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Novysedlak R, Guney M, Al Khouri M, Bartolini R, Koumbas Foley L, Benesova I, Ozaniak A, Novak V, Vesely S, Pacas P, Buchler T, Ozaniak Strizova Z. The Immune Microenvironment in Prostate Cancer: A Comprehensive Review. Oncology 2024:1-25. [PMID: 39380471 DOI: 10.1159/000541881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 10/04/2024] [Indexed: 10/10/2024]
Abstract
BACKGROUND Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity. SUMMARY This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy. KEY MESSAGES The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.
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Affiliation(s)
- Rene Novysedlak
- Third Department of Surgery, 1st Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Miray Guney
- Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Majd Al Khouri
- Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Robin Bartolini
- Lausanne Center for Immuno-oncology Toxicities (LCIT), Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Lily Koumbas Foley
- Chemokine Research Group, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Iva Benesova
- Department of Immunology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Andrej Ozaniak
- Third Department of Surgery, 1st Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Vojtech Novak
- Department of Urology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Stepan Vesely
- Department of Urology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Pavel Pacas
- Department of Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Tomas Buchler
- Department of Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Zuzana Ozaniak Strizova
- Department of Immunology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
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Alsharabasy AM, Pandit A. Hyaluronan-Based Hydrogels for 3D Modeling of Tumor Tissues. Tissue Eng Part C Methods 2024; 30:452-499. [PMID: 39345138 DOI: 10.1089/ten.tec.2024.0271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2024] Open
Abstract
Although routine two-dimensional (2D) cell culture techniques have advanced basic cancer research owing to their simplicity, cost-effectiveness, and reproducibility, they have limitations that necessitate the development of advanced three-dimensional (3D) tumor models that better recapitulate the tumor microenvironment. Various biomaterials have been used to establish these 3D models, enabling the study of cancer cell behavior within different matrices. Hyaluronic acid (HA), a key component of the extracellular matrix (ECM) in tumor tissues, has been widely studied and employed in the development of multiple cancer models. This review first examines the role of HA in tumors, including its function as an ECM component and regulator of signaling pathways that affect tumor progression. It then explores HA-based models for various cancers, focusing on HA as a central component of the 3D matrix and its mobilization within the matrix for targeted studies of cell behavior and drug testing. The tumor models discussed included those for breast cancer, glioblastoma, fibrosarcoma, gastric cancer, hepatocellular carcinoma, and melanoma. The review concludes with a discussion of future prospects for developing more robust and high-throughput HA-based models to more accurately mimic the tumor microenvironment and improve drug testing. Impact Statement This review underscores the transformative potential of hyaluronic acid (HA)-based hydrogels in developing advanced tumor models. By exploring HA's dual role as a critical extracellular matrix component and a regulator of cancer cell dynamics, we highlight its unique contributions to replicating the tumor microenvironment. The recent advancements in HA-based models provide new opportunities for more accurate studies of cancer cell behavior and drug responses. Looking ahead, these innovations pave the way for high-throughput, biomimetic platforms that could revolutionize drug testing and accelerate the discovery of effective cancer therapies.
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Affiliation(s)
- Amir M Alsharabasy
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Abhay Pandit
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
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Sharma D, McNabb E, Law N, Cumal A, Czarnota GJ. Ultrasound-stimulated microbubbles enhancement of fractionated radiation for tumor treatment. BMC Cancer 2023; 23:693. [PMID: 37488490 PMCID: PMC10364378 DOI: 10.1186/s12885-023-10981-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 05/19/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Radiation therapy (XRT) causes numerous biological changes in tumor microenvironment. Radiation vascular response, due to endothelial disruption, can influence treatment outcomes in a dose-dependent manner. Ultrasound-stimulated microbubbles (USMB) have also been demonstrated to create a vascular response in the tumor microenvironment and enhance tumor response when used in combination with XRT. Single doses of 8-10 Gy are known to induce activation of acid sphingomyelinase (ASMase)-induced ceramide production, causing vascular damage. Destruction of vasculature results in endothelial apoptosis followed by tumor cell death. The effect of tumor response is known to be synergistic by 10-fold higher cell kill observed when USMB is combined with radiation. METHODS In this study, we used an USMB approach in combination with conventional low dose fractionated radiation to enhance endothelial cell responses to XRT in human PC3 prostate cancer xenograft model. Mice were divided into untreated, USMB therapy, fractionated XRT, and combined USMB therapy followed by XRT (USMB + XRT) groups. USMB therapy was delivered twice per week in the USMB-alone and combined USMB + XRT treatment groups over four weeks. Radiation treatments were delivered in fractions of 2 Gy/day (total 40 Gy in 20 fractions, BED10 = 48 Gy) in the XRT-alone and combined USMB + XRT groups. The treatment outcome was evaluated using histopathology, power Doppler, and immunohistochemistry assays. RESULTS Tumor growth assessment showed that sizes of tumors increased in the control and the single treatment groups over a treatment period of four weeks, but significantly decreased with the combined treatments of USMB + XRT. Immunohistochemical analysis indicated a statistically significant vascular disruption in mice that received treatment involving a full 4-week schedule of combined (USMB + XRT) treatments. A statistically significant increase in vascular disruption was demonstrated through CD68 and trichrome fibrosis staining. Changes in local perfusion assessed using high-frequency power Doppler imaging demonstrated attenuated blood flow in the combined group. DISCUSSION AND CONCLUSIONS This work demonstrates the efficacy of using USMB as a radiation sensitizer in a mouse model of human PC3 tumor xenograft. This radiation treatment enhancement modality has the advantage of targeting tumor vasculature with ultrasound stimulation that can be implemented prior to radiation treatment.
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Affiliation(s)
- Deepa Sharma
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Departments of Medical Biophysics, and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Evan McNabb
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Niki Law
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Aaron Cumal
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Gregory J Czarnota
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
- Departments of Medical Biophysics, and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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Zhu W, Wu J, Huang J, Xiao D, Li F, Wu C, Li X, Zeng H, Zheng J, Lai W, Wen X. Multi-omics analysis reveals a macrophage-related marker gene signature for prognostic prediction, immune landscape, genomic heterogeneity, and drug choices in prostate cancer. Front Immunol 2023; 14:1122670. [PMID: 37122696 PMCID: PMC10140525 DOI: 10.3389/fimmu.2023.1122670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/03/2023] [Indexed: 05/02/2023] Open
Abstract
INTRODUCTION Macrophages are components of the innate immune system and can play an anti-tumor or pro-tumor role in the tumor microenvironment owing to their high heterogeneity and plasticity. Meanwhile, prostate cancer (PCa) is an immune-sensitive tumor, making it essential to investigate the value of macrophage-associated networks in its prognosis and treatment. METHODS Macrophage-related marker genes (MRMGs) were identified through the comprehensive analysis of single-cell sequencing data from GSE141445 and the impact of macrophages on PCa was evaluated using consensus clustering of MRMGs in the TCGA database. Subsequently, a macrophage-related marker gene prognostic signature (MRMGPS) was constructed by LASSO-Cox regression analysis and grouped based on the median risk score. The predictive ability of MRMGPS was verified by experiments, survival analysis, and nomogram in the TCGA cohort and GEO-Merged cohort. Additionally, immune landscape, genomic heterogeneity, tumor stemness, drug sensitivity, and molecular docking were conducted to explore the relationship between MRMGPS and the tumor immune microenvironment, therapeutic response, and drug selection. RESULTS We identified 307 MRMGs and verified that macrophages had a strong influence on the development and progression of PCa. Furthermore, we showed that the MRMGPS constructed with 9 genes and the predictive nomogram had excellent predictive ability in both the TCGA and GEO-Merged cohorts. More importantly, we also found the close relationship between MRMGPS and the tumor immune microenvironment, therapeutic response, and drug selection by multi-omics analysis. DISCUSSION Our study reveals the application value of MRMGPS in predicting the prognosis of PCa patients. It also provides a novel perspective and theoretical basis for immune research and drug choices for PCa.
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Affiliation(s)
- Weian Zhu
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianjie Wu
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiongduan Huang
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dongming Xiao
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fengao Li
- Department of Urology, Anqing First People’s Hospital of Anhui Medical University, Anqing, China
| | - Chenglun Wu
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojuan Li
- Department of Health Care, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Hengda Zeng
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiayu Zheng
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenjie Lai
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xingqiao Wen
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Ouban A, Raddaoui E, Bakir M. The Clinical Significance of CD163+ Tumor-Associated Macrophages (TAMs) in Laryngeal Squamous Cell Carcinoma. Cureus 2023; 15:e36339. [PMID: 37082492 PMCID: PMC10111153 DOI: 10.7759/cureus.36339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2023] [Indexed: 04/22/2023] Open
Abstract
Background and objective The tumor's microenvironment is currently considered an important indicator of the tumor's prognosis, treatment failure, and recurrence. CD163+ tumor-associated macrophages (TAMs) are a marker of poor prognosis in many types of human cancers. In the present study, the expression of CD163+ TAMs was analyzed in laryngeal squamous cell carcinomas (LSCCs) using immunohistochemistry, and this expression was correlated with the clinical and pathological characteristics of LSCC patients. Materials and methods One commercial human larynx microarray with 80 cases of LSCCs, was used for this study. For comparison with normal laryngeal mucosa, a second microarray carrying normal tissues from all human anatomical sites, including normal laryngeal tissues, was used. Immunohistochemical staining was performed, and the primary antibody was a mouse monoclonal against human CD136. The absence of the primary antibody was used as a negative control. The percentage of positive cells was categorized into five scores: 0 (0%); 1, (1%-10%); 2, (11%-50%); 3, (51%-80%); and 4, (>80%). A case was scored as positive for CD163 with a score >= 1. The χ2 test was used to assess the CD163 expression in LSCC cases (N=80). A statistically significant difference was defined as P 0.05. Results The human larynx microarray containing 80 cases of LSCCs was used for this study. The age of the cancer patients in this array was in the range of 39 to 72, with a median of 53. LSCC grades were distributed as follows: 25 patients were designated as grade I, 43 were designated as grade II, and 6 were designated as grade III. Two tumors' (2/80) cores were missing from the microarray. Six tumors on the microarray did not have a grade designation reported by the manufacturer of the array. The expression of CD163 in normal, benign, unmatched laryngeal tissue was absent. In cancer cases, on the other hand, a significant number of LSCCs had TAMs that were positive for CD163 (87% positive tumors, with an IHC score ranging from 1 to 4, χ2=30.634; p<0.001). The rest of the LSCC cases (10 in total) had negative CD163 expression (score of 0). Conclusion A significant majority of LSCCs were found to have CD163+ TAMs expression using tissue microarrays (TMAs). This expression is positively correlated with the tumor's grade, clinical manifestation, and TNM staging. Morphologic evidence shows that the majority of LSCCs express the highest range of immunohistochemistry (IHC) scores for CD163 protein in the membranes and cytoplasm of their TAMs. This study provides evidence of the clinical significance of CD163+TAMs in LSCCs and proposes further studies to pinpoint the exact role of these cells in LSCC patients.
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Affiliation(s)
- Abderrahman Ouban
- Department of Pathology, College of Medicine, Alfaisal University, Riyadh, SAU
| | - Emadeddin Raddaoui
- Department of Pathology, College of Medicine, Alfaisal University, Riyadh, SAU
| | - Mohamad Bakir
- College of Medicine, Alfaisal University, Riyadh, SAU
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Cheng Z, Wang J, Xu Y, Jiang T, Xue Z, Li S, Zhao Y, Song H, Song J. N7-methylguanosine-related lncRNAs: Distinction between hot and cold tumors and construction of predictive models in colon adenocarcinoma. Front Oncol 2022; 12:951452. [PMID: 36185235 PMCID: PMC9520617 DOI: 10.3389/fonc.2022.951452] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Colon adenocarcinoma (COAD) is a prevalent malignant tumor that severely threatens human health across the globe. Immunotherapy is an essential need for patients with COAD. N7-methylguanosine (m7G) has been associated with human diseases, and non-coding RNAs (lncRNAs) regulate various tumor-related biological processes. Nonetheless, the m7G-related lncRNAs involved in COAD regulation are limited. This study aims to construct the clustering features and prognostic model of m7G-related lncRNAs in COAD. First, The Cancer Genome Atlas (TCGA) database was used to identify m7G-related differentially expressed lncRNAs (DELs), based on which COAD cases could be classified into two subtypes. Subsequently, univariate Cox analysis was used to identify 9 prognostic m7G-related lncRNAs. Further, Five candidates were screened by LASSO-Cox regression to develop new models. The patients were divided into high-risk and low-risk groups based on the median risk score. Consequently, the Kaplan-Meier survival curve demonstrated a statistically significant overall survival (OS) between the high- and low-risk groups (P<0.001). Multivariate Cox regression analysis revealed that risk score is an independent prognostic factor in COAD patients (P<0.001). This confirms the clinical applicability of the model. Additionally, we performed Gene Set Enrichment Analysis (GSEA), which uncovered the biological and functional differences between risk subgroups, i.e., enrichment of immune-related diseases in the high-risk group and enrichment of metabolic-related pathways in the low-risk group. In a drug sensitivity analysis, high-risk group were more sensitive to some chemotherapeutics and targeted drugs than low-risk group. Eventually, the stability of the model was confirmed by qRT-PCR. Our study unraveled the features of different immune states of COAD and established a prognostic model, including five m7G-related lncRNAs for COAD patients. These results will bolster clinical treatment and survival prediction of COAD.
