels interact with each other, and the number of lymphatic vessels also affects cancer survival. CLEVER-1 is a protein expressed both on immunosuppressive M2 macrophages and lymphatic vessels. The aim of this study was to validate our previous results regarding the prognostic role of CLEVER-1+ macrophages, CD68+ macrophages, and CLEVER-1+ lymphatic vessels in stage I–IV colorectal cancer. The results indicate that the prognostic role of tumor-associated macrophages and lymphatic vessels changes during disease progression. The findings resemble our earlier results, but are not completely equal, which may be due to the different types of tumor samples used in the two studies (whole section vs. tissue microarray). Abstract Macrophages, which are key players in the tumor microenvironment and affect the prognosis of many cancers, interact with lymphatic vessels in tumor tissue. However, the prognostic role of tumor-associated macrophages (TAM) and lymphatic vessels in human colorectal cancer (CRC) remains controversial. We investigated the prognostic role of CD68+ and CLEVER-1+ (common lymphatic endothelial and vascular endothelial receptor 1) TAMs in addition to CLEVER-1+ lymphatic vessels in 498 stage I–IV CRC patients. The molecular markers were detected by immunohistochemical (IHC) analysis. The results showed that, in early stage I CRC and in young patients (age below median, ≤67.4 years), a high number of CD68+ and CLEVER-1+ TAMs was associated with longer disease-specific survival (DSS). In early stage I CRC, high intratumoral CLEVER-1+ lymphatic vessel density (LVD) predicted a favorable prognosis, whereas the opposite pattern was observed in stage II CRC. The highest density of CLEVER-1+ lymphatic vessels was found in metastatic disease. The combination of intratumoral CLEVER-1+ lymphatic vesselhigh + CD68+ TAMlow was associated with poor DSS in stage I–IV rectal cancer. The present results indicate that the prognostic significance of intratumoral macrophages and CLEVER-1+ lymphatic vessels differs according to disease stage, reflecting the dynamic changes occurring in the tumor microenvironment during disease progression.
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Interpretable survival prediction for colorectal cancer using deep learning. NPJ Digit Med 2021; 4:71. [PMID: 33875798 PMCID: PMC8055695 DOI: 10.1038/s41746-021-00427-2] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 02/26/2021] [Indexed: 02/07/2023] Open
Abstract
Deriving interpretable prognostic features from deep-learning-based prognostic histopathology models remains a challenge. In this study, we developed a deep learning system (DLS) for predicting disease-specific survival for stage II and III colorectal cancer using 3652 cases (27,300 slides). When evaluated on two validation datasets containing 1239 cases (9340 slides) and 738 cases (7140 slides), respectively, the DLS achieved a 5-year disease-specific survival AUC of 0.70 (95% CI: 0.66–0.73) and 0.69 (95% CI: 0.64–0.72), and added significant predictive value to a set of nine clinicopathologic features. To interpret the DLS, we explored the ability of different human-interpretable features to explain the variance in DLS scores. We observed that clinicopathologic features such as T-category, N-category, and grade explained a small fraction of the variance in DLS scores (R2 = 18% in both validation sets). Next, we generated human-interpretable histologic features by clustering embeddings from a deep-learning-based image-similarity model and showed that they explained the majority of the variance (R2 of 73–80%). Furthermore, the clustering-derived feature most strongly associated with high DLS scores was also highly prognostic in isolation. With a distinct visual appearance (poorly differentiated tumor cell clusters adjacent to adipose tissue), this feature was identified by annotators with 87.0–95.5% accuracy. Our approach can be used to explain predictions from a prognostic deep learning model and uncover potentially-novel prognostic features that can be reliably identified by people for future validation studies.
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7
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Bögels M, Braster R, Nijland PG, Gül N, van de Luijtgaarden W, Fijneman RJA, Meijer GA, Jimenez CR, Beelen RHJ, van Egmond M. Carcinoma origin dictates differential skewing of monocyte function. Oncoimmunology 2021; 1:798-809. [PMID: 23162747 PMCID: PMC3489735 DOI: 10.4161/onci.20427] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Macrophages are versatile cells, which phenotype is profoundly influenced by their environment. Pro-inflammatory classically activated or M1 macrophages, and anti-inflammatory alternatively-activated or M2 macrophages represent two extremes of a continuum of functional states. Consequently, macrophages that are present in tumors can exert tumor-promoting and tumor-suppressing activity, depending on the tumor milieu. In this study we investigated how human monocytes-the precursors of macrophages-are influenced by carcinoma cells of different origin. We demonstrate that monocytes, stimulated with breast cancer supernatant, showed increased expression of interleukin (IL)-10, IL-8 and chemokines CCL17 and CCL22, which are associated with an alternatively-activated phenotype. By contrast, monocytes that were cultured in supernatants of colon cancer cells produced more pro-inflammatory cytokines (e.g., IL-12 and TNFα) and reactive oxygen species. Secretome analysis revealed differential secretion of proteins by colon and breast cancer cell lines, of which the proteoglycan versican was exclusively secreted by colon carcinoma cell lines. Reducing active versican by blocking with monoclonal antibodies or shRNA diminished pro-inflammatory cytokine production by monocytes. Thus, colon carcinoma cells polarize monocytes toward a more classically-activated anti-tumorigenic phenotype, whereas breast carcinomas predispose monocytes toward an alternatively activated phenotype. Interestingly, presence of macrophages in breast or colon carcinomas correlates with poor or good prognosis in patients, respectively. The observed discrepancy in macrophage activation by either colon or breast carcinoma cells may therefore explain the dichotomy between patient prognosis and macrophage presence in these different tumors. Designing new therapies, directing development of monocytes toward M1 activated tumor macrophages in cancer patients, may have great clinical benefits.
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Affiliation(s)
- Marijn Bögels
- Department of Surgery; VU University Medical Center; Amsterdam, The Netherlands ; Department of Molecular Cell Biology and Immunology; VU University Medical Center; Amsterdam, The Netherlands
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8
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Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont A, Fridman WH, Sautès-Fridman C, Ma Y, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology 2021; 1:1323-1343. [PMID: 23243596 PMCID: PMC3518505 DOI: 10.4161/onci.22009] [Citation(s) in RCA: 192] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8+ cytotoxic T lymphocytes, Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4+CD25+FOXP3+ regulatory T cells, Th2 CD4+ T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that—at least in some clinical settings—the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies.
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Affiliation(s)
- Laura Senovilla
- Institut Gustave Roussy; Villejuif, France ; Université Paris-Sud/Paris XI; Orsay, France ; INSERM, U848; Villejuif, France
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9
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Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer 2020; 20:662-680. [PMID: 32753728 DOI: 10.1038/s41568-020-0285-7] [Citation(s) in RCA: 1023] [Impact Index Per Article: 204.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/22/2020] [Indexed: 12/15/2022]
Abstract
The international American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumour-node-metastasis (TNM) staging system provides the current guidelines for the classification of cancer. However, among patients within the same stage, the clinical outcome can be very different. More recently, a novel definition of cancer has emerged, implicating at all stages a complex and dynamic interaction between tumour cells and the immune system. This has enabled the definition of the immune contexture, representing the pre-existing immune parameters associated with patient survival. Even so, the role of distinct immune cell types in modulating cancer progression is increasingly emerging. An immune-based assay named the 'Immunoscore' was defined to quantify the in situ T cell infiltrate and was demonstrated to be superior to the AJCC/UICC TNM classification for patients with colorectal cancer. This Review provides a broad overview of the main immune parameters positively or negatively shaping cancer development, including the Immunoscore, and their prognostic and predictive value. The importance of the immune system in cancer control is demonstrated by the requirement for a pre-existing intratumour adaptive immune response for effective immunotherapies, such as checkpoint inhibitors. Finally, we discuss how the combination of multiple immune parameters, rather than individual ones, might increase prognostic and/or predictive power.
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Affiliation(s)
- Daniela Bruni
- INSERM, Laboratory of Integrative Cancer Immunology; Équipe Labellisée Ligue Contre le Cancer; Sorbonne Université; Sorbonne Paris Cité; Université de Paris; Centre de Recherche des Cordeliers, Paris, France
| | - Helen K Angell
- Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Jérôme Galon
- INSERM, Laboratory of Integrative Cancer Immunology; Équipe Labellisée Ligue Contre le Cancer; Sorbonne Université; Sorbonne Paris Cité; Université de Paris; Centre de Recherche des Cordeliers, Paris, France.
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10
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Ruder B, Becker C. At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine. Cells 2020; 9:E2162. [PMID: 32987848 PMCID: PMC7601053 DOI: 10.3390/cells9102162] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/17/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022] Open
Abstract
Macrophages are part of the innate immunity and are key players for the maintenance of intestinal homeostasis. They belong to the group of mononuclear phagocytes, which exert bactericidal functions and help to clear apoptotic cells. Moreover, they play essential roles for the maintenance of epithelial integrity and tissue remodeling during wound healing processes and might be implicated in intestinal tumor development. Macrophages are antigen-presenting cells and secrete immune-modulatory factors, like chemokines and cytokines, which are necessary to activate other intestinal immune cells and therefore to shape immune responses in the gut. However, overwhelming activation or increased secretion of pro-inflammatory cytokines might also contribute to the pathogenesis of inflammatory bowel disease. Presently, intestinal macrophages are in the center of intense studies, which might help to develop new therapeutic strategies to counteract the development or treat already existing inflammatory diseases in the gut. In this review, we focus on the origin of intestinal macrophages and, based on current knowledge, discuss their role in the gut during homeostasis and inflammation, as well as during intestinal wound healing and tumor development.
