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Elhadary M, Elsayed B, Elshoeibi AM, Karen O, Elmakaty I, Alhmoud J, Hamdan A, Malki MI. The Clinicopathological and Prognostic Value of CCR7 Expression in Breast Cancer Throughout the Literature: A Systematic Review and Meta-Analysis. Biomedicines 2025; 13:1007. [PMID: 40299690 PMCID: PMC12024592 DOI: 10.3390/biomedicines13041007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Accepted: 04/17/2025] [Indexed: 05/01/2025] Open
Abstract
Background/Objective: This study aimed to determine the clinicopathological findings and prognostic value of chemokine receptor 7 (CCR7) expression in patients with breast cancer (BC). Methods: Up to the 25th of March 2025, a search was conducted using five databases: PubMed, Embase, Scopus, Medline, and Web of Science. The methodological standards for the epidemiological research scale were used to assess the quality of the included articles, and Stata software (Stata 19) was used to synthesize the meta-analysis. Results: We considered 12 of 853 studies that included 3119 patients with BC. High CCR7 expression was not associated with age (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.66-1.03); clinicopathological findings, including tumor size (OR 1.062, 95% CI 0.630-1.791); clinical stage (OR 1.753, 95% CI 0.231-13.304); nodal metastasis (OR 1.252, 95% CI 0.571-2.741); or histological differentiation (OR 1.167, 95% CI 0.939-1.450). CCR7 expression did not affect overall survival (hazard ratio 0.996, 95% CI 0.659-1.505). Conclusions: Our quantitative analysis did not reveal an association between CCR7 expression and poor clinicopathological or prognostic features in BC patients. Because of the high heterogeneity and potential publication bias, large high-quality studies are required to further confirm these findings.
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Affiliation(s)
- Mohamed Elhadary
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (M.E.); (B.E.); (A.M.E.); (O.K.); (A.H.)
| | - Basel Elsayed
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (M.E.); (B.E.); (A.M.E.); (O.K.); (A.H.)
| | - Amgad Mohamed Elshoeibi
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (M.E.); (B.E.); (A.M.E.); (O.K.); (A.H.)
| | - Omar Karen
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (M.E.); (B.E.); (A.M.E.); (O.K.); (A.H.)
| | - Ibrahim Elmakaty
- Department of Medical Education, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar;
| | - Jehad Alhmoud
- Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Ahmad Hamdan
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (M.E.); (B.E.); (A.M.E.); (O.K.); (A.H.)
| | - Mohammed Imad Malki
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
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Satofuka H, Suzuki H, Tanaka T, Ubukata R, Hirose M, Yamamoto H, Kaneko Y, Fujisawa S, Li G, Kaneko MK, Kato Y. A novel anti-mouse CCR7 monoclonal antibody, C 7Mab-7, demonstrates high sensitivity in flow cytometry, western blot, and immunohistochemistry. Biochem Biophys Rep 2025; 41:101948. [PMID: 40028039 PMCID: PMC11870228 DOI: 10.1016/j.bbrep.2025.101948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/10/2025] [Accepted: 02/05/2025] [Indexed: 03/05/2025] Open
Abstract
C-C chemokine receptor type 7 (CCR7) is a member of the G protein-coupled receptor family and functions as a lymph node-homing receptor for immune cells. Upon ligand binding, CCR7 promotes the migration of immune cells to secondary lymphoid organs. In cancers, CCR7 has been revealed as a critical molecule in lymph node metastasis. Consequently, anti-CCR7 monoclonal antibodies (mAbs) have been developed as cancer therapeutic agents. In this study, we established an anti-mouse CCR7 (mCCR7) mAb, C7Mab-7 (rat IgG1, kappa) using the Cell-Based Immunization and Screening (CBIS) method. C7Mab-7 demonstrated high sensitivity in flow cytometry. The dissociation constant (K D) value of C7Mab-7 was determined to be 2.5 × 10⁻⁹ M for mCCR7-overexpressed Chinese hamster ovary-K1 (CHO/mCCR7) cells. Furthermore, C7Mab-7 detected mCCR7 with high sensitivity in western blot and immunohistochemistry. C7Mab-7, developed by the CBIS method, accelerates the development of CCR7-targeted antibody therapies and cancer diagnostics.