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Affiliation(s)
- Zhichao Cheng
- The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jiaqi Wang
- Department of General Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yixin Xu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Tao Jiang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zhenyu Xue
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Shuai Li
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ying Zhao
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hu Song
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- *Correspondence: Jun Song, ; Hu Song,
| | - Jun Song
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China
- *Correspondence: Jun Song, ; Hu Song,
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Khoury T, Aljabab S, Yao S, Ambrosone C, Omilian A, Attwood K, Ji W, Gandhi S. Tumor-associated mononuclear cells in the tumor bed of triple-negative breast cancer associate with clinical outcomes in the post-neoadjuvant chemotherapy setting. Breast Cancer Res Treat 2022; 194:531-540. [PMID: 35716216 DOI: 10.1007/s10549-022-06641-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/26/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE To evaluate the clinical role of tumor-associated macrophages, including foamy (FM) and hemosiderin-laden macrophages (HLM) in the tumor bed (TB) of triple-negative breast cancer (TNBC) post-neoadjuvant chemotherapy (NACT). METHODS We conducted a pathologic review of 129 women, diagnosed with TNBC between 2002 and 2016 at our institute. The residual cancer burden (RCB) was calculated. We estimated the percentage of tumor-infiltrating lymphocytes (TILs) in the core needle biopsy (CNB), and FM, HLM, and TILs (in TB) [the combined cells are designated as tumor-associated mononuclear cells (TAMNC)]. The information on patient demographics, chemotherapy regimen, recurrence-free survival (RFS), and overall survival (OS) was extracted from the medical records. RESULTS Pathologic complete response (pCR) was achieved in 34.1% of the women. TILs (10% increment in CNB) only were associated with pCR in the multivariable analysis [odds ratio 1.04 (1.02, 1.06) (p = 0.0003)]. Immune cells associated with better OS included TAMNC (≤ 30%) [hazard ratio (HR) 4.32 (1.93, 9.66) (p = 0.0004)], and FM (0%) [HR 2.30 (1.06, 4.98) (p = 0.036)]. While increased HLM (10% increment) was statistically significant with HR 0.93 and 95% CI (0.88 to 0.98) (p = 0.0061), using a cutoff of 0%, HLM (0%: negative vs. ≥ 1%: positive) achieved only borderline significance with HR 2.05 (0.98, 4.31) (p = 0.058). Similarly, these immune cells were also associated with better RFS: TAMNC (≤ 30%) [HR 4.57 (2.04, 10.21) (p = 0.0002)], FM (0%) [HR 2.80 (1.23, 6.35) (p = 0.014)], and HLM (0%) [HR 2.34 (1.07, 5.11) (p = 0.03)]. TILs (in TB) were not associated with any clinical outcomes. CONCLUSIONS Although TILs may play a role in the response to NACT, they may not be critical to the prognosis after NACT. Instead, FM and HLM may assume this role. More studies are warranted.
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Affiliation(s)
- Thaer Khoury
- Department of Pathology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA.
| | - Saif Aljabab
- Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Song Yao
- Department of Epidemiology and Population Science, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christine Ambrosone
- Department of Epidemiology and Population Science, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Angela Omilian
- Department of Epidemiology and Population Science, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kristopher Attwood
- Department of Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Wenyan Ji
- Department of Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Kader A, Kaufmann JO, Mangarova DB, Moeckel J, Brangsch J, Adams LC, Zhao J, Reimann C, Saatz J, Traub H, Buchholz R, Karst U, Hamm B, Makowski MR. Iron Oxide Nanoparticles for Visualization of Prostate Cancer in MRI. Cancers (Basel) 2022; 14:cancers14122909. [PMID: 35740575 PMCID: PMC9221397 DOI: 10.3390/cancers14122909] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/07/2022] [Accepted: 06/11/2022] [Indexed: 12/16/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common cancers in men. For detection and diagnosis of PCa, non-invasive methods, including magnetic resonance imaging (MRI), can reduce the risk potential of surgical intervention. To explore the molecular characteristics of the tumor, we investigated the applicability of ferumoxytol in PCa in a xenograft mouse model in two different tumor volumes, 500 mm3 and 1000 mm3. Macrophages play a key role in tumor progression, and they are able to internalize iron-oxide particles, such as ferumoxytol. When evaluating T2*-weighted sequences on MRI, a significant decrease of signal intensity between pre- and post-contrast images for each tumor volume (n = 14; p < 0.001) was measured. We, furthermore, observed a higher signal loss for a tumor volume of 500 mm3 than for 1000 mm3. These findings were confirmed by histological examinations and laser ablation inductively coupled plasma-mass spectrometry. The 500 mm3 tumors had 1.5% iron content (n = 14; σ = 1.1), while the 1000 mm3 tumors contained only 0.4% iron (n = 14; σ = 0.2). In vivo MRI data demonstrated a correlation with the ex vivo data (R2 = 0.75). The results of elemental analysis by inductively coupled plasma-mass spectrometry correlated strongly with the MRI data (R2 = 0.83) (n = 4). Due to its long retention time in the blood, biodegradability, and low toxicity to patients, ferumoxytol has great potential as a contrast agent for visualization PCa.
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Affiliation(s)
- Avan Kader
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
- Department of Biology, Chemistry and Pharmacy, Institute of Biology, Freie Universität Berlin, Königin-Luise-Str. 1-3, 14195 Berlin, Germany
- Department of Diagnostic and Interventional Radiology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
- Correspondence:
| | - Jan O. Kaufmann
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
- Division 1.5 Protein Analysis, Bundesanstalt für Materialforschung und-Prüfung (BAM), Richard-Willstätter-Str. 11, 12489 Berlin, Germany
- Department of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
| | - Dilyana B. Mangarova
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
- Department of Veterinary Medicine, Institute of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Str. 15, Building 12, 14163 Berlin, Germany
| | - Jana Moeckel
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
| | - Julia Brangsch
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
| | - Lisa C. Adams
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
| | - Jing Zhao
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
| | - Carolin Reimann
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
| | - Jessica Saatz
- Division 1.1 Inorganic Trace Analysis, Bundesanstalt für Materialforschung und-Prüfung (BAM), Richard-Willstätter-Str. 11, 12489 Berlin, Germany; (J.S.); (H.T.)
| | - Heike Traub
- Division 1.1 Inorganic Trace Analysis, Bundesanstalt für Materialforschung und-Prüfung (BAM), Richard-Willstätter-Str. 11, 12489 Berlin, Germany; (J.S.); (H.T.)
| | - Rebecca Buchholz
- Institute of Inorganic and Analytical Chemistry, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany; (R.B.); (U.K.)
| | - Uwe Karst
- Institute of Inorganic and Analytical Chemistry, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany; (R.B.); (U.K.)
| | - Bernd Hamm
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
| | - Marcus R. Makowski
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.O.K.); (D.B.M.); (J.M.); (J.B.); (L.C.A.); (J.Z.); (C.R.); (B.H.); (M.R.M.)
- Department of Diagnostic and Interventional Radiology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
- School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital Westminster Bridge Road, London SE1 7EH, UK
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9
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Jia G, Wang X, Wu W, Zhang Y, Chen S, Zhao J, Zhao W, Li W, Sun X, Han B. LXA4 enhances prostate cancer progression by facilitating M2 macrophage polarization via inhibition of METTL3. Int Immunopharmacol 2022; 107:108586. [DOI: 10.1016/j.intimp.2022.108586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 12/23/2022]
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10
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Messex JK, Byrd CJ, Thomas MU, Liou GY. Macrophages Cytokine Spp1 Increases Growth of Prostate Intraepithelial Neoplasia to Promote Prostate Tumor Progression. Int J Mol Sci 2022; 23:4247. [PMID: 35457063 PMCID: PMC9027984 DOI: 10.3390/ijms23084247] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 11/27/2022] Open
Abstract
Prostate cancer development and progression are associated with increased infiltrating macrophages. Prostate cancer is derived from prostatic intraepithelial neoplasia (PIN) lesions. However, the effects macrophages have on PIN progression remain unclear. Here, we showed that the recruited macrophages adjacent to PIN expressed M2 macrophage markers. In addition, high levels of Spp1 transcripts, also known as osteopontin, were identified in these macrophages. Extraneously added Spp1 accelerated PIN cell proliferation through activation of Akt and JNK in a 3D culture setting. We also showed that PIN cells expressed CD44, integrin αv, integrin β1, and integrin β3, all of which have been previously reported as receptors for Spp1. Finally, blockade of Akt and JNK activation through their specific inhibitor completely abolished macrophage Spp1-induced cell proliferation of PIN. Hence, our data revealed Spp1 as another macrophage cytokine/growth factor and its mediated mechanism to upregulate PIN cell growth, thus promoting prostate cancer development.
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Affiliation(s)
- Justin K. Messex
- Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA;
| | - Crystal J. Byrd
- Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA; (C.J.B.); (M.U.T.)
| | - Mikalah U. Thomas
- Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA; (C.J.B.); (M.U.T.)
| | - Geou-Yarh Liou
- Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA;
- Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA; (C.J.B.); (M.U.T.)
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11
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Han IH, Jeong C, Yang J, Park SH, Hwang DS, Bae H. Therapeutic Effect of Melittin–dKLA Targeting Tumor-Associated Macrophages in Melanoma. Int J Mol Sci 2022; 23:ijms23063094. [PMID: 35328518 PMCID: PMC8954064 DOI: 10.3390/ijms23063094] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 12/10/2022] Open
Abstract
Melanoma is an immunogenic tumor and a serious type of skin cancer. Tumor-associated macrophages (TAMs) express an M2-like phenotype and are involved in all stages of melanomagenesis; it is hence a promising target for cancer immunotherapy. We herein investigated whether melittin–dKLA inhibits the growth of melanoma by inducing apoptosis of M2-like macrophages. For the in vitro study, a conditioned medium of macrophages was prepared from M0, M1, or M2-differentiated THP-1 cells with and without melittin–dKLA. The affinity of melittin for M2 macrophages was studied with FITC (fluorescein isothiocyanate)-conjugated melittin. For the in vivo study, murine melanoma cells were inoculated subcutaneously in the right flank of mice, melittin–dKLA was intraperitoneally injected at 200 nmol/kg every three days, and flow cytometry analysis of TAMs was performed. Since melittin binds preferentially to M2-like macrophages, melittin–dKLA induced more caspase 3 expression and cell death in M2 macrophages compared with M0 and M1 macrophages and melanoma cells. Melittin–dKLA significantly inhibited the proliferation and migration of M2 macrophages, resulting in a decrease in melanoma tumor growth in vivo. The CD206+ M2-like TAMs were reduced, while the CD86+ M1-like TAMs were not affected. Melittin–dKLA is therapeutically effective against melanoma by inducing the apoptosis of M2-like TAMs.
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Affiliation(s)
- Ik-Hwan Han
- Department of Physiology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea; (I.-H.H.); (C.J.); (J.Y.)
| | - Chanmi Jeong
- Department of Physiology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea; (I.-H.H.); (C.J.); (J.Y.)
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea
| | - Juwon Yang
- Department of Physiology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea; (I.-H.H.); (C.J.); (J.Y.)
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea
| | - Seung-Hyeok Park
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea;
| | - Deok-Sang Hwang
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea;
- Correspondence: (D.-S.H.); (H.B.); Tel.: +82-2-961-9316 (H.B.); Fax: +82-2-962-9316 (H.B.)
| | - Hyunsu Bae
- Department of Physiology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea; (I.-H.H.); (C.J.); (J.Y.)
- Correspondence: (D.-S.H.); (H.B.); Tel.: +82-2-961-9316 (H.B.); Fax: +82-2-962-9316 (H.B.)