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Affiliation(s)
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Hartmannstr. 14, 91052 Erlangen, Germany;
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11
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Bi Y, Shirure VS, Liu R, Cunningham C, Ding L, Meacham JM, Goedegebuure SP, George SC, Fields RC. Tumor-on-a-chip platform to interrogate the role of macrophages in tumor progression. Integr Biol (Camb) 2020; 12:221-232. [PMID: 32930334 DOI: 10.1093/intbio/zyaa017] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/20/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023]
Abstract
Tumor-infiltrating leukocytes, in particular macrophages, play an important role in tumor behavior and clinical outcome. The spectrum of macrophage subtypes ranges from antitumor 'M1'-type to protumor 'M2'-type macrophages. Tumor-associated macrophages (TAMs) typically display phenotypic features of both M1 and M2, and the population distribution is thought to be dynamic and evolves as the tumor progresses. However, our understanding of how TAMs impact the tumor microenvironment remains limited by the lack of appropriate 3D in vitro models that can capture cell-cell dynamics at high spatial and temporal resolution. Using our recently developed microphysiological 'tumor-on-a-chip' (TOC) device, we present here our findings on the impact of defined macrophage subsets on tumor behavior. The TOC device design contains three adjacent and connected chambers in which both the upper and lower chambers are loaded with tumor cells, whereas the central chamber contains a dynamic, perfused, living microvascular network. Introduction of human pancreatic or colorectal cancer cells together with M1-polarized macrophages significantly inhibited tumor growth and tumor-induced angiogenesis. Protein analysis and antibody-based neutralization studies confirmed that these effects were mediated through production of C-X-C motif chemokines (CXCL9), CXCL10 and CXCL11. By contrast, M2-macrophages mediated increased tumor cell migration into the vascularized chamber and did not inhibit tumor growth or angiogenesis. In fact, single-cell RNA sequencing showed that M2 macrophages further segregated endothelial cells into two distinct subsets, corresponding to static cells in vessels versus active cells involved in angiogenesis. The impact of M2 macrophages was mediated mostly by production of matrix metalloproteinase 7 and angiopoietin 2. In summary, our data demonstrate the utility of the TOC device to mechanistically probe biological questions in a 3D in vitro microenvironment.
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Affiliation(s)
- Ye Bi
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Venktesh S Shirure
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA
| | - Ruiyang Liu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.,McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Cassandra Cunningham
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Li Ding
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.,McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - J Mark Meacham
- Department of Mechanical Engineering & Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - S Peter Goedegebuure
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Steven C George
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA
| | - Ryan C Fields
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
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12
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Shabo I, Svanvik J, Lindström A, Lechertier T, Trabulo S, Hulit J, Sparey T, Pawelek J. Roles of cell fusion, hybridization and polyploid cell formation in cancer metastasis. World J Clin Oncol 2020; 11:121-135. [PMID: 32257843 PMCID: PMC7103524 DOI: 10.5306/wjco.v11.i3.121] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/02/2020] [Accepted: 03/01/2020] [Indexed: 02/06/2023] Open
Abstract
Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE 171 77, Sweden
- Patient Area of Breast Cancer, Sarcoma and Endocrine Tumours, Theme Cancer, Karolinska University Hospital, Stockholm SE 171 76, Sweden
| | - Joar Svanvik
- The Transplant Institute, Sahlgrenska University Hospital, Gothenburg SE 413 45, Sweden
- Division of Surgery, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 83, Sweden
| | - Annelie Lindström
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 85, Sweden
| | - Tanguy Lechertier
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Sara Trabulo
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - James Hulit
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Tim Sparey
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - John Pawelek
- Department of Dermatology and the Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
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Alexander PG, McMillan DC, Park JH. The local inflammatory response in colorectal cancer - Type, location or density? A systematic review and meta-analysis. Cancer Treat Rev 2019; 83:101949. [PMID: 31869737 DOI: 10.1016/j.ctrv.2019.101949] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role alongside TNM assessment in dictating future management. However, there is wide disagreement regarding the most efficacious and cost-effective method of assessment. METHODS A comprehensive literature search was performed of EMBASE, MedLine and PubMed as well as an assessment of references to identify all relevant studies relating to the assessment of the peri-tumoural inflammatory response or TILs and prognosis in colorectal cancer (CRC). A meta-analysis was performed of 67 studies meeting the REMARK criteria using RevMan software. RESULTS Intratumoural assessment of both CD3 and CD8 in CRC were significant for disease-free survival (DFS) (combined HRs 0.46; 95%CI: 0.39-0.54 and 0.54; 95%CI: 0.45-0.65), as well as overall survival (OS) and disease-specific survival (DSS). The same was true for assessment of CD3 and CD8 at the invasive margin (DFS: combined HRs 0.45; 95%CI: 0.33-0.61 and 0.51; 95%CI: 0.41-0.62). However, similar fixed effects summaries were also observed for H&E-based methods, like Klintrup-Makinen grade (DFS: HR 0.62; 95%CI: 0.43-0.88). Furthermore, inflammatory assessments were independent of MSI status. CONCLUSION The evidence suggests that it is the density of a co-ordinated local inflammatory infiltrate that confers survival benefit, rather than any individual immune cell subtype. Furthermore, the location of individual cells within the tumour microenvironment does not appear to influence survival. The authors advocate a standardised assessment of the local inflammatory response, but caution against emphasizing the importance of any individual immune cell subtype.
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Affiliation(s)
| | | | - James H Park
- School of Medicine, University of Glasgow, Glasgow, United Kingdom
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14
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An increase in the peripheral lymphocyte-to-monocyte ratio after primary site resection is associated with a prolonged survival in unresectable colorectal carcinoma. Surg Today 2019; 50:604-614. [PMID: 31786682 DOI: 10.1007/s00595-019-01927-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 11/18/2019] [Indexed: 12/14/2022]
Abstract
PURPOSE The prognostic benefits of primary tumor resection in patients with unresectable distant metastatic colorectal cancer remain unclear. A high pre-treatment lymphocyte-to-monocyte ratio (LMR) was previously shown to be associated with a better prognosis. We assessed whether or not primary tumor resection was associated with an improved survival if the peripheral lymphocyte-to-monocyte ratio increased after primary site resection. METHODS The survival in 64 and 59 patients with and without primary tumor resection, respectively, was retrospectively compared. After resection, the survival in 39 patients with a postoperatively increased LMR (LMR-increase) and 25 patients with a decreased LMR (LMR-decrease) was compared. RESULTS Primary tumor resection prolonged the median survival more frequently in cases of non-differentiated adenocarcinoma, obstructive symptoms, high serum albumin levels, and no lymph-node metastasis than in others. Cox regression showed that the potential independent prognostic variable was non-resection of the primary lesion. After resection, the median survival in the LMR-increase vs. LMR-decrease groups was significantly different (27.3 vs. 20.8 months). There were no marked differences in patient background characteristics between the groups, except for in the number of pre-operative peripheral blood lymphocytes. The resected specimens showed significantly lower CD8+:CD163+ invading leukocyte ratios in the LMR-increase group than in the LMR-decrease group. CONCLUSIONS Primary tumor resection in patients with unresectable metastatic colorectal cancer may be associated with an improved survival, especially when the LMR is increased after primary tumor resection.
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15
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Freire Valls A, Knipper K, Giannakouri E, Sarachaga V, Hinterkopf S, Wuehrl M, Shen Y, Radhakrishnan P, Klose J, Ulrich A, Schneider M, Augustin HG, Ruiz de Almodovar C, Schmidt T. VEGFR1 + Metastasis-Associated Macrophages Contribute to Metastatic Angiogenesis and Influence Colorectal Cancer Patient Outcome. Clin Cancer Res 2019; 25:5674-5685. [PMID: 31239322 DOI: 10.1158/1078-0432.ccr-18-2123] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 05/14/2019] [Accepted: 06/20/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence.Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence. RESULTS The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence. CONCLUSIONS Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.
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Affiliation(s)
- Aida Freire Valls
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany.,Biochemistry Center Heidelberg (BZH), Heidelberg University, Heidelberg, Germany
| | - Karl Knipper
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Evangelia Giannakouri
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany.,European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Víctor Sarachaga
- Biochemistry Center Heidelberg (BZH), Heidelberg University, Heidelberg, Germany
| | - Sascha Hinterkopf
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Michael Wuehrl
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Ying Shen
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Praveenkumar Radhakrishnan
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Johannes Klose
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Alexis Ulrich
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany.,European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Carmen Ruiz de Almodovar
- Biochemistry Center Heidelberg (BZH), Heidelberg University, Heidelberg, Germany.,European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.,Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Thomas Schmidt
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany.
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Lo Re D, Montagner D, Tolan D, Di Sanza C, Iglesias M, Calon A, Giralt E. Increased immune cell infiltration in patient-derived tumor explants treated with Traniplatin: an original Pt(iv) pro-drug based on Cisplatin and Tranilast. Chem Commun (Camb) 2018; 54:8324-8327. [PMID: 29796549 DOI: 10.1039/c8cc02071j] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Elevated intra-tumoral immune infiltrate is associated with an improved prognosis in cancer of distinct origins. Traniplatin (TPT) is a novel platinum(iv) pro-drug based on Cisplatin (CDDP) and the marketed drug Tranilast. When compared in vitro to Cisplatin, TPT showed increased cytotoxic activity against colon and lung cancer cells but decreased activity against immune cells. In addition, TPT efficiency was evaluated in tumor explants derived from colorectal cancer samples from patients subjected to intended curative surgery. TPT induced strong intra-tumoral cytotoxic activity yet was associated with an elevated presence of immune cell infiltrate, suggesting a reduced cytotoxic activity against immune cells in colorectal cancer.
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Affiliation(s)
- Daniele Lo Re
- Institute for Research in Biomedicine (IRB Barcelona), C/Baldiri Reixac 10, Barcelona, E-08028, Spain.