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Affiliation(s)
- Hiroyuki Satofuka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Hiroyuki Suzuki
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Rena Ubukata
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Miu Hirose
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Haruto Yamamoto
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Yu Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Shiori Fujisawa
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Guanjie Li
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Mika K. Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
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Zhang Y, Zhou YL, Xu N, Meng T, Wang ZZ, Pan FM, Zhu LX. Chemokines and PI3K/AKT signaling pathway mediate the spontaneously ruptured hepatocellular carcinoma through the regulation of the cell cycle. Hepatobiliary Pancreat Dis Int 2025:S1499-3872(25)00029-3. [PMID: 39952875 DOI: 10.1016/j.hbpd.2025.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 11/26/2024] [Indexed: 02/17/2025]
Abstract
BACKGROUND The incidence of spontaneously ruptured hepatocellular carcinoma (srHCC) has been shown to significantly elevate mortality rates. However, the precise mechanisms underlying srHCC remain poorly understood. METHODS Analysis was conducted on the data of 198 hepatocellular carcinoma (HCC) patients to investigate the factors contributing to srHCC. The clinical data of 33 transcriptome HCC patients were served for verification. An in-depth transcriptome analysis was conducted to investigate the distinctions between 26 cases of srHCC and 35 cases of non-ruptured hepatocellular carcinoma (nrHCC). Weighted Gene Co-expression Network Analysis (WGCNA) tool was utilized to develop a gene co-expression network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathways enrichment, and protein-protein interaction (PPI) network were carried out. The corresponding samples for spontaneously ruptured hepatocellular carcinoma tissue (srHCC-T) and ruptured hepatocellular carcinoma paracancerous tissue (srHCC-P) was selected for verification. Transcriptional data were validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Immunofluorescence (IF), immunohistochemistry (IHC) and Western blot were used to detect the protein expression. RESULTS Our results showed that white blood cell (WBC) and monocyte levels were significant independent risk factors for srHCC (P < 0.05). There was a strong association between the srHCC-T and the expression of cell cycle-related genes BUB1B and macrophage function-related gene MACRO. Furthermore, chemokines and the PI3K/AKT signaling pathway play a crucial role in regulating the cell cycle process through a complex network of interactions, ultimately impacting the occurrence of srHCC. CONCLUSIONS Our study confirms that chemokines and the PI3K/AKT signaling pathway mediate the occurrence of HCC rupture by regulating the cell cycle. We provide a theoretical basis for the clinical treatment of srHCC.
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Affiliation(s)
- Yan Zhang
- Department of General Surgery, the Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Yang-Liu Zhou
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Na Xu
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Tao Meng
- Department of General Surgery, Hefei First People's Hospital, Hefei 230000, China
| | - Zhen-Zhen Wang
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Fa-Ming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei 230032, China.
| | - Li-Xin Zhu
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
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Leonard MR, Jones DM, Read KA, Pokhrel S, Tuazon JA, Warren RT, Yount JS, Oestreich KJ. Aiolos promotes CXCR3 expression on Th1 cells via positive regulation of IFN-γ/STAT1 signaling. JCI Insight 2024; 10:e180287. [PMID: 39560988 PMCID: PMC11721307 DOI: 10.1172/jci.insight.180287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024] Open
Abstract
CD4+ T helper 1 (Th1) cells coordinate adaptive immune responses to intracellular pathogens, including viruses. Key to this function is the ability of Th1 cells to migrate within secondary lymphoid tissues, as well as to sites of inflammation, which relies on signals received through the chemokine receptor CXCR3. CXCR3 expression is driven by the Th1 lineage-defining transcription factor T-bet and the cytokine-responsive STAT family members STAT1 and STAT4. Here, we identify the Ikaros zinc finger (IkZF) transcription factor Aiolos (Ikzf3) as an additional positive regulator of CXCR3 both in vitro and in vivo using a murine model of influenza virus infection. Mechanistically, we found that Aiolos-deficient CD4+ T cells exhibited decreased expression of key components of the IFN-γ/STAT1 signaling pathway, including JAK2 and STAT1. Consequently, Aiolos deficiency resulted in decreased levels of STAT1 tyrosine phosphorylation and reduced STAT1 enrichment at the Cxcr3 promoter. We further found that Aiolos and STAT1 formed a positive feedback loop via reciprocal regulation of each other downstream of IFN-γ signaling. Collectively, our study demonstrates that Aiolos promotes CXCR3 expression on Th1 cells by propagating the IFN-γ/STAT1 cytokine signaling pathway.