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12
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Qian H, Zhou T, Fu Y, Guo M, Yang W, Zhang D, Fang W, Yao M, Shi H, Chai C, Cheng W, Ding S, Chen T. Self-assembled tetrahedral framework nucleic acid mediates tumor-associated macrophage reprogramming and restores antitumor immunity. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:763-773. [PMID: 35116188 PMCID: PMC8783116 DOI: 10.1016/j.omtn.2021.12.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 12/31/2021] [Indexed: 12/20/2022]
Abstract
There is increasing interest in depleting or repolarizing tumor-associated macrophages (TAMs) to generate a proinflammatory effect. However, TAMs usually display an immunosuppressive M2-like phenotype in the tumor microenvironment. Apparently, developing a macrophage-targeting delivery system with immunomodulatory agents is urgent. In this study, an efficient siRNA and CpG ODNs delivery system (CpG-siRNA-tFNA) was prepared with nucleic acid stepwise self-assembled. The tFNA composed of CpG ODNs and siRNA showed a higher stability and an enhanced cellular uptake efficiency. Moreover, the CpG-siRNA-tFNA effectively reprogrammed TAMs toward M1 phenotype polarization with increased proinflammatory cytokine secretion and NF-κB signal pathway activation, which triggers dramatic antitumor immune responses. Additionally, the CpG-siRNA-tFNA exhibited superior antitumor efficacy in a breast cancer xenograft mouse model without obvious systemic side effects. Taken together, CpG-siRNA-tFNA displayed greatly antitumor effect by facilitating TAM polarization toward M1 phenotypes in favor of immunotherapy. Hence, we have developed an efficient therapeutic strategy with immunomodulatory agents for clinical applications.
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Affiliation(s)
- Husun Qian
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ting Zhou
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yixin Fu
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Minkang Guo
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wu Yang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Dian Zhang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wenli Fang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Mengli Yao
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - He Shi
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Chengsen Chai
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wei Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Shijia Ding
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Tingmei Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
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13
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von Amsberg G, Alsdorf W, Karagiannis P, Coym A, Kaune M, Werner S, Graefen M, Bokemeyer C, Merkens L, Dyshlovoy SA. Immunotherapy in Advanced Prostate Cancer-Light at the End of the Tunnel? Int J Mol Sci 2022; 23:2569. [PMID: 35269712 PMCID: PMC8910587 DOI: 10.3390/ijms23052569] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 12/16/2022] Open
Abstract
Immunotherapeutic treatment approaches are now an integral part of the treatment of many solid tumors. However, attempts to integrate immunotherapy into the treatment of prostate cancer have been disappointing so far. This is due to a highly immunosuppressive, "cold" tumor microenvironment, which is characterized, for example, by the absence of cytotoxic T cells, an increased number of myeloid-derived suppressor cells or regulatory T cells, a decreased number of tumor antigens, or a defect in antigen presentation. The consequence is a reduced efficacy of many established immunotherapeutic treatments such as checkpoint inhibitors. However, a growing understanding of the underlying mechanisms of tumor-immune system interactions raises hopes that immunotherapeutic strategies can be optimized in the future. The aim of this review is to provide an overview of the current status and future directions of immunotherapy development in prostate cancer. Background information on immune response and tumor microenvironment will help to better understand current therapeutic strategies under preclinical and clinical development.
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Affiliation(s)
- Gunhild von Amsberg
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (W.A.); (P.K.); (A.C.); (M.K.); (C.B.); (S.A.D.)
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany;
| | - Winfried Alsdorf
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (W.A.); (P.K.); (A.C.); (M.K.); (C.B.); (S.A.D.)
| | - Panagiotis Karagiannis
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (W.A.); (P.K.); (A.C.); (M.K.); (C.B.); (S.A.D.)
| | - Anja Coym
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (W.A.); (P.K.); (A.C.); (M.K.); (C.B.); (S.A.D.)
| | - Moritz Kaune
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (W.A.); (P.K.); (A.C.); (M.K.); (C.B.); (S.A.D.)
| | - Stefan Werner
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (S.W.); (L.M.)
| | - Markus Graefen
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany;
| | - Carsten Bokemeyer
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (W.A.); (P.K.); (A.C.); (M.K.); (C.B.); (S.A.D.)
| | - Lina Merkens
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (S.W.); (L.M.)
| | - Sergey A. Dyshlovoy
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; (W.A.); (P.K.); (A.C.); (M.K.); (C.B.); (S.A.D.)
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany;
- Laboratory of Pharmacology, A.V. Zhirmunsky National Scientific Center of Marine Biology, Palchevskogo Str. 17, 690041 Vladivostok, Russia
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14
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Kwon OJ, Zhang B, Jia D, Zhang L, Wei X, Zhou Z, Liu D, Huynh KT, Zhang K, Zhang Y, Labhart P, Sboner A, Barbieri C, Haffner MC, Creighton CJ, Xin L. Elevated expression of the colony-stimulating factor 1 (CSF1) induces prostatic intraepithelial neoplasia dependent of epithelial-Gp130. Oncogene 2022; 41:1309-1323. [PMID: 34999736 PMCID: PMC8882147 DOI: 10.1038/s41388-021-02169-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 12/06/2021] [Accepted: 12/22/2021] [Indexed: 11/24/2022]
Abstract
Macrophages are increased in human benign prostatic hyperplasia and prostate cancer. We generate a Pb-Csf1 mouse model with prostate-specific overexpression of macrophage colony-stimulating factor (M-Csf/Csf1). Csf1 overexpression promotes immune cell infiltration into the prostate, modulates the macrophage polarity in a lobe-specific manner, and induces senescence and low-grade prostatic intraepithelial neoplasia (PIN). The Pb-Csf1 prostate luminal cells exhibit increased stem cell features and undergo an epithelial-to-mesenchymal transition. Human prostate cancer patients with high CSF-1 expression display similar transcriptional alterations with the Pb-Csf1 model. P53 knockout alleviates senescence but fails to progress PIN lesions. Ablating epithelial Gp130 but not Il1r1 substantially blocks PIN lesion formation. The androgen receptor (AR) is downregulated in Pb-Csf1 mice. ChIP-Seq analysis reveals altered AR binding in 2482 genes although there is no significant widespread change in global AR transcriptional activity. Collectively, our study demonstrates that increased macrophage infiltration causes PIN formation but fails to transform prostate cells.
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Affiliation(s)
- Oh-Joon Kwon
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Boyu Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Deyong Jia
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Li Zhang
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Xing Wei
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Zhicheng Zhou
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Deli Liu
- Sandra and Edward Meyer Cancer Center and Department of Urology, Weill Cornell Medicine, New York, NY, USA
| | - Khoi Trung Huynh
- Department of Biology, University of Washington, Seattle, WA, 98109, USA
| | - Kai Zhang
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Yiqun Zhang
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | | | - Andrea Sboner
- Sandra and Edward Meyer Cancer Center and Department of Urology, Weill Cornell Medicine, New York, NY, USA
| | - Chris Barbieri
- Sandra and Edward Meyer Cancer Center and Department of Urology, Weill Cornell Medicine, New York, NY, USA
| | - Michael C Haffner
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98109, USA
| | - Chad J Creighton
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Li Xin
- Department of Urology, University of Washington, Seattle, WA, 98109, USA.
- Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA.
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15
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Palano MT, Gallazzi M, Cucchiara M, Dehò F, Capogrosso P, Bruno A, Mortara L. The tumor innate immune microenvironment in prostate cancer: an overview of soluble factors and cellular effectors. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:694-718. [PMID: 36338516 PMCID: PMC9630328 DOI: 10.37349/etat.2022.00108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/12/2022] [Indexed: 01/14/2023] Open
Abstract
Prostate cancer (PCa) accounts as the most common non-cutaneous disease affecting males, and as the first cancer, for incidence, in male. With the introduction of the concept of immunoscore, PCa has been classified as a cold tumor, thus driving the attention in the development of strategies aimed at blocking the infiltration/activation of immunosuppressive cells, while favoring the infiltration/activation of anti-tumor immune cells. Even if immunotherapy has revolutionized the approaches to cancer therapy, there is still a window failure, due to the immune cell plasticity within PCa, that can acquire pro-tumor features, subsequent to the tumor microenvironment (TME) capability to polarize them. This review discussed selected relevant soluble factors [transforming growth factor-beta (TGFβ), interleukin-6 (IL-6), IL-10, IL-23] and cellular components of the innate immunity, as drivers of tumor progression, immunosuppression, and angiogenesis within the PCa-TME.
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Affiliation(s)
- Maria Teresa Palano
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, 20138 Milan, Italy
| | - Matteo Gallazzi
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Martina Cucchiara
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Federico Dehò
- Unit of Urology, ASST-Sette Laghi, Ospedale di Circolo e Fondazione Macchi, University of Insubria, 21100 Varese, Italy
| | - Paolo Capogrosso
- Unit of Urology, ASST-Sette Laghi, Ospedale di Circolo e Fondazione Macchi, University of Insubria, 21100 Varese, Italy
| | - Antonino Bruno
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, 20138 Milan, Italy,Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy,Correspondence: Antonino Bruno,
| | - Lorenzo Mortara
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy,Lorenzo Mortara, . Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
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16
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Szulc-Kielbik I, Kielbik M. Tumor-Associated Macrophages: Reasons to Be Cheerful, Reasons to Be Fearful. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:107-140. [PMID: 35165862 DOI: 10.1007/978-3-030-91311-3_4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Tumor microenvironment (TME) is a complex and constantly evolving entity that consists not only of cancer cells, but also of resident host cells and immune-infiltrating cells, among which macrophages are significant components, due to their diversity of functions through which they can influence the immune response against tumor cells. Macrophages present in tumor environment are termed as tumor-associated macrophages (TAMs). They are strongly plastic cells, and depending on the TME stimuli (i.e., cytokines, chemokines), TAMs polarize to antitumoral (M1-like TAMs) or protumoral (M2-like TAMs) phenotype. Both types of TAMs differ in the surface receptors' expression, activation of intracellular signaling pathways, and ability of production and various metabolites release. At the early stage of tumor formation, TAMs are M1-like phenotype, and they are able to eliminate tumor cells, i.e., by reactive oxygen species formation or by presentation of cancer antigens to other effector immune cells. However, during tumor progression, TAMs M2-like phenotype is dominating. They mainly contribute to angiogenesis, stromal remodeling, enhancement of tumor cells migration and invasion, and immunosuppression. This wide variety of TAMs' functions makes them an excellent subject for use in developing antitumor therapies which mainly is based on three strategies: TAMs' elimination, reprograming, or recruitment inhibition.
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Affiliation(s)
| | - Michal Kielbik
- Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
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17
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Jaramillo-Valverde L, Levano KS, Capristano S, Tarazona DD, Cisneros A, Yufra-Picardo VM, Valdivia-Silva J, Guio H. CXCR4 Knockdown Via CRISPR/CAS9 in a Tumor-Associated Macrophage Model Decreases Human Breast Cancer Cell Migration. Cureus 2021; 13:e20842. [PMID: 35111484 PMCID: PMC8794389 DOI: 10.7759/cureus.20842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction Breast cancer is the leading cause of cancer-related deaths in women worldwide with the majority of deaths due to metastasis. The development of metastasis is closely related to the tumor microenvironment where tumor-associated macrophages (TAMs) are the main immune cell component playing a crucial role in tumor migration. Key players in tumor progression, metastasis and survival are the receptor CXCR4 and its ligand CXCL12. CXCR4 is expressed in multiple cell types including macrophages and breast cancer cells. Many studies have focus on the role of CXCR4 expressed in breast cancer cells. Methods In this study, we investigated the role of CXCR4 expressed in TAMs on breast cancer cell migration by reducing CXCR4 expression via CRISPR-CAS9 system in differentiated THP-1 cells (a TAMs model). Results According to wound healing migration assay, MCF7 cancer cells co-cultured with genetically edited dTHP-1 cells have a lower migration rate as compared to MCF7 cancer cells co-cultured with unedited and dTHP-1 cells. Conclusion The study demonstrates the role of CXCR4 on breast cancer cell migration through TAM-cancer cell crosstalk.