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17
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Xi HQ, Zhang KC, Li JY, Cui JX, Gao YH, Wei B, Huang D, Chen L. RNAi-mediated inhibition of Lgr5 leads to decreased angiogenesis in gastric cancer. Oncotarget 2018; 8:31581-31591. [PMID: 28404940 PMCID: PMC5458231 DOI: 10.18632/oncotarget.15770] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is a novel gastric cancer marker. However, it is unclear whether it can play roles in tumor angiogenesis. In this study, we aim to investigate the role of Lgr5 on gastric cancer angiogenesis. Lgr5, VEGF expression levels and microvessel density (MVD) were detected in tumor tissue. Then, Lgr5 mRNA was downregulated by small interference RNA technique. Western blotting and real-time quantitative PCR (qRT-PCR) were performed to detect the expression of Lgr5 and VEGF protein and mRNA in Lgr5 siRNA-transfected gastric cancer cells. The effect of silencing Lgr5 on angiogenesis was examined by assessing human umbilical vein endothelia cell (HUVEC) capillary tube formation. The results indicated that Lgr5 expression was upregulated in gastric cancer and positively correlated with VEGF (r=0.305, P=0.001) and MVD (r=0.312, P=0.001). Silencing of Lgr5 expression resulted in suppression of VEGF mRNA and protein (all P=0.001). Moreover, when HUVECs were stimulated with conditioned medium from Lgr5 siRNA-transfected gastric cancer cells, tube formation was significantly decreased (2.51 ± 0.19 mm/mm2) compared with the treatment with regular cell culture medium (DMEM) (7.34 ± 0.30 mm/mm2) or medium from control siRNA-transfected cells (7.18 ± 0.33 mm/mm2) (all P=0.001). In conclusion, Lgr5 plays important roles in angiogenesis. Lgr5-specific siRNA could be designed into an effective therapeutic agent to inhibit gastric cancer angiogenesis.
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Affiliation(s)
- Hong-Qing Xi
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Ke-Cheng Zhang
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Ji-Yang Li
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Jian-Xin Cui
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Yun-He Gao
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Bo Wei
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Dongsheng Huang
- Department of General Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Lin Chen
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
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18
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GATA3-induced vWF upregulation in the lung adenocarcinoma vasculature. Oncotarget 2017; 8:110517-110529. [PMID: 29299165 PMCID: PMC5746400 DOI: 10.18632/oncotarget.22806] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 11/13/2017] [Indexed: 12/29/2022] Open
Abstract
Lung adenocarcinoma (LAC) is the leading cause of cancer-related death worldwide. Aberrant expression of genes expressed preferentially in the lung tumor vasculature may yield clues for prognosis and treatment. Von Willebrand factor (vWF) is a large multifunctional glycoprotein with a well-known function in hemostasis. However, vWF has been reported to exert an anti-tumor effect, independent of its role in hemostasis. We investigated the expression of vWF in LAC through immunohistochemical staining of tumor tissue microarrays (TMAs). We found that vWF was overexpressed preferentially in the tumor vasculature of LAC compared with the adjacent tissue vasculature. Consistently, elevated vWF expression was found in endothelial cells (ECs) of fresh human LAC tissues and transplanted mouse LAC tissues. To understand the mechanism underlying vWF up-regulation in LAC vessels, we established a co-culture system. In this system, conditioned media (CM) collected from A549 cells increased vWF expression in human umbilical vein endothelial cells (HUVECs), suggesting enhanced expression is regulated by the LAC secretome. Subsequent studies revealed that the transcription factor GATA3, but not ERG, a known regulator of vWF transcription in vascular cells, mediated the vWF elevation. Chromatin immunoprecipitation (ChIP) assays validated that GATA3 binds directly to the +220 GATA binding motif on the human vWF promoter and A549 conditioned media significantly increases the binding of GATA3. Taken together, we demonstrate that vWF expression in ECs of LAC is elevated by the cancer cell-derived secretome through enhanced GATA3-mediated transcription.
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Srivatsa S, Paul MC, Cardone C, Holcmann M, Amberg N, Pathria P, Diamanti MA, Linder M, Timelthaler G, Dienes HP, Kenner L, Wrba F, Prager GW, Rose-John S, Eferl R, Liguori G, Botti G, Martinelli E, Greten FR, Ciardiello F, Sibilia M. EGFR in Tumor-Associated Myeloid Cells Promotes Development of Colorectal Cancer in Mice and Associates With Outcomes of Patients. Gastroenterology 2017; 153:178-190.e10. [PMID: 28400195 PMCID: PMC5766132 DOI: 10.1053/j.gastro.2017.03.053] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 03/13/2017] [Accepted: 03/27/2017] [Indexed: 01/20/2023]
Abstract
BACKGROUND & AIMS Inhibitors of the epidermal growth factor receptor (EGFR) are the first-line therapy for patients with metastatic colorectal tumors without RAS mutations. However, EGFR inhibitors are ineffective in these patients, and tumor level of EGFR does not associate with response to therapy. We screened human colorectal tumors for EGFR-positive myeloid cells and investigated their association with patient outcome. We also performed studies in mice to evaluate how EGFR expression in tumor cells and myeloid cells contributes to development of colitis-associated cancer and ApcMin-dependent intestinal tumorigenesis. METHODS We performed immunohistochemical and immunofluorescent analyses of 116 colorectal tumor biopsies to determine levels of EGFR in tumor and stroma; we also collected information on tumor stage and patient features and outcomes. We used the Mann-Whitney U and Kruskal-Wallis tests to correlate tumor levels of EGFR with tumor stage, and the Kaplan-Meier method to estimate patients' median survival time. We performed experiments in mice lacking EGFR in intestinal epithelial cells (Villin-Cre; Egfrf/f and Villin-CreERT2; Egfrf/f mice) or myeloid cells (LysM-Cre; Egfrf/f mice) on a mixed background. These mice were bred with ApcMin/+ mice; colitis-associated cancer and colitis were induced by administration of dextran sodium sulfate (DSS), with or without azoxymethane (AOM), respectively. Villin-CreERT2 was activated in developed tumors by administration of tamoxifen to mice. Littermates that expressed full-length EGFR were used as controls. Intestinal tissues were collected; severity of colitis, numbers and size of tumors, and intestinal barrier integrity were assessed by histologic, immunohistochemical, quantitative reverse transcription polymerase chain reaction, and flow cytometry analyses. RESULTS We detected EGFR in myeloid cells in the stroma of human colorectal tumors; myeloid cell expression of EGFR associated with tumor metastasis and shorter patient survival time. Mice with deletion of EGFR from myeloid cells formed significantly fewer and smaller tumors than the respective EGFR-expressing controls in an ApcMin/+ background as well as after administration of AOM and DSS. Deletion of EGFR from intestinal epithelial cells did not affect tumor growth. Furthermore, tamoxifen-induced deletion of EGFR from epithelial cells of established intestinal tumors in mice given AOM and DSS did not reduce tumor size. EGFR signaling in myeloid cells promoted activation of STAT3 and expression of survivin in intestinal tumor cells. Mice with deletion of EGFR from myeloid cells developed more severe colitis after DSS administration, characterized by increased intestinal inflammation and intestinal barrier disruption, than control mice or mice with deletion of EGFR from intestinal epithelial cells. EGFR-deficient myeloid cells in the colon of DSS-treated LysM-Cre; Egfrf/f mice had reduced expression of interleukin 6 (IL6), and epithelial STAT3 activation was reduced compared with controls. Administration of recombinant IL6 to LysM-Cre; Egfrf/f mice given DSS protected them from weight loss and restored epithelial proliferation and STAT3 activation, compared with administration of DSS alone to these mice. CONCLUSIONS Increased expression of EGFR in myeloid cells from the colorectal tumor stroma associates with tumor progression and reduced survival time of patients with metastatic colorectal cancer. Deletion of EGFR from myeloid cells, but not intestinal epithelial cells, protects mice from colitis-induced intestinal cancer and ApcMin-dependent intestinal tumorigenesis. Myeloid cell expression of EGFR increases activation of STAT3 and expression of survivin in intestinal epithelial cells and expression of IL6 in colon tissues. These findings indicate that expression of EGFR by myeloid cells of the colorectal tumor stroma, rather than the cancer cells themselves, contributes to tumor development.
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Affiliation(s)
- Sriram Srivatsa
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Mariel C Paul
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Claudia Cardone
- Università degli Studi della Campania L. Vanvitelli, Department of Clinical and Experimental Medicine, Via Pansini 5, Naples, Italy
| | - Martin Holcmann
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Nicole Amberg
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Paulina Pathria
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Michaela A Diamanti
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Markus Linder
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Gerald Timelthaler
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Hans P Dienes
- Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria
| | - Lukas Kenner
- Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research LBI-CR, Vienna, Austria; Department of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Fritz Wrba
- Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria
| | - Gerald W Prager
- Department of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria
| | - Stefan Rose-John
- Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Medical Faculty, Olshausenstraße 40, Kiel, Germany
| | - Robert Eferl
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Giuseppina Liguori
- Pathology Unit, National Cancer Institute, G. Pascale Foundation, Via M Semmola, Naples, Italy
| | - Gerardo Botti
- Pathology Unit, National Cancer Institute, G. Pascale Foundation, Via M Semmola, Naples, Italy
| | - Erika Martinelli
- Università degli Studi della Campania L. Vanvitelli, Department of Clinical and Experimental Medicine, Via Pansini 5, Naples, Italy
| | - Florian R Greten
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Fortunato Ciardiello
- Università degli Studi della Campania L. Vanvitelli, Department of Clinical and Experimental Medicine, Via Pansini 5, Naples, Italy
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria.