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Affiliation(s)
- Melissa R. Leonard
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
- Combined Anatomic Pathology Residency/PhD Program, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA
| | - Devin M. Jones
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
- Biomedical Sciences Graduate Program and
| | - Kaitlin A. Read
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
- Biomedical Sciences Graduate Program and
| | - Srijana Pokhrel
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
| | - Jasmine A. Tuazon
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
- Biomedical Sciences Graduate Program and
- Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Robert T. Warren
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
| | - Jacob S. Yount
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
- Infectious Diseases Institute, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
| | - Kenneth J. Oestreich
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
- Infectious Diseases Institute, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
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Cabioglu N, Onder S, Karatay H, Bayram A, Oner G, Tukenmez M, Muslumanoglu M, Igci A, Dinccag A, Ozmen V, Aydiner A, Saip P, Yavuz E. New Emerging Chemokine Receptors: CCR5 or CXCR5 on Tumor Is Associated with Poor Response to Chemotherapy and Poor Prognosis in Locally Advanced Triple-Negative Breast Cancer. Cancers (Basel) 2024; 16:2388. [PMID: 39001456 PMCID: PMC11240792 DOI: 10.3390/cancers16132388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND We aim to investigate any possible associations between chemokine receptor expression and responses to neoadjuvant chemotherapy (NAC) along with outcomes in patients with triple-negative breast cancer (TNBC) with locally advanced disease. METHOD Expressions of chemokine receptors were examined immunohistochemically after staining archival tissue of surgical specimens (n = 63) using specific antibodies for CCR5, CCR7, CXCR4, and CXCR5. RESULTS Patients with high CCR5, CCR7, CXCR4, and CXCR5 expression on tumors and high CXCR4 expression on tumor-infiltrating lymphocytes (TILs) were less likely to have a pathological complete response (pCR) or Class 0-I RCB-Index compared to others. Patients with residual lymph node metastases (ypN-positive), high CCR5TM(tumor), and high CXCR4TM expressions had an increased hazard ratio (HR) compared to others (DFS: HR = 2.655 [1.029-6.852]; DSS: HR = 2.763 [1.008-7.574]), (DFS: HR = 2.036 [0.805-5.148]; DSS: HR = 2.689 [1.020-7.090]), and (DFS: HR = 2.908 [1.080-7.829]; DSS: HR = 2.132 (0.778-5.846)), respectively. However, patients without CXCR5TIL expression had an increased HR compared to those with CXCR5TIL (DFS: 2.838 [1.266-6.362]; DSS: 4.211 [1.770-10.016]). CONCLUSIONS High expression of CXCR4TM and CCR5TM was found to be associated with poor prognosis, and CXCR5TM was associated with poor chemotherapy response in the present cohort with locally advanced TNBC. Our results suggest that patients with TNBC could benefit from a chemokine receptor inhibitor therapy containing neoadjuvant chemotherapy protocols.