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18
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Kim KS, Moon HS, Kim SS, Ryu JS. Involvement of Macrophages in Proliferation of Prostate Cancer Cells Infected with Trichomonas vaginalis. THE KOREAN JOURNAL OF PARASITOLOGY 2021; 59:557-564. [PMID: 34974662 PMCID: PMC8721302 DOI: 10.3347/kjp.2021.59.6.557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 11/23/2022]
Abstract
Macrophages play a key role in chronic inflammation, and are the most abundant immune cells in the tumor microenvironment. We investigated whether an interaction between inflamed prostate cancer cells stimulated with Trichomonas vaginalis and macrophages stimulates the proliferation of the cancer cells. Conditioned medium was prepared from T. vaginalis-infected (TCM) and uninfected (CM) mouse prostate cancer (PCa) cell line (TRAMP-C2 cells). Thereafter conditioned medium was prepared from macrophages (J774A.1 cell line) after incubation with CM (MCM) or TCM (MTCM). When TRAMP-C2 cells were stimulated with T. vaginalis, protein and mRNA levels of CXCL1 and CCL2 increased, and migration of macrophages toward TCM was more extensive than towards CM. Macrophages stimulated with TCM produced higher levels of CCL2, IL-6, TNF-α, their mRNAs than macrophages stimulated with CM. MTCM stimulated the proliferation and invasiveness of TRAMP-C2 cells as well as the expression of cytokine receptors (CCR2, GP130, CXCR2). Importantly, blocking of each cytokine receptors with anti-cytokine receptor antibody significantly reduced the proliferation and invasiveness of TRAMP-C2 cells. We conclude that inflammatory mediators released by TRAMP-C2 cells in response to infection by T. vaginalis stimulate the migration and activation of macrophages and the activated macrophages stimulate the proliferation and invasiveness of the TRAMP-C2 cells via cytokine-cytokine receptor binding. Our results therefore suggested that macrophages contribute to the exacerbation of PCa due to inflammation of prostate cancer cells reacted with T. vaginalis.
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Affiliation(s)
- Kyu-Shik Kim
- Department of Urology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923,
Korea
| | - Hong-Sang Moon
- Department of Urology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923,
Korea
| | - Sang-Su Kim
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul 04763,
Korea
| | - Jae-Sook Ryu
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul 04763,
Korea
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19
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Li B, Xia Y, Lv J, Wang W, Xuan Z, Chen C, Jiang T, Fang L, Wang L, Li Z, He Z, Li Q, Xie L, Qiu S, Zhang L, Zhang D, Xu H, Xu Z. miR-151a-3p-rich small extracellular vesicles derived from gastric cancer accelerate liver metastasis via initiating a hepatic stemness-enhancing niche. Oncogene 2021; 40:6180-6194. [PMID: 34535770 DOI: 10.1038/s41388-021-02011-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 08/18/2021] [Accepted: 09/06/2021] [Indexed: 12/24/2022]
Abstract
Liver metastasis (LM) severely affects gastric cancer (GC) patients' prognosis. Small extracellular vesicles (sEVs) play key roles in intercellular communication. Specific sEV-miRNAs from several types of cancer were found to induce a premetastatic niche in target organs before tumor cell arrive. However, whether the primary GC affects hepatic microenvironment or the role of sEV-miRNAs in GC-LM is yet unclear. We report that GC-derived sEVs are primarily absorbed by Kupffer cells (KCs). sEV-miR-151a-3p is highly expressed in GC-LM patients' plasma and presents poor prognosis. Treating mice with sEVs-enriched in miR-151a-3p promotes GC-LM, whereas has no influence on the proliferation of GC cells in situ. Mechanistically, sEV-miR-151a-3p inhibits SP3 in KCs. Simultaneously, sEV-miR-151a-3p targets YTHDF3 to decrease the transcriptional inhibitory activity of SP3 by reducing SUMO1 translation in a N6-methyladenosine-dependent manner. These factors contribute to TGF-β1 transactivation in KCs, subsequently activating the SMAD2/3 pathway and enhancing the stem cell-like properties of incoming GC cells. Furthermore, sEV-miR-151a-3p induces miR-151a-3p transcription in KCs to form a positive feedback loop. In summary, our results reveal a previously unidentified regulatory axis initiated by sEV-miR-151a-3p that establishes a hepatic stemness-permissive niche to support GC-LM. sEV-miR-151a-3p could be a promising diagnostic biomarker and preventive treatment candidate for GC-LM.
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Affiliation(s)
- Bowen Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Yiwen Xia
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Jialun Lv
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Zhe Xuan
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Cen Chen
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, the First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu Province, China
| | - Tianlu Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Lang Fang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Linjun Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Zhongyuan He
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Qingya Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Li Xie
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Shengkui Qiu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.,Department of General Surgery, the Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Lu Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Diancai Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China. .,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
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20
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Hu J, Ma Y, Ma J, Yang Y, Ning Y, Zhu J, Wang P, Chen G, Liu Y. M2 Macrophage-Based Prognostic Nomogram for Gastric Cancer After Surgical Resection. Front Oncol 2021; 11:690037. [PMID: 34458140 PMCID: PMC8397443 DOI: 10.3389/fonc.2021.690037] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/29/2021] [Indexed: 12/24/2022] Open
Abstract
A good prediction model is useful to accurately predict patient prognosis. Tumor-node-metastasis (TNM) staging often cannot accurately predict prognosis when used alone. Some researchers have shown that the infiltration of M2 macrophages in many tumors indicates poor prognosis. This approach has the potential to predict prognosis more accurately when used in combination with TNM staging, but there is less research in gastric cancer. A multivariate analysis demonstrated that CD163 expression, TNM staging, age, and gender were independent risk factors for overall survival. Thus, these parameters were assessed to develop the nomogram in the training data set, which was tested in the validation and whole data sets. The model showed a high degree of discrimination, calibration, and good clinical benefit in the training, validation, and whole data sets. In conclusion, we combined CD163 expression in macrophages, TNM staging, age, and gender to develop a nomogram to predict 3- and 5-year overall survivals after curative resection for gastric cancer. This model has the potential to provide further diagnostic and prognostic value for patients with gastric cancer.
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Affiliation(s)
- Jianwen Hu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yongchen Ma
- Endoscopy Center, Peking University First Hospital, Beijing, China
| | - Ju Ma
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yanpeng Yang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yingze Ning
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Jing Zhu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Pengyuan Wang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Guowei Chen
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yucun Liu
- Department of General Surgery, Peking University First Hospital, Beijing, China
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21
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High Monocyte Count and Expression of S100A9 and S100A12 in Peripheral Blood Mononuclear Cells Are Associated with Poor Outcome in Patients with Metastatic Prostate Cancer. Cancers (Basel) 2021; 13:cancers13102424. [PMID: 34067757 PMCID: PMC8156049 DOI: 10.3390/cancers13102424] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/05/2021] [Accepted: 05/14/2021] [Indexed: 01/14/2023] Open
Abstract
Increasing evidence indicates calcium-binding S100 protein involvement in inflammation and tumor progression. In this prospective study, we evaluated the mRNA levels of two members of this family, S100A9 and S100A12, in peripheral blood mononuclear cells (PBMCs) in a cohort of 121 prostate cancer patients using RT-PCR. Furthermore, monocyte count was determined by flow cytometry. By stratifying patients into different risk groups, according to TNM stage, Gleason score and PSA concentration at diagnosis, expression of S100A9 and S100A12 was found to be significantly higher in patients with metastases compared to patients without clinically detectable metastases. In line with this, we observed that the protein levels of S100A9 and S100A12 in plasma were higher in patients with advanced disease. Importantly, in patients with metastases at diagnosis, high monocyte count and high levels of S100A9 and S100A12 were significantly associated with short progression free survival (PFS) after androgen deprivation therapy (ADT). High monocyte count and S100A9 levels were also associated with short cancer-specific survival, with monocyte count providing independent prognostic information. These findings indicate that circulating levels of monocytes, as well as S100A9 and S100A12, could be biomarkers for metastatic prostate cancer associated with particularly poor prognosis.
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22
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Bahmad HF, Jalloul M, Azar J, Moubarak MM, Samad TA, Mukherji D, Al-Sayegh M, Abou-Kheir W. Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development. Front Genet 2021; 12:652747. [PMID: 33841508 PMCID: PMC8033163 DOI: 10.3389/fgene.2021.652747] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer (PCa) is by far the most commonly diagnosed cancer in men worldwide. Despite sensitivity to androgen deprivation, patients with advanced disease eventually develop resistance to therapy and may die of metastatic castration-resistant prostate cancer (mCRPC). A key challenge in the management of PCa is the clinical heterogeneity that is hard to predict using existing biomarkers. Defining molecular biomarkers for PCa that can reliably aid in diagnosis and distinguishing patients who require aggressive therapy from those who should avoid overtreatment is a significant unmet need. Mechanisms underlying the development of PCa are not confined to cancer epithelial cells, but also involve the tumor microenvironment. The crosstalk between epithelial cells and stroma in PCa has been shown to play an integral role in disease progression and metastasis. A number of key markers of reactive stroma has been identified including stem/progenitor cell markers, stromal-derived mediators of inflammation, regulators of angiogenesis, connective tissue growth factors, wingless homologs (Wnts), and integrins. Here, we provide a synopsis of the stromal-epithelial crosstalk in PCa focusing on the relevant molecular biomarkers pertaining to the tumor microenvironment and their role in diagnosis, prognosis, and therapy development.
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Affiliation(s)
- Hisham F. Bahmad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, United States
| | - Mohammad Jalloul
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Joseph Azar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Maya M. Moubarak
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Tamara Abdul Samad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Deborah Mukherji
- Department of Internal Medicine, Division of Hematology-Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mohamed Al-Sayegh
- Biology Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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23
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Sletta KY, Castells O, Gjertsen BT. Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia. Front Oncol 2021; 11:654817. [PMID: 33842370 PMCID: PMC8027480 DOI: 10.3389/fonc.2021.654817] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/03/2021] [Indexed: 11/13/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive heterogeneous blood cancer derived from hematopoietic stem cells. Tumor-stromal interactions in AML are of importance for disease development and therapy resistance, and bone marrow stroma seem like an attractive therapeutic target. Of particular interest is colony stimulating factor 1 receptor (CSF1R, M-CSFR, c-FMS, CD115) and its role in regulating plasticity of tumor-associated macrophages. We discuss first the potential of CSF1R-targeted therapy as an attractive concept with regards to the tumor microenvironment in the bone marrow niche. A second therapy approach, supported by preclinical research, also suggests that CSF1R-targeted therapy may increase the beneficial effect of conventional and novel therapeutics. Experimental evidence positioning inhibitors of CSF1R as treatment should, together with data from preclinical and early phase clinical trials, facilitate translation and clinical development of CSF1R-targeted therapy for AML.
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Affiliation(s)
- Kristine Yttersian Sletta
- CCBIO, Centre for Cancer Biomarkers, Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Bergen, Norway
| | - Oriol Castells
- Department of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway
| | - Bjørn Tore Gjertsen
- CCBIO, Centre for Cancer Biomarkers, Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Bergen, Norway
- Department of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway
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24
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Lodewijk I, Nunes SP, Henrique R, Jerónimo C, Dueñas M, Paramio JM. Tackling tumor microenvironment through epigenetic tools to improve cancer immunotherapy. Clin Epigenetics 2021; 13:63. [PMID: 33761971 PMCID: PMC7992805 DOI: 10.1186/s13148-021-01046-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage. MAIN BODY Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy. CONCLUSION Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.
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Affiliation(s)
- Iris Lodewijk
- Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales Y Tecnológicas (CIEMAT), 28040 Madrid, Spain
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, 28041 Madrid, Spain
| | - Sandra P. Nunes
- Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales Y Tecnológicas (CIEMAT), 28040 Madrid, Spain
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, 28041 Madrid, Spain
- Cancer Biology and Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal
- Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar – University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar – University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Marta Dueñas
- Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales Y Tecnológicas (CIEMAT), 28040 Madrid, Spain
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, 28041 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Jesús M. Paramio
- Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales Y Tecnológicas (CIEMAT), 28040 Madrid, Spain
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, 28041 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
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25
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The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment. J Xenobiot 2021; 11:16-32. [PMID: 33535458 PMCID: PMC7931005 DOI: 10.3390/jox11010002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer is one of the most common cancers diagnosed in men in the United States and the second leading cause of cancer-related deaths worldwide. Since over 60% of prostate cancer cases occur in men over 65 years of age, and this population will increase steadily in the coming years, prostate cancer will be a major cancer-related burden in the foreseeable future. Accumulating data from more recent research suggest that the tumor microenvironment (TME) plays a previously unrecognized role in every stage of cancer development, including initiation, proliferation, and metastasis. Prostate cancer is not only diagnosed in the late stages of life, but also progresses relatively slowly. This makes prostate cancer an ideal model system for exploring the potential of natural products as cancer prevention and/or treatment reagents because they usually act relatively slowly compared to most synthetic drugs. Resveratrol (RSV) is a naturally occurring stilbenoid and possesses strong anti-cancer properties with few adverse effects. Accumulating data from both in vitro and in vivo experiments indicate that RSV can interfere with prostate cancer initiation and progression by targeting the TME. Therefore, this review is aimed to summarize the recent advancement in RSV-inhibited prostate cancer initiation, proliferation, and metastasis as well as the underlying molecular mechanisms, with particular emphasis on the effect of RSV on TME. This will not only better our understanding of prostate cancer TMEs, but also pave the way for the development of RSV as a potential reagent for prostate cancer prevention and/or therapy.