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20
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Kwak Y, Koh J, Kim DW, Kang SB, Kim WH, Lee HS. Immunoscore encompassing CD3+ and CD8+ T cell densities in distant metastasis is a robust prognostic marker for advanced colorectal cancer. Oncotarget 2016; 7:81778-81790. [PMID: 27835889 PMCID: PMC5348429 DOI: 10.18632/oncotarget.13207] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/28/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The immunoscore (IS), an index based on the density of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs) in the tumor center (CT) and invasive margin (IM), has gained considerable attention as a prognostic marker. Tumor-associated macrophages (TAMs) have also been reported to have prognostic value. However, its clinical significance has not been fully clarified in patients with advanced CRC who present with distant metastases. METHODS The density of CD3+, CD4+, CD8+, FOXP3+, CD68+, and CD163+ immune cells within CRC tissue procured from three sites-the primary CT, IM, and distant metastasis (DM)-was determined using immunohistochemistry and digital image analyzer (n=196). The IS was obtained by quantifying the densities of CD3+ and CD8+ TILs in the CT and IM. IS-metastatic and IS-macrophage-additional IS models designed in this study-were obtained by adding the score of CD3 and CD8 in DM and the score of CD163 in primary tumors (CT and IM), respectively, to the IS. RESULTS Higher IS, IS-metastatic, and IS-macrophage values were significantly correlated with better prognosis (p=0.020, p≤0.001, and p=0.005, respectively). Multivariate analysis revealed that only IS-metastatic was an independent prognostic marker (p=0.012). No significant correlation was observed between KRAS mutation and three IS models. However, in the subgroup analysis, IS-metastatic showed a prognostic association regardless of the KRAS mutational status. CONCLUSIONS IS is a reproducible method for predicting the survival of patients with advanced CRC. Additionally, an IS including the CD3+ and CD8+ TIL densities at DM could be a strong prognostic marker for advanced CRC.
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Affiliation(s)
- Yoonjin Kwak
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Duck-Woo Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Sung-Bum Kang
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
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Gao L, Zhou Y, Zhou SX, Yu XJ, Xu JM, Zuo L, Luo YH, Li XA. PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells. Oncol Rep 2016; 37:408-416. [PMID: 27840999 DOI: 10.3892/or.2016.5216] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/17/2016] [Indexed: 11/06/2022] Open
Abstract
Phospholipase D4 (PLD4) is a newly identified protein expressed in microglia. However, the function of PLD4 in tumor-associated macrophages (TAMs) is unknown. In the present study, we revealed that the expression of PLD4 was located in macrophages in the colon cancer mesenchymal and lymph nodes as shown by immunohistochemical analysis. furthermore, its expression was associated with clinical staging of colon cancer. Then, THP-1 as a cell model induced into TAMs. Western blot and RT-PCR analysis showed that PLD4 was mainly presented in M1 phenotype TAMs. The secretion of pro-inflammatory cytokines in M1 macrophages was significantly reduced after the expression of PLD4 inhibited by PLD4-siRNA. Furthermore, co-cultured with condition-medium from control or PLD4-siRNA M1 macrophages for 24 h, cell apoptosis, cycle and proliferation of cancer cells improved compared to control. These results indicated that PLD4 could be involved in the activation process of M1 phenotype macrophages.
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Affiliation(s)
- Long Gao
- The Gastroenterology Tumor and Microenvironment Laboratory, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, Sichuan 610041, P.R. China
| | - Yan Zhou
- The Gastroenterology Tumor and Microenvironment Laboratory, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, Sichuan 610041, P.R. China
| | - Shu-Xian Zhou
- The Gastroenterology Tumor and Microenvironment Laboratory, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, Sichuan 610041, P.R. China
| | - Xian-Jing Yu
- The Gastroenterology Tumor and Microenvironment Laboratory, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, Sichuan 610041, P.R. China
| | - Jin-Mei Xu
- The Gastroenterology Tumor and Microenvironment Laboratory, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, Sichuan 610041, P.R. China
| | - Luo Zuo
- The Gastroenterology Tumor and Microenvironment Laboratory, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, Sichuan 610041, P.R. China
| | - Yong-Hui Luo
- Burn and Plastic Surgery Department, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
| | - Xiao-An Li
- The Gastroenterology Tumor and Microenvironment Laboratory, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, Sichuan 610041, P.R. China
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DONG YOUHONG, WANG ANPING. Pioglitazone does not increase the risk of type II diabetes in patients with bladder cancer: A retrospective study. Oncol Lett 2016; 12:89-92. [PMID: 27347105 PMCID: PMC4907043 DOI: 10.3892/ol.2016.4566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 05/13/2016] [Indexed: 11/06/2022] Open
Abstract
The aim of the retrospective study was to analyze the effect of pioglitazone on the expression of tumor tissue inflammation factor interleukin (IL)-8, macrophage colony-stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF) of type II diabetes in bladder cancer patients. In addition, whether there was a correlation between pioglitazone and the occurrence of male bladder cancer was also investigated. In total, 42 male cases diagnosed with type II diabetes secondary to bladder cancer were selected. Forty male cases, with simplex type II diabetes but not with bladder cancer, served as the control. Tumor biopsy specimens were collected to detect the expression levels of IL-8, M-CSF and VEGF. The results showed that the expression of IL-8, M-CSF and VEGF of the simplex diabetes group was significantly lower than that of the secondary to tumor group (P<0.05). The comparison of the two groups in terms of daily dose and time of oral pioglitazone, duration of diabetes, average fasting blood sugar and glycated hemoglobin levels, was not statistically significant. Multivariable logistic regression analysis revealed that the expression levels of IL-8, M-CSF and VEGF were independent risk factors for the occurrence of bladder cancer (P<0.05), but were not associated with daily dose and time of oral pioglitazone (P>0.05). In conclusion, oral pioglitazone may not increase the risk of type II diabetes patients with bladder cancer. However, the occurrence of bladder cancer be associated with the increasing expression levels of IL-8, M-CSF and VEGF.
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High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma. Eur Arch Otorhinolaryngol 2016; 273:4515-4524. [DOI: 10.1007/s00405-016-4150-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 06/14/2016] [Indexed: 01/28/2023]
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Delgado-Plasencia L, Álvarez-Argüelles H, Salido-Ruiz E, Castro-Peraza ME, Bravo-Gutiérrez A, Fernández-Peralta A, González-Aguilera J, Alarcó-Hernández A, Medina-Arana V. MTHFR C677T polymorphism and anatomopathological characteristics with prognostic significance in sporadic colorectal cancer. Pathol Res Pract 2015; 211:989-95. [PMID: 26564107 DOI: 10.1016/j.prp.2015.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 08/20/2015] [Accepted: 10/05/2015] [Indexed: 11/18/2022]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair and synthesis. The MTHFR C677T polymorphism is associated with decreased risk of CRC and increased sensitivity to 5-FU treatment. The present study addressed the relationship between this polymorphism and histopathological and immunohistochemical characteristics of prognostic significance in 50 patients from the Canary Islands. No differences were found between the MTHFR C677T genotypes with respect to tumor budding, tumor necrosis, desmoplastic fibrosis and tumoral eosinophilia. No significant differences were found in Ki-67, bcl-2 (cytoplasmic and nuclear), CD31, CD3+ T lymphocytes (both stromal and intraepithelial) and peritumoral CD20+ B lymphocytes. In carriers of the MTHFR CC variant, tumor margins were infiltrative more frequently (68.7%) than in CT+TT carriers (33.3%, p=0.03). In addition, wild-type CC genotype showed stromal CD20+ B lymphocytes (68.8%) more often than CT+TT carriers (33.3%, p=0.03). Both parameters indicate a better tumor prognosis when the MTHFR 677T variant is present.
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Affiliation(s)
- Luciano Delgado-Plasencia
- Department of General and Digestive Surgery, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
| | - Hugo Álvarez-Argüelles
- Department of Pathology, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
| | - Eduardo Salido-Ruiz
- Department of Pathology, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
| | - M Elisa Castro-Peraza
- Department of General and Digestive Surgery, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
| | - Alberto Bravo-Gutiérrez
- Department of General and Digestive Surgery, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
| | | | | | - Antonio Alarcó-Hernández
- Department of General and Digestive Surgery, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
| | - Vicente Medina-Arana
- Department of General and Digestive Surgery, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
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Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions. Sci Rep 2015; 5:15651. [PMID: 26503803 PMCID: PMC4621525 DOI: 10.1038/srep15651] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 09/30/2015] [Indexed: 12/26/2022] Open
Abstract
Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.
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Braster R, Bögels M, Beelen RHJ, van Egmond M. The delicate balance of macrophages in colorectal cancer; their role in tumour development and therapeutic potential. Immunobiology 2015; 222:21-30. [PMID: 26358365 DOI: 10.1016/j.imbio.2015.08.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 07/28/2015] [Accepted: 08/29/2015] [Indexed: 02/07/2023]
Abstract
Most tumours are heavily infiltrated by immune cells. This has been correlated with either a good or a bad patient prognosis, depending on the (sub) type of immune cells. Macrophages represent one of the most prominent leukocyte populations in the majority of tumours. Functions of macrophages range from cytotoxicity, to stimulation of tumour growth by secretion of cytokines, growth and angiogenic factors, or suppressing immune responses. In most tumours macrophages are described as cells with immune suppressing, and wound healing properties, which aids tumour development. Yet, increasing evidence shows that macrophages are potent inhibitors of tumour growth in colorectal cancer. Macrophages in this respect show high plasticity. The presence of high macrophage numbers in the tumour may therefore become advantageous, if cells can be reprogrammed from tumour promoting macrophages into potent effector cells. Enhancing cytotoxic properties of macrophages by microbial products, pro-inflammatory cytokines or monoclonal antibody therapy are promising possibilities, and are currently tested in clinical trials.