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Affiliation(s)
- Neslihan Cabioglu
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Semen Onder
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Hüseyin Karatay
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Aysel Bayram
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Gizem Oner
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Mustafa Tukenmez
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Mahmut Muslumanoglu
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Abdullah Igci
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Ahmet Dinccag
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Vahit Ozmen
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Adnan Aydiner
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul 34452, Turkey; (A.A.); (P.S.)
| | - Pınar Saip
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul 34452, Turkey; (A.A.); (P.S.)
| | - Ekrem Yavuz
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
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Li JJ, Mao JX, Zhong HX, Zhao YY, Teng F, Lu XY, Zhu LY, Gao Y, Fu H, Guo WY. Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review. World J Hepatol 2024; 16:537-549. [PMID: 38689749 PMCID: PMC11056903 DOI: 10.4254/wjh.v16.i4.537] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/11/2024] [Accepted: 03/18/2024] [Indexed: 04/24/2024] Open
Abstract
The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
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Affiliation(s)
- Jing-Jing Li
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jia-Xi Mao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Han-Xiang Zhong
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yuan-Yu Zhao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xin-Yi Lu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Li-Ye Zhu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yang Gao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wen-Yuan Guo
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
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Wang Z, Kirkwood KL, Wang Y, Du W, Lin S, Zhou W, Yan C, Gao J, Li Z, Sun C, Liu F. Analysis of the effect of CCR7 on the microenvironment of mouse oral squamous cell carcinoma by single-cell RNA sequencing technology. J Exp Clin Cancer Res 2024; 43:94. [PMID: 38539232 PMCID: PMC10976828 DOI: 10.1186/s13046-024-03013-y] [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: 11/27/2023] [Accepted: 03/15/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Studies have shown that CCR7, an important inflammatory factor, can promote the proliferation and metastasis of oral squamous cell carcinoma (OSCC), but its role in the tumor microenvironment (TME) remains unclear. This paper explores the role of CCR7 in the TME of OSCC. METHODS In this work, we constructed CCR7 gene knockout mice and OSCC mouse models. Single-cell RNA sequencing (scRNA-seq) and bioinformatics were used to analyze the differences in the OSCC microenvironment between three CCR7 gene knockout mice (KO) and three wild-type mice (WT). Immunohistochemistry, immunofluorescence staining, and flow cytometry were used to analyze the expression of key genes in significantly different cell types between the KO and WT groups. An in vitro experiment was used to verify the effect of CCR7 on M2 macrophage polarization. RESULTS In the mouse OSCC models, the tumor growth rate in the KO group was significantly lower than that in the WT group. Eight main cell types (including tumor cells, fibroblasts, macrophages, granulocytes, T cells, endothelial cells, monocytes, and B cells) were identified by Seurat analysis. The scRNA-seq results showed that the proportion of tumor cells was lower, but the proportion of inflammatory cells was significantly higher in the KO group than in the WT group. CellPhoneDB analysis results indicated a strong interaction relationship between tumor cells and macrophages, T cells, fibroblasts, and endothelial cells. Functional enrichment results indicated that the expression level of the Dusp1 gene in the KO group was generally higher than that in the WT group in various cell types. Macrophage subclustering results indicated that the proportion of M2 macrophages in the KO group was lower than that in the WT group. In vitro experimental results showed that CCR7 can promote M2 macrophage polarization, thus promoting the proliferation, invasion and migration of OSCC cells. CONCLUSIONS CCR7 gene knockout can significantly inhibit the growth of mouse oral squamous cell carcinoma by promoting the polarization of M2 macrophages.
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Affiliation(s)
- Zengxu Wang
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Keith L Kirkwood
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, NY, Buffalo, 14214-8006, USA
| | - Yao Wang
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Weidong Du
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Shanfeng Lin
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Wanhang Zhou
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Cong Yan
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Jiaxing Gao
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Zhenning Li
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Changfu Sun
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Fayu Liu
- Department of Oral Maxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Road, Heping District, Shenyang, Liaoning, 110002, People's Republic of China.