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26
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Halin Bergström S, Rudolfsson S, Lundholm M, Josefsson A, Wikström P, Bergh A. High-grade tumours promote growth of other less-malignant tumours in the same prostate. J Pathol 2021; 253:396-403. [PMID: 33330991 PMCID: PMC7986692 DOI: 10.1002/path.5604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022]
Abstract
Prostate cancer is a multifocal disease, but if and how individual prostate tumours influence each other is largely unknown. We therefore explored signs of direct or indirect tumour–tumour interactions in experimental models and patient samples. Low‐metastatic AT1 and high‐metastatic MatLyLu (MLL) Dunning rat prostate cancer cells were injected into separate lobes of the ventral prostate of immunocompetent rats. AT1 tumours growing in the same prostate as MLL tumours had increased tumour size and proliferation compared to AT1 tumours growing alone. In addition, the vasculature and macrophage density surrounding the AT1 tumours were increased by MLL tumour closeness. In patient prostatectomy samples, selected to contain an index tumour [tumour with the highest grade, International Society of Urological Pathology (ISUP) grade 1, 2, 3 or 4] and a low‐grade satellite tumour (ISUP grade 1), cell proliferation in low‐grade satellite tumours gradually increased with increasing histological grade of the index tumour. The density of blood vessels and CD68+ macrophages also increased around the low‐grade satellite tumour if a high‐grade index tumour was present. This suggests that high‐grade tumours, by changing the prostate microenvironment, may increase the aggressiveness of low‐grade lesions in the organ. Future studies are needed to explore the mechanisms behind tumour–tumour interactions and their clinical importance. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
| | - Stina Rudolfsson
- Department of Surgical and Perioperative Sciences, Urology, Umeå University, Umeå, Sweden
| | - Marie Lundholm
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Andreas Josefsson
- Department of Surgical and Perioperative Sciences, Urology, Umeå University, Umeå, Sweden
| | - Pernilla Wikström
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Anders Bergh
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
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27
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Iwamoto H, Izumi K, Mizokami A. Is the C-C Motif Ligand 2-C-C Chemokine Receptor 2 Axis a Promising Target for Cancer Therapy and Diagnosis? Int J Mol Sci 2020; 21:ijms21239328. [PMID: 33297571 PMCID: PMC7730417 DOI: 10.3390/ijms21239328] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/03/2020] [Accepted: 12/05/2020] [Indexed: 12/13/2022] Open
Abstract
C-C motif ligand 2 (CCL2) was originally reported as a chemical mediator attracting mononuclear cells to inflammatory tissue. Many studies have reported that CCL2 can directly activate cancer cells through a variety of mechanisms. CCL2 can also promote cancer progression indirectly through increasing the recruitment of tumor-associated macrophages into the tumor microenvironment. The role of CCL2 in cancer progression has gradually been understood, and various preclinical cancer models elucidate that CCL2 and its receptor C-C chemokine receptor 2 (CCR2) are attractive targets for intervention in cancer development. However, clinically available drugs that regulate the CCL2-CCR2 axis as anticancer agents are not available at this time. The complete elucidation of not only the oncological but also the physiological functions of the CCL2-CCR2 axis is required for achieving a satisfactory effect of the CCL2-CCR2 axis-targeted therapy.
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Affiliation(s)
| | - Kouji Izumi
- Correspondence: ; Tel.: +81-76-265-2393; Fax: +81-76-234-4263
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28
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Larionova I, Tuguzbaeva G, Ponomaryova A, Stakheyeva M, Cherdyntseva N, Pavlov V, Choinzonov E, Kzhyshkowska J. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers. Front Oncol 2020; 10:566511. [PMID: 33194645 PMCID: PMC7642726 DOI: 10.3389/fonc.2020.566511] [Citation(s) in RCA: 259] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth and metastasis. The accumulated data are essential for using TAMs as biomarkers and therapeutic targets to develop cancer-specific immunotherapy and to design efficient combinations of traditional therapy and new immunomodulatory approaches.
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Affiliation(s)
- Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Gulnara Tuguzbaeva
- Department of Pathophysiology, Bashkir State Medical University, Ufa, Russia
| | - Anastasia Ponomaryova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Marina Stakheyeva
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Nadezhda Cherdyntseva
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Valentin Pavlov
- Department of Urology, Bashkir State Medical University, Ufa, Russia
| | - Evgeniy Choinzonov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg—Hessen, Mannheim, Germany
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Chatterjee B, Saha P, Bose S, Shukla D, Chatterjee N, Kumar S, Tripathi PP, Srivastava AK. MicroRNAs: As Critical Regulators of Tumor- Associated Macrophages. Int J Mol Sci 2020; 21:ijms21197117. [PMID: 32992449 PMCID: PMC7582892 DOI: 10.3390/ijms21197117] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 12/11/2022] Open
Abstract
Emerging shreds of evidence suggest that tumor-associated macrophages (TAMs) modulate various hallmarks of cancer during tumor progression. Tumor microenvironment (TME) prime TAMs to execute important roles in cancer development and progression, including angiogenesis, matrix metalloproteinases (MMPs) secretion, and extracellular matrix (ECM) disruption. MicroRNAs (miRNAs) are critical epigenetic regulators, which modulate various functions in diverse types of cells, including macrophages associated with TME. In this review article, we provide an update on miRNAs regulating differentiation, maturation, activation, polarization, and recruitment of macrophages in the TME. Furthermore, extracellular miRNAs are secreted from cancerous cells, which control macrophages phenotypic plasticity to support tumor growth. In return, TAMs also secrete various miRNAs that regulate tumor growth. Herein, we also describe the recent updates on the molecular connection between tumor cells and macrophages. A better understanding of the interaction between miRNAs and TAMs will provide new pharmacological targets to combat cancer.
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Affiliation(s)
- Bilash Chatterjee
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
| | - Priyanka Saha
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
| | - Subhankar Bose
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
| | - Devendra Shukla
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
| | - Nabanita Chatterjee
- Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, WB 700026, India;
| | - Sanjay Kumar
- Division of Biology, Indian Institute of Science Education & Research, Tirupati, Andhra Pradesh 517507, India;
| | - Prem Prakash Tripathi
- Cell Biology & Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India;
| | - Amit Kumar Srivastava
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
- Correspondence:
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Gwak J, Jeong H, Lee K, Shin JY, Sim T, Na J, Kim J, Ju BG. SFMBT2-Mediated Infiltration of Preadipocytes and TAMs in Prostate Cancer. Cancers (Basel) 2020; 12:E2718. [PMID: 32971847 PMCID: PMC7565541 DOI: 10.3390/cancers12092718] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/07/2020] [Accepted: 08/16/2020] [Indexed: 12/22/2022] Open
Abstract
Infiltration of diverse cell types into tumor microenvironment plays a critical role in cancer progression including metastasis. We previously reported that SFMBT2 (Scm-like with four mbt domains 2) regulates the expression of matrix metalloproteinases (MMPs) and migration and invasion of cancer cells in prostate cancer. Here we investigated whether the down-regulation of SFMBT2 regulates the infiltration of preadipocytes and tumor-associated macrophages (TAMs) in prostate cancer. We found that the down-regulation of SFMBT2 promotes the infiltration of preadipocytes and TAMs through up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression in prostate cancer. Expression of CXCL8, CCL2, CXCL10, and CCL20 was also elevated in prostate cancer patients having a higher Gleason score (≥8), which had substantially lower SFMBT2 expression. We also found that the up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression is dependent on NF-κB activation in prostate cancer cells expressing a low level of SFMBT2. Moreover, increased IL-6 from infiltrated preadipocytes and TAMs promoted migration and invasion of prostate cancer cells expressing a low level of SFMBT2. Our study may suggest that SFMBT2 a critical regulator for the infiltration of preadipocytes and TAMs into the prostate tumor microenvironment. Thus, the regulation of SFMBT2 may provide a new therapeutic strategy to inhibit prostate cancer metastasis, and SFMBT2 could be used as a potential biomarker in prostate cancer metastasis.
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Affiliation(s)
| | | | | | | | | | | | | | - Bong-Gun Ju
- Department of Life Science, Sogang University, Seoul 04107, Korea; (J.G.); (H.J.); (K.L.); (J.Y.S.); (T.S.); (J.N.); (J.K.)
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31
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Krijgsman D, De Vries NL, Andersen MN, Skovbo A, Tollenaar RA, Møller HJ, Hokland M, Kuppen PJ. CD163 as a Biomarker in Colorectal Cancer: The Expression on Circulating Monocytes and Tumor-Associated Macrophages, and the Soluble Form in the Blood. Int J Mol Sci 2020; 21:E5925. [PMID: 32824692 PMCID: PMC7460610 DOI: 10.3390/ijms21165925] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/12/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022] Open
Abstract
The macrophage-associated molecule CD163 has been reported as a prognostic biomarker in different cancer types, but its role in colorectal cancer (CRC) is unclear. We studied CD163 in the tumor microenvironment and circulation of patients with CRC in relation to clinicopathological parameters. An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum sCD163 levels and multiparameter flow cytometry was used to study the peripheral blood monocytes and their CD163 expression in CRC patients (N = 78) and healthy donors (N = 50). The distribution of tumor-associated macrophages (TAMs) was studied in primary colorectal tumors with multiplex immunofluorescence. We showed that CRC patients with above-median sCD163 level had a shorter overall survival (OS, p = 0.035) as well as disease-free survival (DFS, p = 0.005). The above-median sCD163 remained significantly associated with a shorter DFS in the multivariate analysis (p = 0.049). Moreover, a shorter OS was observed in CRC patients with an above-median total monocyte percentage (p = 0.007). The number and phenotype of the stromal and intraepithelial TAMs in colorectal tumors were not associated with clinical outcome. In conclusion, sCD163 and monocytes in the circulation may be potential prognostic biomarkers in CRC patients, whereas TAMs in the tumor showed no association with clinical outcome. Thus, our results emphasize the importance of the innate systemic immune response in CRC disease progression.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antigens, CD/blood
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Differentiation, Myelomonocytic/blood
- Antigens, Differentiation, Myelomonocytic/genetics
- Antigens, Differentiation, Myelomonocytic/metabolism
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Colorectal Neoplasms/blood
- Colorectal Neoplasms/pathology
- Disease-Free Survival
- Female
- Humans
- Male
- Middle Aged
- Monocytes/metabolism
- Receptors, Cell Surface/blood
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Tumor-Associated Macrophages/metabolism
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Affiliation(s)
- Daniëlle Krijgsman
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (D.K.); (N.L.D.V.); (R.A.E.M.T.)
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (M.N.A.); (A.S.); (M.H.)
| | - Natasja L. De Vries
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (D.K.); (N.L.D.V.); (R.A.E.M.T.)
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (M.N.A.); (A.S.); (M.H.)
| | - Morten N. Andersen
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (M.N.A.); (A.S.); (M.H.)
- Department of Clinical Biochemistry, Aarhus University Hospital, 8200 Aarhus, Denmark;
| | - Anni Skovbo
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (M.N.A.); (A.S.); (M.H.)
- FACS Core Facility, Aarhus University, 8200 Aarhus, Denmark
| | - Rob A.E.M. Tollenaar
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (D.K.); (N.L.D.V.); (R.A.E.M.T.)
| | - Holger J. Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, 8200 Aarhus, Denmark;
| | - Marianne Hokland
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (M.N.A.); (A.S.); (M.H.)
| | - Peter J.K. Kuppen
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (D.K.); (N.L.D.V.); (R.A.E.M.T.)