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Affiliation(s)
- R Braster
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
| | - M Bögels
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
| | - R H J Beelen
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
| | - M van Egmond
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands; Department of Surgery, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
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Yang X, Sun HJ, Li ZR, Zhang H, Yang WJ, Ni B, Wu YZ. Gastric cancer-associated enhancement of von Willebrand factor is regulated by vascular endothelial growth factor and related to disease severity. BMC Cancer 2015; 15:80. [PMID: 25886574 PMCID: PMC4340498 DOI: 10.1186/s12885-015-1083-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 02/12/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND von Willebrand factor (vWF) is a potent regulator of angiogenesis, tumor growth, and metastasis. Yet, the expression pattern of vWF in human gastric cancer (GC) tissues and its relation to clinicopathological features of these cases remains unknown. METHODS Tumor and 5-cm adjacent non-tumoral parenchyma specimens were collected from 99 patients with GC (early stages I/II and late stages III/IV), and normal specimens were collected from 32 healthy controls (reference group). Plasma vWF antigen (vWF:Ag) and vWF activity were assessed by ELISA. The role of vascular endothelial growth factor (VEGF) in differential vWF expression was investigated using cultured human umbilical vein endothelial cells (HUVECs). vWF and VEGF protein and mRNA expression levels were investigated by qRT-PCR, western blotting and immunohistochemistry (IHC) respectively. The correlation of IHC-detected vWF expression with patient clinicopathological characteristics was analyzed. RESULTS Compared to the reference group, the patients with late GC showed significantly higher levels of vWF:Ag (72% (21-115) vs. 101% (40-136)) and vWF activity (62% (20-112) vs. 117% (33-169)) (both P < 0.001). The GC tumor tissues also showed higher vWF mRNA and protein levels than the adjacent non-tumoral parenchyma. Patients at late GC stage had significantly higher median number of vWF-positive cells than patients at early GC stage (P < 0.05). VEGF induced vWF mRNA and protein expression in HUVECs in dose- and time-dependent manners. Patients with late GC stage also had significantly higher serum VEGF than patients at early GC stage (23 ± 26 vs. 10 ± 12 pg/mL, P < 0.01). Most of the undifferentiated GC tumor tissues at late disease stage exhibited strong VEGF and VEGFR2 protein staining, which co-localized with the vWF protein staining pattern. CONCLUSIONS GC-related plasma vWF:Ag and vWF activity levels become substantially elevated in the late stage of disease. The higher mRNA and protein expression of vWF in GC tumor stroma may be regulated by the VEGF-VEGFR2 signaling pathway in vitro and may contribute to GC progression in vivo.
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Affiliation(s)
- Xia Yang
- Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China.
| | - Hai-jian Sun
- Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China.
| | - Zhi-rong Li
- Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China.
| | - Hao Zhang
- Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China.
| | - Wei-jun Yang
- Department of General Surgery, First People's Hospital of Guiyang, Guiyang, 550002, PR China.
| | - Bing Ni
- Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China.
| | - Yu-zhang Wu
- Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China.
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HLA class II antigen expression in colorectal carcinoma tumors as a favorable prognostic marker. Neoplasia 2014; 16:31-42. [PMID: 24563618 DOI: 10.1593/neo.131568] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 12/16/2013] [Accepted: 12/19/2013] [Indexed: 02/07/2023] Open
Abstract
The goal of this study was to determine the frequency of HLA class II antigen expression in colorectal carcinoma (CRC) tumors, its association with the clinical course of the disease, and the underlying mechanism(s). Two tissue microarrays constructed with 220 and 778 CRC tumors were stained with HLA-DR, DQ, and DP antigen-specific monoclonal antibody LGII-612.14, using the immunoperoxidase staining technique. The immunohistochemical staining results were correlated with the clinical course of the disease. The functional role of HLA class II antigens expressed on CRC cells was analyzed by investigating their in vitro interactions with immune cells. HLA class II antigens were expressed in about 25% of the 220 and 21% of the 778 tumors analyzed with an overall frequency of 23%. HLA class II antigens were detected in 19% of colorectal adenomas. Importantly, the percentage of stained cells and the staining intensity were significantly lower than those detected in CRC tumors. However, HLA class II antigen staining was weakly detected only in 5.4% of 37 normal mucosa tissues. HLA class II antigen expression was associated with a favorable clinical course of the disease. In vitro stimulation with interferon gamma (IFNγ) induced HLA class II antigen expression on two of the four CRC cell lines tested. HLA class II antigen expression on CRC cells triggered interleukin-1β (IL-1β) production by resting monocytes. HLA class II antigen expression in CRC tumors is a favorable prognostic marker. This association may reflect stimulation of IL-1β production by monocytes.
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Shabo I, Olsson H, Elkarim R, Sun XF, Svanvik J. Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer. CANCER MICROENVIRONMENT 2014; 7:61-9. [PMID: 24771466 DOI: 10.1007/s12307-014-0145-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 04/07/2014] [Indexed: 12/11/2022]
Abstract
The scavenger receptor, CD163, is a macrophage-specific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression as a macrophage trait in cancer cells, and macrophage infiltration and its clinical significance in colorectal cancer. Immunostaining of CD163 and macrophage infiltration were evaluated in paraffin-embedded specimens, earlier analyzed for CD31, D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 75 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data. CD163 expression was positive in cancer cells in 20 % of colorectal cancer patients and was related to advanced tumor stages (P = 0.008) and unfavorable prognosis (p = 0.001). High macrophage infiltration was related to shorter survival and positive CD163 expression in tumor cells. The prognostic impact of macrophage infiltration was independent of tumor stage and CD163 expression in cancer cells (p = 0.034). The expression of macrophage phenotype in colorectal cancer cells is associated with macrophage density in tumor stroma and lower survival rates. Macrophage infiltration has an independent prognostic impact on mortality in colorectal cancer. In accordance with previous experimental studies, these findings provide new insights into the role of macrophages in colorectal cancer.
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Affiliation(s)
- Ivan Shabo
- Department of surgery, County Council of Östergötland, Linköping, Sweden,
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30
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The Association of Immune Cell Infiltration and Prognosis in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2013. [DOI: 10.1007/s11888-013-0192-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Edin S, Wikberg ML, Rutegård J, Oldenborg PA, Palmqvist R. Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells. PLoS One 2013; 8:e74982. [PMID: 24058644 PMCID: PMC3776729 DOI: 10.1371/journal.pone.0074982] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 08/13/2013] [Indexed: 02/06/2023] Open
Abstract
Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a “mixed” M1/M2 phenotype, which in turn could contribute to a “good inflammatory response”. This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer.
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Affiliation(s)
- Sofia Edin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
- * E-mail:
| | - Maria L. Wikberg
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Jörgen Rutegård
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - Per-Arne Oldenborg
- Department of Integrative Medical Biology, Section for Histology and Cell Biology, Umeå University, Umeå, Sweden
| | - Richard Palmqvist
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
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Dighe S, Blake H, Jeyadevan N, Castellano I, Koh DM, Orton M, Chandler I, Swift I, Brown G. Perfusion CT vascular parameters do not correlate with immunohistochemically derived microvessel density count in colorectal tumors. Radiology 2013; 268:400-10. [PMID: 23592771 DOI: 10.1148/radiol.13112460] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE To determine whether perfusion computed tomography (CT)-derived vascular parameters-namely, blood flow, mean transit time (MTT), volume transfer constant (K(trans)), permeability-surface area product (PS), extracellular extravascular space volume, and vascular volume-correlate with the immunohistologic markers of angiogenesis in colorectal tumors. MATERIALS AND METHODS This prospective study was approved by the Regional Ethics and Research and Development Committees. The perfusion CT protocol was incorporated in the staging CT after informed consent in 29 patients (14 men, 15 women; mean age, 70 years; age range, 55-94 years). The perfusion parameters were calculated over two regions of interest (ROIs), at the invasive and luminal site defined by two radiologists independently. Accurate representative data were captured manually by correcting for motion artifacts and were analyzed by using Matlab software. The vascular heterogeneity between ROIs was assessed by using the Wilcoxon signed rank test. Perfusion CT parameters were correlated with the microvessel density (MVD) count at both corresponding sites obtained by means of immunohistochemical staining of the selected histologic slide with factor VIII and CD105 antigens by using Spearmen rank coefficient. RESULTS There was no statistically significant difference found between perfusion CT vascular parameters at the two ROIs by either of the radiologists. The Pearson coefficient for blood flow, MTT, K(trans), and PS at the two ROIs demonstrated good to moderate interobserver variability (for the two ROIs, 0.46 and 0.44; 0.67 and 0.64; 0.41 and 0.72; and 0.86 and 0.56, respectively). None of these parameters correlated with MVD count at the invasive or the luminal site for either of the two antigens. CONCLUSION Perfusion CT measurements may measure vascularity of colorectal tumors, however, correlation with MVD, which is a morphologic measure, appears inappropriate. © RSNA, 2013.
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Affiliation(s)
- Shwetal Dighe
- Department of Surgery, Mayday University Hospital NHS Trust, Croydon, London, England
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Wang WF, Li J, Du LT, Wang LL, Yang YM, Liu YM, Liu H, Zhang X, Dong ZG, Zheng GX, Wang CX. Krüppel-like factor 8 overexpression is correlated with angiogenesis and poor prognosis in gastric cancer. World J Gastroenterol 2013; 19:4309-4315. [PMID: 23885141 PMCID: PMC3718898 DOI: 10.3748/wjg.v19.i27.4309] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Revised: 04/30/2013] [Accepted: 06/20/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate Krüppel-like factor 8 (KLF8) expression in gastric cancer and its relationship with angiogenesis and prognosis of gastric cancer.
METHODS: One hundred and fifty-four patients with gastric cancer who underwent successful curative resection were retrospectively enrolled in the study. Fifty tumor-adjacent healthy gastric tissues (≥ 5 cm from the tumor margin) obtained during the original resection were randomly selected for comparative analysis. In situ expression of KLF8 and CD34 proteins were examined by immunohistochemistry. The intratumoral microvessel density (MVD) was determined by manually counting the immunostained CD34-positive endothelial cells in three consecutive high-magnification fields (× 200). The relationship between differential KLF8 expression and MVD was assessed using Spearman’s correlation coefficient test. χ2 test was performed to evaluate the effects of differential KLF8 expression on clinicopathologic factors. Kaplan-Meier and multivariate Cox survival analyses were used to assess the prognostic value of differential KLF8 expression in gastric cancer.