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Zhao Y, Zhao L, Wang T, Liu Z, Tang S, Huang H, Wu L, Sun Y. The Herbal Combination Shu Gan Jie Yu Regulates the SNCG/ER-a/AKT-ERK Pathway in DMBA-Induced Breast Cancer and Breast Cancer Cell Lines Based on RNA-Seq and IPA Analysis. Integr Cancer Ther 2024; 23:15347354241233258. [PMID: 38369762 PMCID: PMC10878215 DOI: 10.1177/15347354241233258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 01/19/2024] [Accepted: 02/01/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Soothing the liver (called Shu Gan Jie Yu in Chinese, SGJY) is a significant therapeutic method for breast cancer in TCM. In this study, 3 liver-soothing herbs, including Cyperus rotundus L., Citrus medica L. var. sarcodactylis Swingle and Rosa rugosa Thunb. were selected and combined to form a SGJY herbal combinatory. THE AIM OF THE STUDY To investigate the inhibiting effect of SGJY on breast cancer in vivo and vitro, and to explore the potential mechanisms. MATERIALS AND METHODS SGJY herbal combination was extracted using water. A breast cancer rat model was developed by chemical DMBA by gavage, then treated with SGJY for 11 weeks. The tumor tissue was preserved for RNA sequencing and analyzed by IPA software. The inhibition effects of SGJY on MCF-7 and T47D breast cancer cells were investigated by SRB assay and cell apoptosis analysis, and the protein expression levels of SNCG, ER-α, p-AKT and p-ERK were measured by western blotting. RESULTS SGJY significantly reduced the tumor weight and volume, and the level of estradiol in serum. The results of IPA analysis reveal SGJY upregulated 7 canonical pathways and downregulated 16 canonical pathways. Estrogen receptor signaling was the key canonical pathway with 9 genes downregulated. The results of upstream regulator analysis reveal beta-estradiol was the central target; the upstream regulator network scheme showed that 86 genes could affect the expression of the beta-estradiol, including SNCG, CCL21 and MB. Additionally, SGJY was verified to significantly alter the expression of SNCG mRNA, CCL21 mRNA and MB mRNA which was consistent with the data of RNA-Seq. The inhibition effects of SGJY exhibited a dose-dependent response. The apoptosis rates of MCF7 and T47D cells were upregulated. The protein expression of SNCG, ER-α, p-AKT and p-ERK were all significantly decreased by SGJY on MCF-7 and T47D cells. CONCLUSION The results demonstrate that SGJY may inhibit the growth of breast cancer. The mechanism might involve downregulating the level of serum estradiol, and suppressing the protein expression in the SNCG/ER-α/AKT-ERK pathway.
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Affiliation(s)
- Yi Zhao
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Linan Zhao
- Chinese Medical Hospital of Puyang, Puyang, China
| | - Tao Wang
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Zhenghao Liu
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Suyuan Tang
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Hongxia Huang
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Li Wu
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Youzhi Sun
- Jiangxi University of Chinese Medicine, Nanchang, China
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Bagbudar S, Karanlık H, Cabioglu N, Bayram A, Tükenmez M, Aydıner A, Yavuz E, Onder S. Evaluation of immune density, PD-L1, and CXCR4 expressions in metaplastic breast carcinoma to predict potential immunotherapy benefit. Med Oncol 2023; 41:18. [PMID: 38102446 DOI: 10.1007/s12032-023-02243-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/07/2023] [Indexed: 12/17/2023]
Abstract
Metaplastic breast carcinoma (MBC) -rare but fatal subtype of invasive breast carcinomas- provides limited benefit from conventional triple-negative breast carcinoma chemotherapy. We aimed to determine the immune density of this tumor and to evaluate of programmed death-ligand 1 (PD-L1) and chemokine receptor type 4 (CXCR4) expressions to determine whether it would benefit from immunotherapy. Clinicopathological characteristics of 85 patients diagnosed as MBC between 1997 and 2017 were retrospectively assessed. We evaluated the immunohistochemical expression of PD-L1 and CXCR4, and the extent of tumour infiltrating lymphocytes (TILs), with survival data. TILs groups were statistically significantly associated with lymph node status, histological subtype, squamous component, local recurrence and/or systemic metastasis, and disease-related deaths (p < 0.05). PD-L1 positivity in immune cells (ICs) has a statistically significant relationship with the presence of squamous component (p = 0.011) and HER2 positivity (p = 0.031). PD-L1 positivity in tumor cells (TCs) was found to be significantly more frequent in high-TILs density (p = 0.003). PD-L1 combined positive score was significantly associated with the tumors containing high-TILs density (p = 0.012) and squamous component (p = 0.035). Disease-free and disease-specific survival rates were found to be longer for the cases displaying PD-L1 positivity in ICs; and also PD-L1 positivity in ICs was found to be an independent prognostic factor. When the expression of CXCR4 was compared with clinicopathological and survival parameters, no statistically significant association was found (p > 0.05). Based on the results of this retrospective study, PD-L1 and TILs appear to be prognostic. This study provides rationale for further studies to determine whether a subset of patients with metaplastic breast cancer could derive a meaningful benefit from immune-targeting therapies.