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32
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Sun YL, Zhang Y, Guo YC, Yang ZH, Xu YC. A Prognostic Model Based on the Immune-related Genes in Colon Adenocarcinoma. Int J Med Sci 2020; 17:1879-1896. [PMID: 32788867 PMCID: PMC7415395 DOI: 10.7150/ijms.45813] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/07/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Immune-related genes (IRGs) are critically involved in the tumor microenvironment (TME) of colon adenocarcinoma (COAD). Here, the study was mainly designed to establish a prognostic model of IRGs to predict the survival of COAD patients. Methods: The Cancer Genome Atlas (TCGA), Immunology Database and Analysis Portal (ImmPort) database, and Cistrome database were utilized for extracting data regarding the expression of immune gene- and tumor-related transcription factors (TFs), aimed at the identification of differentially expressed genes (DEGs), differentially expressed IRGs (DEIRGs), and differentially expressed TFs (DETFs). Univariate Cox regression analysis was subsequently performed for the acquisition of prognosis-related IRGs, followed by establishment of TF regulatory network for uncovering the possible molecular regulatory association in COAD. Subsequently, multivariate Cox regression analysis was conducted to further determine the role of prognosis-related IRGs for prognostic prediction in COAD. Finally, the feasibility of a prognostic model with immunocytes was explored by immunocyte infiltration analysis. Results: A total of 2450 DEGs, 8 DETFs, and 79 DEIRGs were extracted from the corresponding databases. Univariate Cox regression analysis revealed 11 prognosis-related IRGs, followed by establishment of a regulatory network on prognosis-related IRGs at transcriptional levels. Functionally, IRG GLP2R was negatively modulated by TF MYH11, whereas IRG TDGF1 was positively modulated by TF TFAP2A. Multivariate Cox regression analysis was subsequently performed to establish a prognostic model on the basis of seven prognosis-related IRGs (GLP2R, ESM1, TDGF1, SLC10A2, INHBA, STC2, and CXCL1). Moreover, correlation analysis of immunocyte infiltration also revealed that the seven-IRG prognostic model was positively associated with five types of immunocytes (dendritic cell, macrophage, CD4 T cell, CD8 T cell, and neutrophil), which may directly reflect tumor immune state in COAD. Conclusions: Our present findings indicate that the prognostic model based on prognosis-related IRGs plays a crucial role in the clinical supervision and prognostic prediction of COAD patients at both molecular and cellular levels.
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Affiliation(s)
| | | | | | | | - Yue-Chao Xu
- Department of Gastrointestinal Surgery, The First Hospital, Jilin University, Changchun 130021, Jilin Province, China
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33
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Consiglio CR, Udartseva O, Ramsey KD, Bush C, Gollnick SO. Enzalutamide, an Androgen Receptor Antagonist, Enhances Myeloid Cell-Mediated Immune Suppression and Tumor Progression. Cancer Immunol Res 2020; 8:1215-1227. [PMID: 32661092 DOI: 10.1158/2326-6066.cir-19-0371] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/02/2019] [Accepted: 06/30/2020] [Indexed: 01/31/2023]
Abstract
Androgen receptor (AR) antagonism increases overall survival in prostate cancer; however, treatment failure leads to tumor progression and patient mortality. The effect of AR modulation on AR+ nontumor cells that participate in the resistance to AR antagonism is poorly understood. Tumor-infiltrating myeloid cells, including macrophages and myeloid-derived suppressor cells (MDSC), express AR and promote prostate cancer progression. We investigated how AR antagonism affects myeloid cell function and metabolism in an AR-independent murine colon tumor model. Systemic blockade of AR with enzalutamide resulted in increased MC-38 tumor growth in vivo even when AR was knocked out of MC-38 tumor cells. MC-38 tumor growth was also increased when immunocompetent, but not immunodeficient, mice were coinjected with tumor cells and MDSCs treated with enzalutamide or lacking AR, suggesting that AR regulated the ability of MDSCs to suppress adaptive immunity. Myeloid AR-knockout male mice also displayed increased growth of TRAMP C2 prostate tumors when compared with wild type. Inhibition of AR signaling suppressed mitochondrial respiration in myeloid cells via MPC/AMPK signaling pathways; suppression of mitochondrial respiration increased MDSC tumor-promoting functions. Our work showed that AR regulates a tumor-promoting myeloid cell phenotype and influences myeloid cell metabolism. These findings suggest that tumor resistance to AR antagonism is due, in part, to changes in myeloid cell function and metabolism.
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Affiliation(s)
- Camila R Consiglio
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Olga Udartseva
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kimberly D Ramsey
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Chioma Bush
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Sandra O Gollnick
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York. .,Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
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34
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Jamiyan T, Kuroda H, Yamaguchi R, Abe A, Hayashi M. CD68- and CD163-positive tumor-associated macrophages in triple negative cancer of the breast. Virchows Arch 2020; 477:767-775. [PMID: 32607685 PMCID: PMC7683466 DOI: 10.1007/s00428-020-02855-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 05/24/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022]
Abstract
Tumor-associated macrophages (TAMs) have recently been reported as an important factor in tumor growth and the progression of cancer. The prognostic significance of localizations and densities of TAMs in triple negative cancer (TNC) of the breast is not well understood. The aim of this study was to assess the localizations and densities of the TAMs subtype in TNC and examine their clinicopathological features. The study was based on 107 TNC cases operated on at Dokkyo Medical University Hospital using the pan-macrophage marker CD68 and the M2 macrophage marker CD163 in the tumor stroma (TS) and tumor nest (TN), respectively, and examined the clinicopathological significance. Multivariate Cox regression analyses revealed that age and CD163+ TAMs in both the TS and TN were independent prognostic factors for relapse-free survival and overall survival. No correlation was found between the number of CD68+ cells or the CD163/CD68 ratio either in TS or TN, or clinicopathological features. Our study found that infiltration of CD163+ TAMs, rather than CD68+, in both TS and TN was associated with poor prognosis in TNC patients by multivariate analysis. This suggests that CD163+ TAMs may affect the prognosis of TNC by not only regulating the immune reaction by TAMs in TS, but also because of their direct influence on TN.
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Affiliation(s)
- Tsengelmaa Jamiyan
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga District, Tochigi, 321-0293, Japan.,Department of Pathology and Forensic medicine, Mongolian National University of Medical Sciences, Jamyan St 3, Ulaanbaatar, 14210, Mongolia
| | - Hajime Kuroda
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga District, Tochigi, 321-0293, Japan. .,Department of Diagnostic Pathology, Tokyo Women's Medical University, Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo 116-8567, Japan.
| | - Rin Yamaguchi
- Department of Pathology and Laboratory Medicine, Kurume University Medical Center, 155-1 Kokubumachi, Kurume, Fukuoka, 839-0863, Japan
| | - Akihito Abe
- Breast center, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga District, Tochigi 321-0293, Japan.,Department of Surgery II, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga District, Tochigi, 321-0293, Japan
| | - Mitsuhiro Hayashi
- Breast center, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga District, Tochigi 321-0293, Japan
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35
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Jairath NK, Farha MW, Srinivasan S, Jairath R, Green MD, Dess RT, Jackson WC, Weiner AB, Schaeffer EM, Zhao SG, Feng FY, El Naqa I, Spratt DE. Tumor Immune Microenvironment Clusters in Localized Prostate Adenocarcinoma: Prognostic Impact of Macrophage Enriched/Plasma Cell Non-Enriched Subtypes. J Clin Med 2020; 9:jcm9061973. [PMID: 32599760 PMCID: PMC7356642 DOI: 10.3390/jcm9061973] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/11/2020] [Accepted: 06/23/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Prostate cancer (PCa) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of prostate adenocarcinomas (n = 492) was utilized. The immune microenvironment was characterized using the CIBERSORTX tool to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Analyses of progression-free survival (PFS), distant metastases, and overall survival (OS) were performed using Kaplan–Meier estimates and Cox regression multivariable analyses. Results: Four immune clusters were identified, largely defined by plasma cell, CD4+ Memory Resting T Cells (CD4 MR), and M0 and M2 macrophage content (CD4 MRHighPlasma CellHighM0LowM2Mid, CD4 MRLowPlasma CellHighM0LowM2Low, CD4 MRHighPlasma CellLowM0HighM2Low, and CD4 MRHighPlasma CellLowM0LowM2High). The two macrophage-enriched/plasma cell non-enriched clusters (3 and 4) demonstrated worse PFS (HR 2.24, 95% CI 1.46–3.45, p = 0.0002) than the clusters 1 and 2. No metastatic events occurred in the plasma cell enriched, non-macrophage-enriched clusters. Comparing clusters 3 vs. 4, in patients treated by surgery alone, cluster 3 had zero progression events (p < 0.0001). However, cluster 3 patients had worse outcomes after post-operative radiotherapy (p = 0.018). Conclusion: Distinct tumor immune clusters with a macrophage-enriched, plasma cell non-enriched phenotype and reduced plasma cell enrichment independently characterize an aggressive phenotype in localized prostate cancer that may differentially respond to treatment.
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Affiliation(s)
- Neil K. Jairath
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
| | - Mark W. Farha
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
| | - Sudharsan Srinivasan
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
| | - Ruple Jairath
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
| | - Michael D. Green
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
- Veterans Affair Ann Arbor Healthcare System, University of Michigan, Ann Arbor, MI 48104, USA
| | - Robert T. Dess
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
| | - William C. Jackson
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
| | - Adam B. Weiner
- Department of Urology, Northwestern University, Chicago, IL 60611, USA; (A.B.W.); (E.M.S.)
| | - Edward M. Schaeffer
- Department of Urology, Northwestern University, Chicago, IL 60611, USA; (A.B.W.); (E.M.S.)
| | - Shuang G. Zhao
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
| | - Felix Y. Feng
- Department of Radiation Oncology, UCSF, San Francisco, CA 94143, USA;
| | - Issam El Naqa
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
| | - Daniel E. Spratt
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48104, USA; (N.K.J.); (M.W.F.); (S.S.); (R.J.); (M.D.G.); (R.T.D.); (W.C.J.); (S.G.Z.); (I.E.N.)
- Correspondence: ; Tel.: +734-647-1372; Fax: +734-936-1900
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Yuri P, Shigemura K, Kitagawa K, Hadibrata E, Risan M, Zulfiqqar A, Soeroharjo I, Hendri AZ, Danarto R, Ishii A, Yamasaki S, Yan Y, Heriyanto DS, Fujisawa M. Increased tumor-associated macrophages in the prostate cancer microenvironment predicted patients' survival and responses to androgen deprivation therapies in Indonesian patients cohort. Prostate Int 2020; 8:62-69. [PMID: 32647642 PMCID: PMC7335973 DOI: 10.1016/j.prnil.2019.12.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 10/14/2019] [Accepted: 12/11/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) and microvessel density (MVD) play an essential role for tumor progression in prostate cancer (PCa). In this study, we evaluated the association between TAMs, the infiltration with tumor angiogenesis and the response to androgen deprivation therapies (ADTs) in PCa to evaluate TAM infiltration as a predictive factor for PCa survival. MATERIALS AND METHODS Fifty-four specimens were collected and stained with CD 68 antibody to investigated TAM infiltration in tumor. Von Willebrand factor was stained to evaluate MVD around the cancer foci. We assessed the association between patient's age, preoperative serum prostate-specific antigen, pathologic Gleason sum (GS), TAM infiltration, MVD, and the response to ADT for 5 years after PCa diagnosis. RESULTS The median TAM was observed in 28 (6-76)/high power field (x400). Increasing TAM correlated with increasing tumor angiogenesis (P < 0.001, r = 0.61), and the response to ADT was significantly better in patients with fewer TAMs (<28) than in patients with higher TAMs (>28) (P = 0.003). TAM infiltration was significantly higher in those with higher serum prostate-specific antigen, higher GS, and metastasis. Multivariate analysis showed that GS, ADT type, and MVD number were significant prognostic factors for response to ADT in PCa (P < 0.0001). An increased infiltration of TAM [hazards ratio (HR) = 4.47; 95% confidence interval (CI): 1.97-10.15], MVD (HR = 2.66; 95% CI: 1.27-5.61), metastatic status (HR = 2.29; 95% CI: 0.14-0.60), and prostate volume (HR = 2.19; 95% CI: 1.27-3.12) significantly correlated with shorter survival in PCa patients by univariate analysis (P < 0.05). Multivariate analyses revealed that TAM and metastatic status significantly correlated with poor overall survival. CONCLUSIONS TAM infiltration is associated with response to ADT and increased tumor angiogenesis in PCa. GS, ADT type, and MVD in PCa specimens are useful predictive factors for poor response to ADT. Increasing TAM and positive metastatic status were prognostic factors for a poorer survival in PCa patients.