RESULTS: Significantly higher levels of KLF8 protein were detected in gastric cancer tissues than in the adjacent non-cancerous tissues (54.5% vs 34.0%, P < 0.05). KLF8 expression was associated with tumor size (P < 0.001), local invasion (P = 0.005), regional lymph node metastasis (P = 0.029), distant metastasis (P = 0.023), and tumor node metastasis (TNM) stage (P = 0.002), as well as the MVD (r = 0.392, P < 0.001). Patients with KLF8 positive expression had poorer overall survival (P < 0.001) and cancer-specific survival (P < 0.001) than those with negative expression. Multivariate analysis demonstrated that KLF8 expression independently affected both overall and cancer-specific survival of gastric cancer patients (P = 0.035 and 0.042, respectively).
CONCLUSION: KLF8 is closely associated with gastric tumor progression, angiogenesis and poor prognosis, suggesting it may represent a novel prognostic biomarker and therapeutic target for gastric cancer.
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The density of macrophages in colorectal cancer is inversely correlated to TGF-β1 expression and patients' survival. J Mol Histol 2013; 44:679-92. [PMID: 23801404 DOI: 10.1007/s10735-013-9520-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 06/17/2013] [Indexed: 12/19/2022]
Abstract
The role of macrophages in colorectal cancer tumorogenesis is complex because they can both prevent and promote tumor development. We investigated CD68-positive cell infiltration in tumor tissue and its correlations with proteins of TGF-β1 signaling pathway and survival of the patients after surgical therapy. A non-selected panel of 210 primary tumors of colorectal origin was investigated immunohistochemically with antibodies against CD68, TGF-β1, TGFβRII and Smad4. Lower CD68 infiltration in tumor stroma was associated with expression of TGF-β1 (p = 0.002) and SMAD4 (p = 0.090) in tumor cell cytoplasm and with TGFβRII expression (p = 0.017) in tumor cells membranes. The absence of SMAD4 immune deposits in tumor cell nuclei was more often seen in biopsies with low number of CD68 in the invasive front (p = 0.044). The low number of CD68-positive cells was significantly associated with several adverse clinical and histological tumor characteristics as the presence of metastases in local lymph nodes (p = 0.047), distant metastases (p = 0.0003), advanced tumor stage (p = 0.006), tumor cell invasion of blood, lymph vessels or perineural invasion (p = 0.004), higher histological types (p = 0.0002) and lower grade of inflammatory infiltration in the invasive front (p = 0.002). Moreover, the low grade of CD68 appeared to be significant unfavorable factors of prognosis of the patients with colorectal cancer. The results of our study confirm the prognostic significance of low level of tumor-associated macrophage infiltration in colorectal cancer as unfavorable marker for survival of the patients.
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Guthrie GJK, Roxburgh CSD, Richards CH, Horgan PG, McMillan DC. Circulating IL-6 concentrations link tumour necrosis and systemic and local inflammatory responses in patients undergoing resection for colorectal cancer. Br J Cancer 2013; 109:131-7. [PMID: 23756867 PMCID: PMC3708575 DOI: 10.1038/bjc.2013.291] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 05/15/2013] [Accepted: 05/17/2013] [Indexed: 12/21/2022] Open
Abstract
Background: Cancer-associated inflammation, in the form of local and systemic inflammatory responses, appear to be linked to tumour necrosis and have prognostic value in patients with colorectal cancer. However, their relationship with circulating biochemical mediators is unclear. The aim of the present study was to examine the interrelationships between circulating mediators, in particular interleukin-6 (IL-6) and tumour necrosis, and local and systemic inflammatory responses in patients undergoing resection for colorectal cancer. Methods: Data were collected from preoperative blood tests for 118 patients who underwent resection for colorectal cancer. Analysis of circulating IL-6, IL-10, vascular endothelial growth factor (VEGF), differential white cell count, C-reactive protein, and albumin were carried out. Routine pathology specimens were examined for tumour characteristics including necrosis and the extent of the inflammatory cell infiltrate. Body composition was examined using body mass index (BMI), total body fat, subcutaneous body fat, visceral fat, and skeletal muscle mass. Results: Circulating IL-6 concentrations were significantly associated with increased T stage (P<0.05), tumour necrosis (P<0.001), IL-10 (P<0.001), VEGF (P<0.001), modified Glasgow Prognostic Score (mGPS; P<0.001), white cell (P<0.01) and platelet (P<0.01) counts, and low skeletal muscle index (P<0.01). When normalised for T stage, tumour necrosis was associated with IL-6 (P<0.001), IL-10 (P<0.01), VEGF (P<0.001), mGPS (P<0.001), neutrophil–lymphocyte ratio (NLR; P<0.05), white cell (P<0.001), neutrophil (P<0.05), and platelet counts (P<0.005), and skeletal muscle index (P<0.001). Conclusion: The present study provides, for the first time, supportive evidence for the hypothesis that tumour necrosis, independent of T stage, is associated with elevated circulating IL-6 concentrations, thereby modulating both local and systemic inflammatory responses including angiogenesis that, in turn, may promote tumour progression and metastases.
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Affiliation(s)
- G J K Guthrie
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, G31 2ER, UK.
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Ning S, Guo S, Xie J, Xu Y, Lu X, Chen Y. TROP2 correlates with microvessel density and poor prognosis in hilar cholangiocarcinoma. J Gastrointest Surg 2013. [PMID: 23207686 DOI: 10.1007/s11605-012-2105-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Trophoblast cell surface antigen 2 (TROP2) was found to be associated with tumor progression and poor prognosis in a variety of epithelial carcinomas. The aim of the study was to investigate TROP2 expression and its prognostic impact in hilar cholangiocarcinoma. METHODS Immunohistochemistry and quantitative real-time PCR were used to determine TROP2 expression in surgical specimens from 70 hilar cholangiocarcinoma patients receiving radical resection. The relationship between TROP2 expression and microvessel density was investigated and standard statistical analysis was used to evaluate TROP2 prognosis significance in hilar cholangiocarcinoma. RESULTS High TROP2 expression by immunohistochemistry was found in 43 (61.4 %) of the 70 tumor specimens. Quantitative real-time PCR confirmed that TROP2 level in tumor was significantly higher than in non-tumoral biliary tissues (P = 0.001). Significant correlations were found between TROP2 expression and histological differentiation (P = 0.016) and tumor T stage (P = 0.031) in hilar cholangiocarcinoma. TROP2 expression correlated with microvessel density in hilar cholangiocarcinoma (P = 0.026). High TROP2 expression patients had a significantly poorer overall survival rate than those with low TROP2 expression (30 vs. 68.5 %, P = 0.001), and multivariate Cox regression analysis indicated TROP2 as an independent prognostic factor for hilar cholangiocarcinoma (P = 0.004). CONCLUSION TROP2 expression correlates with microvessel density significantly and is an independent prognostic factor in human hilar cholangiocarcinoma.
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Affiliation(s)
- Shanglei Ning
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, 250012, Jinan, China
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Edin S, Wikberg ML, Dahlin AM, Rutegård J, Öberg Å, Oldenborg PA, Palmqvist R. The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One 2012; 7:e47045. [PMID: 23077543 PMCID: PMC3471949 DOI: 10.1371/journal.pone.0047045] [Citation(s) in RCA: 383] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 09/07/2012] [Indexed: 12/20/2022] Open
Abstract
High macrophage infiltration has been correlated to improved survival in colorectal cancer (CRC). Tumor associated macrophages (TAMs) play complex roles in tumorigenesis since they are believed to hold both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we have applied an immunohistochemical approach to determine the degree of infiltrating macrophages with a M1 or M2 phenotype in clinical specimens of CRC in relation to prognosis, both in CRC in general but also in subgroups of CRC defined by microsatellite instability (MSI) screening status and the CpG island methylator phenotype (CIMP). A total of 485 consecutive CRC specimens were stained for nitric oxide synthase 2 (NOS2) (also denoted iNOS) as a marker for the M1 macrophage phenotype and the scavenger receptor CD163 as a marker for the M2 macrophage phenotype. The average infiltration of NOS2 and CD163 expressing macrophages along the invasive tumor front was semi-quantitatively evaluated using a four-graded scale. Two subtypes of macrophages, displaying M1 (NOS2+) or M2 (CD163+) phenotypes, were recognized. We observed a significant correlation between the amount of NOS2+ and CD163+ cells (P<0.0001). A strong inverse correlation to tumor stage was found for both NOS2 (P<0.0001) and CD163 (P<0.0001) infiltration. Furthermore, patients harbouring tumors highly infiltrated by NOS2+ cells had a significantly better prognosis than those infiltrated by few NOS2+ cells, and this was found to be independent of MSI screening status and CIMP status. No significant difference was found on cancer-specific survival in groups of CRC with different NOS2/CD163 ratios. In conclusion, an increased infiltration of macrophages with a M1 phenotype at the tumor front is accompanied by a concomitant increase in macrophages with a M2 phenotype, and in a stage dependent manner correlated to a better prognosis in patients with CRC.
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Affiliation(s)
- Sofia Edin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
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Luo GP, Ni B, Yang X, Wu YZ. von Willebrand factor: more than a regulator of hemostasis and thrombosis. Acta Haematol 2012; 128:158-69. [PMID: 22890291 DOI: 10.1159/000339426] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 05/03/2012] [Indexed: 12/13/2022]
Abstract
von Willebrand factor (vWF) was first identified as an adhesive glycoprotein involved in hemostasis by Zimmermann in 1971. Since then, vWF has been shown to play a vital role in platelet adhesion, platelet binding to collagen and factor VIII protection. Recent studies have implicated vWF as a regulator of angiogenesis, smooth muscle cell proliferation, tumor cell metastasis and crosstalk in the immune system. In this review, we will discuss the aspects of vWF structure that facilitate its biological effects and speculate on its newly discovered and hypothesized roles in the pathogenesis of several diseases.