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Affiliation(s)
- Sidar Bagbudar
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Çapa, Fatih, 34390, Istanbul, Turkey.
| | - Hasan Karanlık
- Department of Surgical Oncology Unit, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Neslihan Cabioglu
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Aysel Bayram
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Çapa, Fatih, 34390, Istanbul, Turkey
| | - Mustafa Tükenmez
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Adnan Aydıner
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Ekrem Yavuz
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Çapa, Fatih, 34390, Istanbul, Turkey
| | - Semen Onder
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Çapa, Fatih, 34390, Istanbul, Turkey
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10
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Giotopoulou N, Shi W, Parniewska MM, Sun W, Fuxe J. TGFß1 Stimulates Lymphatic Endothelial Cells to Produce IL7 and IL15, Which Act as Chemotactic Factors for Breast Cancer Cells with Mesenchymal Properties. J Mammary Gland Biol Neoplasia 2023; 28:25. [PMID: 38055067 PMCID: PMC10700205 DOI: 10.1007/s10911-023-09552-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 11/30/2023] [Indexed: 12/07/2023] Open
Abstract
The lymphatic system is a major gateway for tumor cell dissemination but the mechanisms of how tumor cells gain access to lymphatic vessels are not completely understood. Breast cancer cells undergoing epithelial-mesenchymal transition (EMT) gain invasive and migratory properties. Overexpression of the cytokine transforming growth factor β1 (TGFβ1), a potent inducer of EMT, is frequently detected in the tumor microenvironment and correlates with invasion and lymph metastasis. Recently, we reported that TGFβ1 stimulated breast cancer cells with mesenchymal properties to migrate in a targeted fashion towards the lymphatic system via CCR7/CCL21-mediated chemotaxis, similar to dendritic cells during inflammation. Here, we aimed to identify additional chemotactic factors and corresponding receptors that could be involved in guiding breast cancer cells through the lymphatic system. Through a combination of RNA sequencing analysis, database screening and invasion assays we identified IL7/IL7R and IL15/IL15R as pairs of chemokines and receptors with potential roles in promoting chemotactic migration of breast cancer cells with mesenchymal properties towards the lymphatics. The results demonstrate the capacity of TGFβ1 to orchestrate crosstalk between tumor cells and lymphatic endothelial cells and warrant further studies to explore the roles of IL7 and IL15 in promoting lymph metastasis of breast cancer.
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Affiliation(s)
- Nikolina Giotopoulou
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, SE-14152, Sweden
| | - Wenyang Shi
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, SE-14152, Sweden
| | - Malgorzata Maria Parniewska
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, SE-14152, Sweden
| | - Wenwen Sun
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SE-17164, Sweden
- Division of Clinical Pathology and Cancer Diagnostics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, SE-14186, Sweden
| | - Jonas Fuxe
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, SE-14152, Sweden.
- Division of Clinical Pathology and Cancer Diagnostics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, SE-14186, Sweden.