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Affiliation(s)
- Prahara Yuri
- Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
| | - Katsumi Shigemura
- Division of Urology, Department of Organ Therapeutics, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
- Department of International Health, Kobe University Graduate School of Health Science, Kobe, 654-0142, Japan
| | - Koichi Kitagawa
- Department of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, 650-0017, Japan
| | - Exsa Hadibrata
- Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
| | - Muhammad Risan
- Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
| | - Andy Zulfiqqar
- Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
| | - Indrawarman Soeroharjo
- Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
| | - Ahmad Z. Hendri
- Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
| | - Raden Danarto
- Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
| | - Aya Ishii
- Department of International Health, Kobe University Graduate School of Health Science, Kobe, 654-0142, Japan
| | - Saya Yamasaki
- Department of International Health, Kobe University Graduate School of Health Science, Kobe, 654-0142, Japan
| | - Yongmin Yan
- Department of International Health, Kobe University Graduate School of Health Science, Kobe, 654-0142, Japan
| | - Didik S. Heriyanto
- Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
| | - Masato Fujisawa
- Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta, 55281, Indonesia
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Han IH, Song HO, Ryu JS. IL-6 produced by prostate epithelial cells stimulated with Trichomonas vaginalis promotes proliferation of prostate cancer cells by inducing M2 polarization of THP-1-derived macrophages. PLoS Negl Trop Dis 2020; 14:e0008126. [PMID: 32196489 PMCID: PMC7138318 DOI: 10.1371/journal.pntd.0008126] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 04/07/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Trichomonas vaginalis (Tv), a protozoan parasite causing sexually-transmitted disease, has been detected in tissue of prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa). IL-6, a mediator of chronic inflammation, induces the progression of prostate cancer, and influences the polarization of M2 macrophages, which are the main tumor-associated macrophages. We investigated whether IL-6 produced by human prostate epithelial cells stimulated with Tv induces the M2 polarization of THP-1-derived macrophages, which in turn promotes the progression of PCa. Conditioned medium was prepared from Tv-infected (TCM) and uninfected (CM) prostate epithelial cells (RWPE-1). Thereafter conditioned medium was prepared from macrophages after incubation with CM (M-CM) or TCM (M-TCM). RWPE-1 cells infected with Tv produced IL-6 and chemokines such as CCL2 and CXCL8. When human macrophages were treated with conditioned medium of RWPE-1 cells co-cultured with Tv (TCM), they became polarized to M2-like macrophages as indicated by the production of IL-10 and TGF-β, and the expression of CD36 and arginase-1, which are M2 macrophage markers. Moreover, proliferation of the M2-like macrophages was also increased by TCM. Blockade of IL-6 signaling with IL-6 receptor antibody and JAK inhibitor (Ruxolitinib) inhibited M2 polarization of THP-1-derived macrophages and proliferation of the macrophages. To assess the effect of crosstalk between macrophages and prostate epithelial cells inflamed by Tv infection on the growth of prostate cancer (PCa) cells, PC3, DU145 and LNCaP cells were treated with conditioned medium from THP-1-derived macrophages stimulated with TCM (M-TCM). Proliferation and migration of the PCa cells were significantly increased by the M-TCM. Our findings suggest that IL-6 produced in response to Tv infection of the prostate has an important effect on the tumor microenvironment by promoting progression of PCa cells following induction of M2 macrophage polarization. In male, T. vaginalis infection have been proposed to involve in several prostate diseases such as prostatitis, benign prostatic hyperplasia and prostate cancer. However, studies for these mechanisms have been rare. We have previously reported that T. vaginalis induce the production of inflammatory cytokines in prostate cells. Among these cytokines, IL-6 have been reported to play an important role in M2 macrophage polarization, which lead to formation of tumor microenvironment in various cancers. Here we show that IL-6 produced by T. vaginalis infection in prostate epithelial cells induces M2 polarization of macrophages and these macrophages promote proliferation of prostate cancer cells. These findings suggest that T. vaginalis indirectly induces progression of prostate cancer by creating a tumor microenvironment through an inflammatory response.
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Affiliation(s)
- Ik-Hwan Han
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul, Korea
| | - Hyun-Ouk Song
- Department of Parasitology, School of Medicine, Catholic University of Daegu, Daegu, Korea
| | - Jae-Sook Ryu
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul, Korea
- * E-mail:
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Trac NT, Chung EJ. Peptide-based targeting of immunosuppressive cells in cancer. Bioact Mater 2020; 5:92-101. [PMID: 31956738 PMCID: PMC6962647 DOI: 10.1016/j.bioactmat.2020.01.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 01/06/2020] [Accepted: 01/09/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer progression is marked by the infiltration of immunosuppressive cells, such as tumor-associated macrophages (TAMs), regulatory T lymphocytes (Tregs), and myeloid-derived suppressor cells (MDSCs). These cells play a key role in abrogating the cytotoxic T lymphocyte-mediated (CTL) immune response, allowing tumor growth to proceed unabated. Furthermore, targeting these immunosuppressive cells through the use of peptides and peptide-based nanomedicine has shown promising results. Here we review the origins and functions of immunosuppressive cells in cancer progression, peptide-based systems used in their targeting, and explore future avenues of research regarding cancer immunotherapy. The success of these studies demonstrates the importance of the tumor immune microenvironment in the propagation of cancer and the potential of peptide-based nanomaterials as immunomodulatory agents.
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Affiliation(s)
- Noah T. Trac
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA
- Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Vascular Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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He J, Yin P, Xu K. Effect and Molecular Mechanisms of Traditional Chinese Medicine on Tumor Targeting Tumor-Associated Macrophages. Drug Des Devel Ther 2020; 14:907-919. [PMID: 32184560 PMCID: PMC7053810 DOI: 10.2147/dddt.s223646] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 02/05/2020] [Indexed: 12/17/2022] Open
Abstract
Traditional Chinese medicine (TCM) has been used as a significant cancer treatment method for many years in China. It has been demonstrated that TCM could assist in inhibiting the growth of tumors and prolonging the survival rates of cancer patients. Although the mechanism of TCM are still not clear, accumulating evidence has shown that they may be related to the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a significant role in TME and are polarized to two phenotypes, M1 (classically activated) and M2 (alternatively activated) TAMs. The two different phenotypes of TAMs play converse roles in the TME and M2-polarized tumor-associated macrophages (M2-TAMs) always lead to poor prognosis in cancer patients compared to M1-polarized tumor-associated macrophages (M1-TAMs). In this review, the potential correlation between TCM and TAMs (especially the M2 phenotype) in tumor progression and promising TCM strategies targeting TAMs in cancer are discussed.
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Affiliation(s)
- Jing He
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Peihao Yin
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medicine University, Anhui, People’s Republic of China
- Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Ke Xu
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medicine University, Anhui, People’s Republic of China
- Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
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Tissue Infiltrating Immune Cells as Prognostic Biomarkers in Endometrial Cancer: A Meta-Analysis. DISEASE MARKERS 2020; 2020:1805764. [PMID: 32076456 PMCID: PMC7008300 DOI: 10.1155/2020/1805764] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/01/2020] [Accepted: 01/14/2020] [Indexed: 12/22/2022]
Abstract
Background The association between tumour-infiltrating immune cells and the prognosis of endometrial cancer (EC) is controversial due to the smaller sample sizes and limited statistical power of the extant studies. We carried out a meta-analysis of the relationship between tumour-infiltrating immune cells and EC survival outcomes. Methods A literature search in multiple databases was carried out up to December 2019. Pooled hazard ratio (HRs) and 95% confidence intervals (CIs) were calculated by the Z-test to assess the association between infiltrating immune cells and overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), disease-specific survival (DSS), and disease-free survival (DFS). A subgroup analysis was performed based on the localisation of immune cells in tumour parenchyma or stroma, immune markers, and the International Federation of Gynecology and Obstetrics stage. Heterogeneity and publication bias between studies were evaluated by Cochran's Q-test and Egger regression test, respectively. Results Seventeen studies were included in the analysis. The pooled HR of OS, PFS, DSS, and DFS indicated that a high CD8+ T cell density was associated with a favorable prognosis in EC patients. A significant relationship was found between a high density of CD45RO+ T cells and a favorable OS in EC patients, but the FoxP3+ T cell density was not associated with either OS or RFS. A high TAM density was associated with a worse PFS. However, a sensitivity analysis indicated that the findings of PFS and DSS in CD8+ T cell and PFS in TAM were not robust results. Conclusion This is the first meta-analysis of the relationship between tumour-infiltrating immune cells and the prognosis of EC. High CD8+ and CD45RO+ T cell densities in tumours were associated with favorable outcomes in EC patients.
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Gouveia-Fernandes S. Monocytes and Macrophages in Cancer: Unsuspected Roles. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1219:161-185. [PMID: 32130699 DOI: 10.1007/978-3-030-34025-4_9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The behavior of cancer is undoubtedly affected by stroma. Macrophages belong to this microenvironment and their presence correlates with reduced survival in most cancers. After a tumor-induced "immunoediting", these monocytes/macrophages, originally the first line of defense against tumor cells, undergo a phenotypic switch and become tumor-supportive and immunosuppressive.The influence of these tumor-associated macrophages (TAMs) on cancer is present in all traits of carcinogenesis. These cells participate in tumor initiation and growth, migration, vascularization, invasion and metastasis. Although metastasis is extremely clinically relevant, this step is always reliant on the angiogenic ability of tumors. Therefore, the formation of new blood vessels in tumors assumes particular importance as a limiting step for disease progression.Herein, the once unsuspected roles of macrophages in cancer will be discussed and their importance as a promising strategy to treat this group of diseases will be reminded.
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Affiliation(s)
- Sofia Gouveia-Fernandes
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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Ding W, Tan Y, Qian Y, Xue W, Wang Y, Jiang P, Xu X. Clinicopathologic and prognostic significance of tumor-associated macrophages in patients with hepatocellular carcinoma: A meta-analysis. PLoS One 2019; 14:e0223971. [PMID: 31618252 PMCID: PMC6795444 DOI: 10.1371/journal.pone.0223971] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/02/2019] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Tumor-associated macrophages (TAMs) deserve more focus because of its clinicopathologic and prognostic roles in solid tumors. However, the prognostic value of TAMs in patients with hepatocellular carcinoma (HCC) is still controversial. We performed a meta-analysis to resolve the issue. METHODS We selected relevant studies from the Cochrane Library, Embase and PubMed databases. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials. Moreover, we also performed subgroup analysis, cumulative meta-analysis, sensitivity analysis, and bias analysis (Egger's test). RESULTS A total of 20 observational studies with 4297 patients were enrolled. For TAMs subsets, high density of CD68+ TAMs in either intratumor (IT) (pooled HR = 1.417; 95% CI = 1.092-1.839; P = 0.009) or peritumor (PT) (pooled HR = 1.393; 95% CI = 1.022-1.899; P = 0.036) was associated with a poor OS. High density of CD68+ TAMs in IT was also associated with high AFP value, large tumor size, absent encapsulation, present vascular invasion, and later tumor-nodes-metastasis (TNM) stage. High density of CD163+ macrophages in serum was associated with a poor OS (pooled HR = 5.698; 95% CI = 3.062-10.603; P < 0.001). High density of CD204+ TAMs in IT was associated with a poor OS (pooled HR = 1.947; 95% CI = 1.387-2.733; P < 0.001. High density of CD206+ TAMs in IT was associated with a poor OS (pooled HR = 1.723; 95% CI = 1.308-2.270; P < 0.001) and DFS (pooled HR = 1.711; 95% CI = 1.214-2.412; P = 0.002). However, high density of CD169+ TAMs in IT was associated with a good OS (pooled HR = 0.471; 95% CI = 0.343-0.647; P = 0.037). CONCLUSIONS TAMs could serve as independent predictive indicators and therapeutic targets for HCC. Further trials are needed to elucidate the exact relationship and the underlying mechanism.
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Affiliation(s)
- Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
| | - Yulin Tan
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
| | - Yan Qian
- Department of Respiration, Changzhou Second People’s Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Wenbo Xue
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
| | - Yibo Wang
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
| | - Peng Jiang
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
| | - Xuezhong Xu
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
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Reconfigurable open microfluidics for studying the spatiotemporal dynamics of paracrine signalling. Nat Biomed Eng 2019; 3:830-841. [PMID: 31427781 DOI: 10.1038/s41551-019-0421-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 06/04/2019] [Indexed: 12/17/2022]
Abstract
The study of intercellular signalling networks requires organotypic microscale systems that facilitate the culture, conditioning and manipulation of cells. Here, we describe a reconfigurable microfluidic cell-culture system that facilitates the assembly of three-dimensional tissue models by stacking layers that contain preconditioned microenvironments. By using principles of open and suspended microfluidics, the Stacks system is easily assembled or disassembled to provide spatial and temporal manoeuvrability in two-dimensional and three-dimensional assays of multiple cell types, enabling the modelling of sequential paracrine-signalling events, such as tumour-cell-mediated differentiation of macrophages and macrophage-facilitated angiogenesis. We used Stacks to recapitulate the in vivo observation that different prostate cancer tissues polarize macrophages with distinct gene-expression profiles of pro-inflammatory and anti-inflammatory cytokines. Stacks also enabled us to show that these two types of macrophages signal distinctly to endothelial cells, leading to blood vessels with different morphologies. Our proof-of-concept experiments exemplify how Stacks can efficiently model multicellular interactions and highlight the importance of spatiotemporal specificity in intercellular signalling.