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Affiliation(s)
- Gui-Ping Luo
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, PR China
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Qin L, Bromberg-White JL, Qian CN. Opportunities and challenges in tumor angiogenesis research: back and forth between bench and bed. Adv Cancer Res 2012; 113:191-239. [PMID: 22429856 DOI: 10.1016/b978-0-12-394280-7.00006-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Angiogenesis is essential for tumor growth and metastasis. Many signaling pathways are involved in regulating tumor angiogenesis, with the vascular endothelial growth factor pathway being of particular interest. The recognition of the heterogeneity in tumor vasculature has led to better predictions of prognosis through differential analyses of the vasculature. However, the clinical benefits from antiangiogenic therapy are limited, because many antiangiogenic agents cannot provide long-term survival benefits, suggesting the development of drug resistance. Activation of the hypoxia and c-Met pathways, as well as other proangiogenic factors, has been shown to be responsible for such resistance. Vessel co-option could be another important mechanism. For future development, research to improve the efficacy of antiangiogenic therapy includes (a) using tumor-derived endothelial cells for drug screening; (b) developing the drugs focusing on specific tumor types; (c) developing a better preclinical model for drug study; (d) developing more accurate biomarkers for patient selection; (e) targeting the c-Met pathway or other pathways; and (f) optimizing the dose and schedule of antiangiogenic therapy. In summary, the future of antiangiogenic therapy for cancer patients depends on our efforts to develop the right drugs, select the right patients, and optimize the treatment conditions.
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Affiliation(s)
- Li Qin
- State Key Laboratory on Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China
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Xi HQ, Wu XS, Wei B, Chen L. Aberrant expression of EphA3 in gastric carcinoma: correlation with tumor angiogenesis and survival. J Gastroenterol 2012; 47:785-94. [PMID: 22350700 DOI: 10.1007/s00535-012-0549-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 01/02/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND EphA3, a member of the Eph receptor tyrosine kinases, plays important roles in tumor angiogenesis and progression. However, the function of EphA3 in solid tumors has not been widely studied. We aimed to explore EphA3 expression in gastric carcinoma and analyze its role as a potential prognostic factor. METHODS Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess EphA3 mRNA in a normal gastric mucosa cell line and carcinoma cell lines. Immunohistochemistry for EphA3 and vascular endothelial growth factor (VEGF) was performed in 318 cases of gastric carcinoma. CD34 immunohistochemical staining was used for microvessel density (MVD) counting. Western blotting was used to analyze EphA3 expression in the cell lines and to determine the expression of EphA3 and VEGF in 75 cases of gastric carcinoma and matched normal mucosa. RESULTS EphA3 mRNA and protein expression was significantly higher in gastric cancer than that in normal mucosa (all P < 0.001). EphA3 was significantly correlated with TNM stage and poor prognosis (all P < 0.001). Multivariate analysis showed that EphA3 had an independent effect on survival (P = 0.037). EphA3 was positively correlated with VEGF (P < 0.001), and MVD (P < 0.001). According to Western blot analysis, both EphA3 and VEGF expression were significantly higher in carcinoma than that in normal mucosa (all P < 0.001). A positive correlation was observed between EphA3 and VEGF expression in cancer (P < 0.001, r = 0.513). CONCLUSIONS EphA3 may play important roles in the angiogenesis and prognosis of gastric carcinoma, and thus may become a useful target for therapeutic intervention and a potential indicator for clinical assessment of tumor prognosis.
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Affiliation(s)
- Hong-Qing Xi
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
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Algars A, Irjala H, Vaittinen S, Huhtinen H, Sundström J, Salmi M, Ristamäki R, Jalkanen S. Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients. Int J Cancer 2011; 131:864-73. [PMID: 21952788 DOI: 10.1002/ijc.26457] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 09/13/2011] [Indexed: 11/08/2022]
Abstract
The type of tumor-infiltrating macrophages may be decisive in tumor immunity, lymphangiogenesis and in the clinical outcome of cancer. Here, we elucidated the prognostic significance of lymphatic vessels, different types of macrophages and the balance between different macrophage types in colorectal cancer. We analyzed the impact of density, type and location of macrophages on the clinical behavior of 159 primary colorectal carcinomas using CD68 as a pan-macrophage marker and CLEVER-1/Stabilin-1 as a marker for regulatory/suppressive macrophages. Podoplanin was used as a pan-lymphatic vessel marker. A high number of CLEVER-1/Stabilin-1(+) peritumoral macrophages positively correlated with survival (p = 0.04). However, in more advanced disease (Stage IV), the patients with a high number of peritumoral or intratumoral CLEVER-1/Stabilin-1(+) macrophages had a shorter disease-specific survival (p = 0.05, and p = 0.008, respectively). Moreover, a low number of suppressive intratumoral CLEVER-1/Stabilin-1(+) macrophages among high numbers of CD68(+) macrophages correlated with a low number of distant recurrences (p = 0.01) and to fewer disease relapses exclusively in the liver as well (p = 0.006). A high number of intratumoral lymphatics correlated with poor survival (p = 0.03). The results of this work suggest that the type of macrophages, number of lymphatic vessels and their location contribute to the clinical behavior of colorectal cancer in a disease stage-specific manner.
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Affiliation(s)
- Annika Algars
- Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland
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Roxburgh CSD, McMillan DC. The role of the in situ local inflammatory response in predicting recurrence and survival in patients with primary operable colorectal cancer. Cancer Treat Rev 2011; 38:451-66. [PMID: 21945823 DOI: 10.1016/j.ctrv.2011.09.001] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2011] [Revised: 08/22/2011] [Accepted: 09/03/2011] [Indexed: 12/22/2022]
Abstract
Colorectal cancer progression and survival is dependent on complex interactions between the tumour and the host. The pronounced local inflammatory response in and around the tumour is thought to represent the in situ host anti-tumour immune response. Since early reports, 40 years ago, there has been a continuing interest in establishing the cellular composition of immune cell infiltrates and their relationship with survival in colorectal cancer. In this review, we comprehensively examine the evidence for the local inflammatory cell reaction/in situ immune response in predicting outcome in primary operable colorectal cancer and make recommendations as to how such information may be incorporated into routine clinical assessment. Generally, an increasing number/density of immune cells in and around the tumour is associated with improved outcome in over 100 studies. Whilst the prognostic value of a generalized lymphocytic infiltrate or non-specific peritumoural inflammatory response is strongly related to survival based on 40 different studies, it is also apparent that most individual immune cell types relate to recurrence and cancer specific survival. The evidence is particularly robust for tumour infiltrating T lymphocytes and their subsets (CD3+, CD8+, CD45RO+, FOXP3+) in addition to tumour associated macrophages, dendritic cells and neutrophils. Taken together, the evidence suggests both adaptive and innate anti-tumour immune responses play key roles in determining cancer progression. In order to establish routine clinical utility there is a need to rationalise this prognostic information, published over a 40 years period, into a standardized assessment of tumour inflammatory cell infiltrate. Such standardization may also guide development of novel therapeutic interventions.
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Affiliation(s)
- C S D Roxburgh
- University Department of Surgery, University of Glasgow, Royal Infirmary, Glasgow, UK.
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Gulubova M, Vlaykova T. Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. J Gastroenterol Hepatol 2009; 24:1265-75. [PMID: 17645466 DOI: 10.1111/j.1440-1746.2007.05009.x] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM The prognostic relevance of tumor-related angiogenesis and mast cell presence in colorectal cancer remains controversial. The aim of the current study was to assess the mast cell and microvessel densities (MCD and MVD) in the invasive front of colorectal cancers and to determine their prognostic relevance for survival of the patient with colorectal carcinoma. METHODS Histochemistry and immunohistochemistry were used to identify mast cells by toluidine blue (TB) histochemical staining and tryptase (Try) immunohistochemical staining and to determine the MVD in 106 biopsies from patients with 57 colonic and 49 rectal primary cancers. The MVD was assessed using CD31 as an endothelial cell marker. RESULTS Significant positive correlations were found between the MVD in the 'hot spots' and MCD-Try and MCD-TB (R = 0.623 and R = 0.414, respectively, P < 0.001). The survival analyses showed that the patients with hypovascular tumor tissues had significantly longer survival than those with hypervascular tumor biopsies (P < 0.0001). Analogous significant correlation was observed for MCD-Try: patients with low MCD-Try had significantly better prognosis compared to those with high MCD (P = 0.038). In the multivariate Cox's hazard analysis of the 'hot spots' MVD was found to be an independent prognostic factor (P = 0.0007), together with the presence of invasion of lymph vessels (P = 0.017) and the presence of regional lymph node metastases (P = 0.028). CONCLUSION We suggest that the assessment of MVD and tryptase-positive mast cells in the invasive front of the primary colorectal cancer could be a useful tool for prognosis of patients after surgical therapy.
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Affiliation(s)
- Maya Gulubova
- Department of General and Clinical Pathology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria.
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Gulubova M, Vlaykova T. Chromogranin A-, serotonin-, synaptophysin- and vascular endothelial growth factor-positive endocrine cells and the prognosis of colorectal cancer: an immunohistochemical and ultrastructural study. J Gastroenterol Hepatol 2008; 23:1574-85. [PMID: 18771509 DOI: 10.1111/j.1440-1746.2008.05560.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Endocrine differentiation in colorectal adenocarcinoma has been reported but its significance as a prognostic marker remains uncertain. The aim of the present study was to analyze the prognostic significance of endocrine differentiation in colorectal cancer. METHODS The presence of endocrine cells (EC) was determined in 137 colorectal cancers using light and electron immunohistochemistry and the immunogold method with chromogranin A, serotonin and synaptophysin. Vascular endothelial growth factor (VEGF) expression in tumor biopsies was also analyzed applying anti-VEGF antibodies. RESULTS EC labeled with at least one of the studied markers were detected in 47 (34.3%) primary colorectal cancers (30% chromogranin A-positive, 33% synaptophysin-positive and 18% serotonin-positive). In 23% of tumor biopsies, VEGF-positive EC were also detected. The immunostaining on serial sections showed that some chromogranin A-, synaptophysin- or serotonin-positive EC also contained VEGF immune deposits. By the immunogold method, the presence of VEGF was localized to the granules of EC. Tumors with VEGF-positive EC appeared to have significantly higher vascularization, detected as systematic microvessel density (28.89 vs 15.22 vessels/mm(2), P = 0.044, Mann-Whitney U-test) compared to those without VEGF-positive EC. Ultrastructurally, EC in the tumor tissue displayed some features different from those in the normal colon. The survival analyses revealed that patients with EC in primary tumor tissues had a worse prognosis after surgical therapy than those without endocrine cell differentiation (P < 0.05, log-rank test). CONCLUSIONS Endocrine differentiation is not an uncommon event in primary colorectal cancer and it could be a useful marker for a worse prognosis after the surgical therapy. Tumors positive for VEGF and containing VEGF-positive EC have higher vascularization, which probably also contributes to the unfavorable prognosis of patients.