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11
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Padgett LE, Marcovecchio PM, Olingy CE, Araujo DJ, Steel K, Dinh HQ, Alimadadi A, Zhu YP, Meyer MA, Kiosses WB, Thomas GD, Hedrick CC. Nonclassical monocytes potentiate anti-tumoral CD8 + T cell responses in the lungs. Front Immunol 2023; 14:1101497. [PMID: 37426658 PMCID: PMC10325638 DOI: 10.3389/fimmu.2023.1101497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/15/2023] [Indexed: 07/11/2023] Open
Abstract
CD8+ T cells drive anti-cancer immunity in response to antigen-presenting cells such as dendritic cells and subpopulations of monocytes and macrophages. While CD14+ classical monocytes modulate CD8+ T cell responses, the contributions of CD16+ nonclassical monocytes to this process remain unclear. Herein we explored the role of nonclassical monocytes in CD8+ T cell activation by utilizing E2-deficient (E2-/-) mice that lack nonclassical monocytes. During early metastatic seeding, modeled by B16F10-OVA cancer cells injected into E2-/- mice, we noted lower CD8+ effector memory and effector T cell frequencies within the lungs as well as in lung-draining mediastinal lymph nodes in the E2-/- mice. Analysis of the myeloid compartment revealed that these changes were associated with depletion of MHC-IIloLy6Clo nonclassical monocytes within these tissues, with little change in other monocyte or macrophage populations. Additionally, nonclassical monocytes preferentially trafficked to primary tumor sites in the lungs, rather than to the lung-draining lymph nodes, and did not cross-present antigen to CD8+ T cells. Examination of the lung microenvironment in E2-/- mice revealed reduced CCL21 expression in endothelial cells, which is chemokine involved in T cell trafficking. Our results highlight the previously unappreciated importance of nonclassical monocytes in shaping the tumor microenvironment via CCL21 production and CD8+ T cell recruitment.
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Affiliation(s)
- Lindsey E. Padgett
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Paola M. Marcovecchio
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Claire E. Olingy
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Daniel J. Araujo
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Kathleen Steel
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Huy Q. Dinh
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Ahmad Alimadadi
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Yanfang Peipei Zhu
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, United States
| | - Melissa A. Meyer
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - William B. Kiosses
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Graham D. Thomas
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Catherine C. Hedrick
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, United States
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12
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Sadeghi M, Dehnavi S, Asadirad A, Xu S, Majeed M, Jamialahmadi T, Johnston TP, Sahebkar A. Curcumin and chemokines: mechanism of action and therapeutic potential in inflammatory diseases. Inflammopharmacology 2023; 31:1069-1093. [PMID: 36997729 PMCID: PMC10062691 DOI: 10.1007/s10787-023-01136-w] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 01/09/2023] [Indexed: 04/01/2023]
Abstract
Chemokines belong to the family of cytokines with chemoattractant properties that regulate chemotaxis and leukocyte migration, as well as the induction of angiogenesis and maintenance of hemostasis. Curcumin, the major component of the Curcuma longa rhizome, has various pharmacological actions, including anti-inflammatory, immune-regulatory, anti-oxidative, and lipid-modifying properties. Chemokines and chemokine receptors are influenced/modulated by curcumin. Thus, the current review focuses on the molecular mechanisms associated with curcumin's effects on chemoattractant cytokines, as well as putting into context the many studies that have reported curcumin-mediated regulatory effects on inflammatory conditions in the organs/systems of the body (e.g., the central nervous system, liver, and cardiovascular system). Curcumin's effects on viral and bacterial infections, cancer, and adverse pregnancy outcomes are also reviewed.
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Affiliation(s)
- Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Dehnavi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Asadirad
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Suowen Xu
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | | | - Tannaz Jamialahmadi
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- School of Medicine, The University of Western Australia, Perth, Australia.
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box, Mashhad, 91779-48564, Iran.