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Ghiringhelli F, Fumet JD. Is There a Place for Immunotherapy for Metastatic Microsatellite Stable Colorectal Cancer? Front Immunol 2019; 10:1816. [PMID: 31447840 PMCID: PMC6691024 DOI: 10.3389/fimmu.2019.01816] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 07/18/2019] [Indexed: 12/21/2022] Open
Abstract
Immunotherapy using checkpoint inhibitor targeting PD-1 and PD-L1 revolutionized the treatment of microsatellite instable metastatic colon cancer. Such treatment is now a standard of care for these patients. However, when used as monotherapy checkpoint inhibitors targeting PD-1 and PD-L1 are not effective in metastatic colorectal cancer patients with microsatellite stable tumors. Recent advances in biology provide a rationale for this intrinsic resistance and support the evaluation of combination therapy to reverse resistance. This article will highlight recent findings on the mechanism of intrinsic resistance and recent advances in clinical trials for combination therapy.
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Cao L, Che X, Qiu X, Li Z, Yang B, Wang S, Hou K, Fan Y, Qu X, Liu Y. M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer. Cancer Manag Res 2019; 11:6125-6138. [PMID: 31308749 PMCID: PMC6613613 DOI: 10.2147/cmar.s199832] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 05/10/2019] [Indexed: 01/07/2023] Open
Abstract
Background: Lung cancer is the leading cause of cancer-related death worldwide. Although the macrophages can affect the development of tumor, the contribution of macrophages to the prognosis of non-small-cell lung cancer (NSCLC) is still controversial. Moreover, anti-PD-1 therapy can redirect macrophages from an M2 to an M1 phenotype, suggesting that tumor PD-L1 may affect the prognostic role of macrophages. Therefore, in this study, we aimed to display a macrophage landscape to clarify the function of macrophages, considering the localization and polarization of the macrophages, and evaluate the effect of M2 macrophages and tumor PD-L1 in combination on the prognosis of NSCLC. Methods: We performed multiplex quantitative immunofluorescence staining of pan-cytokeratin (CK), CD68, CD163, PD-L1, and DAPI on one tissue specimen simultaneously from 137 NSCLC patients. Results: M2 macrophages, involved marginM2 (M2 macrophages in tumor stroma), and centralM2 (M2 macrophages infiltrating into tumor islets) increased as the tumor stage increased. More macrophages were found in lung squamous cell carcinoma (LUSC) patients, patients with wild-type EGFR, and smokers than in patients with lung adenocarcinoma (LUAD), patients with EGFR mutations, and non-smokers. Infiltration of centralM2 was an independent prognostic factor of poor overall survival (OS) and disease-free survival (DFS) for NSCLC patients (P<0.05), which was superior to total macrophages and total M2 macrophages. Moreover, patients with centralM2lessPD-L1- tumors showed the best OS and DFS, while the patients with centralM2morePD-L1+ tumors showed the worst OS and DFS, and the two groups with centralM2lessPD-L1+ and centralM2morePD-L1- were in the middle (P=0.002, 0.034, respectively). Conclusion: Tumor islet-infiltrating M2 macrophages influence the prognosis of NSCLC patients. The analysis of M2 macrophages and tumor PD-L1 in combination may enhance the accuracy of prognostic prediction. This study provides a new understanding of macrophages in the development of NSCLC through the analysis of macrophage landscape.
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Affiliation(s)
- Lili Cao
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
| | - Xueshan Qiu
- Department of Pathology, College of Basic Medical Sciences of China Medical University, Shenyang 110001, People's Republic of China
| | - Zhi Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
| | - Bowen Yang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
| | - Shuo Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
| | - Yibo Fan
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China
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Segovia-Mendoza M, Morales-Montor J. Immune Tumor Microenvironment in Breast Cancer and the Participation of Estrogen and Its Receptors in Cancer Physiopathology. Front Immunol 2019; 10:348. [PMID: 30881360 PMCID: PMC6407672 DOI: 10.3389/fimmu.2019.00348] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/11/2019] [Indexed: 12/22/2022] Open
Abstract
Breast cancer is characterized by cellular and molecular heterogeneity. Several molecular events are involved in controlling malignant cell process. In this sense, the importance of studying multiple cell alterations in this pathology is overriding. A well-identified fact on immune response is that it can vary depend on sex. Steroid hormones and their receptors may regulate different functions and the responses of several subpopulations of the immune system. Few reports are focused on the function of estrogen receptors (ERs) on immune cells and their roles in different breast cancer subtypes. Thus, the aim of this review is to investigate the immune infiltrating tumor microenvironment and prognosis conferred by it in different breast cancer subtypes, discuss the current knowledge and point out the roles of estrogens and its receptors on the infiltrating immune cells, as well as to identify how different immune subsets are modulated after anti-hormonal treatments in breast cancer patients.
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Affiliation(s)
| | - Jorge Morales-Montor
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Erlandsson A, Carlsson J, Lundholm M, Fält A, Andersson S, Andrén O, Davidsson S. M2 macrophages and regulatory T cells in lethal prostate cancer. Prostate 2019; 79:363-369. [PMID: 30500076 PMCID: PMC6587459 DOI: 10.1002/pros.23742] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 10/23/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (Tregs ) can contribute to cancer progression by suppressing the anti-tumor immune response. This study investigated the number of CD163-positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and Tregs . METHODS This nested case-control study included subjects from a cohort of men diagnosed with PCa as an incidental finding during transurethral resection of the prostate. The cases were 225 men who died from PCa, and the controls were 367 men who survived more than 10 years after PCa diagnosis without disease progression. Infiltrating CD163-positive M2 macrophages and FOXP3/CD4-positive Tregs in PCa tissue were identified using immunohistochemistry. The correlation and interaction of M2 macrophages and Tregs were assessed using Spearman's rank-order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts. RESULTS The number of M2 macrophages and Tregs showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23-3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis. CONCLUSIONS Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as Tregs , promote an immunosuppressive environment.
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Affiliation(s)
- Ann Erlandsson
- Department of Urology, Faculty of Medicine and HealthÖrebro UniversityÖrebroSweden
| | - Jessica Carlsson
- Department of Urology, Faculty of Medicine and HealthÖrebro UniversityÖrebroSweden
| | - Marie Lundholm
- Department of Medical BiosciencesUmeå UniversityUmeåSweden
| | - Anna Fält
- Clinical Epidemiology and BiostatisticsSchool of Medical SciencesÖrebro UniversityÖrebroSweden
| | - Sven‐Olof Andersson
- Department of Urology, Faculty of Medicine and HealthÖrebro UniversityÖrebroSweden
| | - Ove Andrén
- Department of Urology, Faculty of Medicine and HealthÖrebro UniversityÖrebroSweden
| | - Sabina Davidsson
- Department of Urology, Faculty of Medicine and HealthÖrebro UniversityÖrebroSweden
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Mouse-Derived Isograft (MDI) In Vivo Tumor Models I. Spontaneous sMDI Models: Characterization and Cancer Therapeutic Approaches. Cancers (Basel) 2019; 11:cancers11020244. [PMID: 30791466 PMCID: PMC6406567 DOI: 10.3390/cancers11020244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 02/13/2019] [Accepted: 02/15/2019] [Indexed: 01/05/2023] Open
Abstract
Syngeneic in vivo tumor models are valuable for the development and investigation of immune-modulating anti-cancer drugs. In the present study, we established a novel syngeneic in vivo model type named mouse-derived isografts (MDIs). Spontaneous MDIs (sMDIs) were obtained during a long-term observation period (more than one to two years) of naïve and untreated animals of various mouse strains (C3H/HeJ, CBA/J, DBA/2N, BALB/c, and C57BL/6N). Primary tumors or suspicious tissues were assessed macroscopically and re-transplanted in a PDX-like manner as small tumor pieces into sex-matched syngeneic animals. Nine outgrowing primary tumors were histologically characterized either as adenocarcinomas, histiocytic carcinomas, or lymphomas. Growth of the tumor pieces after re-transplantation displayed model heterogeneity. The adenocarcinoma sMDI model JA-0009 was further characterized by flow cytometry, RNA-sequencing, and efficacy studies. M2 macrophages were found to be the main tumor infiltrating leukocyte population, whereas only a few T cells were observed. JA-0009 showed limited sensitivity when treated with antibodies against inhibitory checkpoint molecules (anti-mPD-1 and anti-mCTLA-4), but high sensitivity to gemcitabine treatment. The generated sMDI are spontaneously occurring tumors of low passage number, propagated as tissue pieces in mice without any tissue culturing, and thus conserving the original tumor characteristics and intratumoral immune cell populations.
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PKCζ facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model. Oncogene 2019; 38:4215-4231. [PMID: 30705401 PMCID: PMC6756056 DOI: 10.1038/s41388-019-0722-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 11/20/2018] [Accepted: 01/15/2019] [Indexed: 12/18/2022]
Abstract
Prostate cancer disseminates primarily into the adjacent lymph nodes, which is related to a poor outcome. Atypical protein kinase C ζ (PKCζ) is highly expressed in aggressive prostate cancer and correlates with Gleason score, clinical stage, and poor prognosis. Here, we report the molecular mechanisms of PKCζ in lymphatic metastasis during prostate cancer progression. Using zinc-finger nuclease technology or PKCζ shRNA lentiviral particles, and orthotopic mouse xenografts, we show that PKCζ-knockout or knockdown from aggressive prostate cancer (PC3 and PC3U) cells, decreasesd tumor growth and lymphatic metastasis in vivo. Intriguingly, PKCζ-knockout or knockdown impaired the activation of AKT, ERK, and NF-κB signaling in prostate cancer cells, thereby impairing the expression of lymphangiogenic factors and macrophage recruitment, resulting in aberrant lymphangiogenesis. Moreover, PKCζ regulated the expression of hyaluronan synthase enzymes, which is important for hyaluronan-mediated lymphatic drainage and tumor dissemination. Thus, PKCζ plays a crucial oncogenic role in the lymphatic metastasis of prostate cancer and is predicted to be a novel therapeutic target for prostate cancer.
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Lo CH, Lynch CC. Multifaceted Roles for Macrophages in Prostate Cancer Skeletal Metastasis. Front Endocrinol (Lausanne) 2018; 9:247. [PMID: 29867776 PMCID: PMC5968094 DOI: 10.3389/fendo.2018.00247] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 05/02/2018] [Indexed: 12/11/2022] Open
Abstract
Bone-metastatic prostate cancer is common in men with recurrent castrate-resistant disease. To date, therapeutic focus has largely revolved around androgen deprivation therapy (ADT) and chemotherapy. While second-generation ADTs and combination ADT/chemotherapy approaches have been successful in extending overall survival, the disease remains incurable. It is clear that molecular and cellular components of the cancer-bone microenvironment contribute to the disease progression and potentially to the emergence of therapy resistance. In bone, metastatic prostate cancer cells manipulate bone-forming osteoblasts and bone-resorbing osteoclasts to produce growth and survival factors. While osteoclast-targeted therapies such as bisphosphonates have improved quality of life, emerging data have defined important roles for additional cells of the bone microenvironment, including macrophages and T cells. Disappointingly, early clinical trials with checkpoint blockade inhibitors geared at promoting cytotoxic T cell response have not proved as promising for prostate cancer compared to other solid malignancies. Macrophages, including bone-resident osteomacs, are a major component of the bone marrow and play key roles in coordinating normal bone remodeling and injury repair. The role for anti-inflammatory macrophages in the progression of primary prostate cancer is well established yet relatively little is known about macrophages in the context of bone-metastatic prostate cancer. The focus of the current review is to summarize our knowledge of macrophage contribution to normal bone remodeling and prostate-to-bone metastasis, while also considering the impact of standard of care and targeted therapies on macrophage behavior in the tumor-bone microenvironment.
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Affiliation(s)
- Chen Hao Lo
- Cancer Biology Program, University of South Florida, Tampa, FL, United States
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Conor C. Lynch
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
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