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Affiliation(s)
- Maya Gulubova
- Department of General and Clinical Pathology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria.
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Abstract
The primary focus in the pathogenesis and treatment of human malignancies has been the tumor cell. However, the biologic properties of a malignancy are not all intrinsically determined. Interactions between heterogeneous cell populations influence the growth and survival of both normal and malignant cells. Studies defining the origin of endothelial cells involved in tumor angiogenesis first demonstrated the contributions of normal cellular environment. Recently, the mononuclear phagocyte lineage has been found to have biologically and clinically significant tumor enhancing and tumor suppressive effects. This article reviews the multiple roles of mononuclear phagocytes in cancer biology. A companion manuscript (J Pediatr Hematol Oncol. 2008, in press) describes the targeting of these cells for therapeutic benefit. Incorporating these strategies into future childhood cancer protocols could be an innovative approach for improving patient outcome.
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Tissue Factor Expression in Non-small Cell Lung Cancer: Relationship with Vascular Endothelial Growth Factor Expression, Microvascular Density, and K-ras Mutation. J Thorac Oncol 2008; 3:689-97. [DOI: 10.1097/jto.0b013e31817c1b21] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Shah CA, Allison KH, Garcia RL, Gray HJ, Goff BA, Swisher EM. Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer. Gynecol Oncol 2008; 109:215-9. [PMID: 18314181 DOI: 10.1016/j.ygyno.2008.01.010] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2007] [Revised: 12/31/2007] [Accepted: 01/10/2008] [Indexed: 10/22/2022]
Abstract
OBJECTIVES Forty percent of women with ovarian cancer have circulating free tumor DNA. We sought to determine if the tumor immune infiltrate varied based on tumor p53 mutation status or presence of circulating tumor DNA. METHODS We performed immunohistochemistry on 119 ovarian cancer specimens with CD3 and CD8 (Intratumoral T cells (TILs)), CD68 (tumor-associated macrophages (TAMs)), and FoxP3 (T regulatory cells (Tregs)). Tumors had been previously sequenced for mutations in exons 4-10 of p53, and plasma from women characterized for free tumor DNA. RESULTS TIL and TAM levels were positively correlated (P<0.0001). High levels of TILs were identified in 54 of 119 tumors (45.4%). No survival difference was identified according to the presence of TILs or TAMs. Patients with greater TILs were more likely to be optimally cytoreduced (P=0.005). p53 mutations were associated with more TILs (P=0.008). The presence of circulating tumor DNA did not correlate with TILs, TAMs, or Tregs. In the subgroup with a low host antitumor immune response, the intermediate response Tregs group did have a survival advantage (P=0.049). CONCLUSIONS p53 mutations are associated with higher levels of TILs. The ratio of Tregs to TILS may be more important than absolute levels. A brisk T cell response within the tumor predicts adequacy of cytoreduction, suggesting successful cytoreduction may be partially due to underlying tumor biology and host response.
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Affiliation(s)
- Chirag A Shah
- University of Washington Medical Center, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Seattle, Washington 98195, USA.
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van der Bij GJ, Bögels M, Oosterling SJ, Kroon J, Schuckmann DTM, de Vries HE, Meijer S, Beelen RHJ, van Egmond M. Tumor infiltrating macrophages reduce development of peritoneal colorectal carcinoma metastases. Cancer Lett 2008; 262:77-86. [PMID: 18187256 DOI: 10.1016/j.canlet.2007.11.040] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2007] [Revised: 11/22/2007] [Accepted: 11/23/2007] [Indexed: 01/23/2023]
Abstract
Macrophages generally constitute a major component of tumor stroma, and possess either tumor growth promoting or inhibiting capabilities. Classically activated macrophages exert cytotoxicity and produce inflammatory cytokines, which limits tumor growth. By contrast, alternatively activated or M2 macrophages induce tumor progression by stimulating angiogenesis and proliferation. Previously we showed that resident macrophages control metastatic spread of coloncarcinoma cells in liver and peritoneal tumor models. However, it is proposed that newly recruited macrophages develop into tumor-associated M2 macrophages, as they are exposed to a microenvironment that favors alternative activation. Previously we showed that monocyte migration was diminished after flavonoid treatment in an experimental autoimmune encephalomyelitis animal model. In the present study, we investigated the role of newly recruited macrophages in colon carcinoma development, by using the flavonoids rutin and luteolin to reduce monocyte migration into peritoneal tumors. Increased tumor development was observed in animals that were treated with rutin and luteolin. Immunohistochemical analyses showed that the number of ED2(+) resident macrophages was normal in tumors of animals that received rutin and luteolin treatment. However, the number of ED1(+) cells (marker immature macrophages) was reduced, indicating decreased macrophage recruitment. Thus, inhibition of monocyte migration promotes tumor growth, supporting that not only resident, but also newly recruited macrophages limit peritoneal colon carcinoma metastases development.
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Affiliation(s)
- Gerben J van der Bij
- Department of Surgical Oncology, VU University Medical Center, Amsterdam, The Netherlands
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Nagorsen D, Voigt S, Berg E, Stein H, Thiel E, Loddenkemper C. Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. J Transl Med 2007; 5:62. [PMID: 18047662 PMCID: PMC2212626 DOI: 10.1186/1479-5876-5-62] [Citation(s) in RCA: 178] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2007] [Accepted: 11/29/2007] [Indexed: 12/15/2022] Open
Abstract
Introduction Although systemic T-cell responses against tumor antigens and tumor infiltration by T cells have been investigated in colorectal cancer (CRC), the initiation of spontaneous immune responses in situ is not well understood. Macrophages and dendritic cells (DC) play an important role as a link between innate and adaptive immune response. The aim of the present study was to analyze macrophage and DC infiltration in CRC and to investigate whether there is a correlation to systemic T-cell response, regulatory T cell (Treg) infiltration, and survival. Methods Immunohistological staining was performed with nine markers for macrophages and DC (CD68, CD163, S100, CD11c, CD208, CD209, CD123, CD1a, Langerin) in 40 colorectal cancer samples from patients, in whom the state of systemic T-cell responses against tumor-associated antigens (TAA) and Treg infiltration had previously been determined. Results All specimens contained cells positive for CD68, CD163, S100 and CD1a in epithelial tumor tissue and tumor stroma. Only a very few (less than median 3/HPF) CD123+, CD1a+, CD11c+, CD 208+, CD209+, or Langerin+ cells were detected in the specimens. Overall, we found a trend towards increased infiltration by S100-positive DC and a significantly increased number of stromal S100-positive DC in patients without T-cell response. There was an increase of stromal S100 DC and CD163 macrophages in limited disease (S100: 11.1/HPF vs. 7.3/HPF, p = 0.046; CD163: 11.0/HPF vs. 8.1/HPF, p = 0.06). We found a significant, positive correlation between S100-positive DC and FOXP3-positive Tregs. Survival in patients with high DC infiltration was significantly better than that in those with low DC infiltration (p < 0.05). Furthermore, we found a trend towards better survival for increased infiltration with CD163-positive macrophages (p = 0.07). Conclusion The present in situ study adds new data to the discussion on the interaction between the innate and adoptive immune system. Our data strongly support the hypothesis that tumor-infiltrating DC are a key factor at the interface between innate and adaptive immune response in malignant disease. Tumor infiltrating S100-positive DC show an inverse relationship with the systemic antigen-specific T-cell response, a positive correlation with regulatory T cells, and a positive association with survival in CRC. These data put tumor-infiltrating DC at the center of the relevant immune response in CRC.
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Affiliation(s)
- Dirk Nagorsen
- Department of Hematology and Oncology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
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Kiss J, Tímár J, Somlai B, Gilde K, Fejôs Z, Gaudi I, Ladányi A. Association of microvessel density with infiltrating cells in human cutaneous malignant melanoma. Pathol Oncol Res 2007; 13:21-31. [PMID: 17387385 DOI: 10.1007/bf02893437] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2007] [Accepted: 02/12/2007] [Indexed: 02/06/2023]
Abstract
Vascularization and host response to malignant tumors may have common molecular regulators, therefore, we analyzed the relationship between microvessel density (MVD) and tumor infiltrating cells in cutaneous malignant melanoma. Density of lymphocyte subpopulations, macrophages, dendritic cells and CD34(+) microvessels was determined by immunohistochemistry in primary tumor samples from fifty-two patients with melanoma thicker than 1 mm. Intratumoral MVD did not show significant association with infiltration for any of these cell types. In the case of peritumoral reactive cell densities analyzed in the whole patient population, a positive correlation of MVD was found with CD3(+) T cell density. This association was stronger in melanomas >4.0 mm and in visceral metastatic tumors. In these subgroups similar phenomenon was observed for CD8(+) cells. We found significant correlation of MVD with CD68(+) macrophage density only in the highest thickness category, and weak associations with B-cell and dendritic cell infiltration in visceral metastatic cases. MVD did not vary significantly in tumors categorized according to thickness, localization, ulceration or histological type. However, both intratumoral MVD and macrophage infiltration were significantly higher in male patients compared to females. The correlation of immune cell density with tumor vascularization and gender differences in vascularity and macrophage infiltration of melanoma deserve further attention.
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Affiliation(s)
- Judit Kiss
- Department of Tumor Progression, National Institute of Oncology, Budapest, H-1122, Hungary
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