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13
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Factors Influencing Lymph Node Positivity in HER2/neu+ Breast Cancer Patients. Curr Oncol 2023; 30:2825-2833. [PMID: 36975428 PMCID: PMC10047436 DOI: 10.3390/curroncol30030215] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/14/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Axillary lymph node metastases are a key prognostic factor in breast cancer treatment. Our aim was to evaluate how tumor size, tumor location, and imaging results correlate to axillary lymph node diseases for patients with stage I-III HER2/neu+ breast cancer. This is a single-institution retrospective chart review of female breast cancer patients diagnosed with primary invasive Her2/neu+ breast cancer who were treated with upfront surgical resection from 2000–2021. Of 75 cases, 44/75 (58.7%) had nodal metastasis, and there was a significant association of larger tumor size to nodal metastases (p ≤ 0.001). Patients with negative nodes had a smaller mean tumor size (n = 30; 15.10 mm) than patients with positive nodes (n = 45; 23.9 mm) (p = 0.002). Preoperative imaging detected suspicious nodes in 36 patients, and ultrasound detected the most positive nodes (14/18; p = 0.027). Our data confirms that tumor size at diagnosis is correlated with a higher likelihood of axillary involvement in patients with Her2/neu+ breast cancer; notably, a large proportion of Her2/neu+ breast cancers have metastatic involvement of axillary lymph nodes even with small primary lesions.
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14
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The Lymphatic Endothelium in the Context of Radioimmuno-Oncology. Cancers (Basel) 2022; 15:cancers15010021. [PMID: 36612017 PMCID: PMC9817924 DOI: 10.3390/cancers15010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/11/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
The study of lymphatic tumor vasculature has been gaining interest in the context of cancer immunotherapy. These vessels constitute conduits for immune cells' transit toward the lymph nodes, and they endow tumors with routes to metastasize to the lymph nodes and, from them, toward distant sites. In addition, this vasculature participates in the modulation of the immune response directly through the interaction with tumor-infiltrating leukocytes and indirectly through the secretion of cytokines and chemokines that attract leukocytes and tumor cells. Radiotherapy constitutes the therapeutic option for more than 50% of solid tumors. Besides impacting transformed cells, RT affects stromal cells such as endothelial and immune cells. Mature lymphatic endothelial cells are resistant to RT, but we do not know to what extent RT may affect tumor-aberrant lymphatics. RT compromises lymphatic integrity and functionality, and it is a risk factor to the onset of lymphedema, a condition characterized by deficient lymphatic drainage and compromised tissue homeostasis. This review aims to provide evidence of RT's effects on tumor vessels, particularly on lymphatic endothelial cell physiology and immune properties. We will also explore the therapeutic options available so far to modulate signaling through lymphatic endothelial cell receptors and their repercussions on tumor immune cells in the context of cancer. There is a need for careful consideration of the RT dosage to come to terms with the participation of the lymphatic vasculature in anti-tumor response. Here, we provide new approaches to enhance the contribution of the lymphatic endothelium to radioimmuno-oncology.
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15
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Seibel AJ, Kelly OM, Dance YW, Nelson CM, Tien J. Role of Lymphatic Endothelium in Vascular Escape of Engineered Human Breast Microtumors. Cell Mol Bioeng 2022; 15:553-569. [PMID: 36531861 PMCID: PMC9751254 DOI: 10.1007/s12195-022-00745-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 10/06/2022] [Indexed: 11/09/2022] Open
Abstract
Introduction Lymphatic vasculature provides a route for metastasis to secondary sites in the body. The role of the lymphatic endothelium in mediating the entry of breast cancer cells into the vasculature remains unclear. Methods In this study, we formed aggregates of MDA-MB-231 human breast carcinoma cells next to human microvascular lymphatic endothelial cell (LEC)-lined cavities in type I collagen gels to model breast microtumors and lymphatic vessels, respectively. We tracked invasion and escape of breast microtumors into engineered lymphatics or empty cavities under matched flow rates for up to sixteen days. Results After coming into contact with a lymphatic vessel, tumor cells escape by moving between the endothelium and the collagen wall, between endothelial cells, and/or into the endothelial lumen. Over time, tumor cells replace the LECs within the vessel wall and create regions devoid of endothelium. The presence of lymphatic endothelium slows breast tumor invasion and escape, and addition of LEC-conditioned medium to tumors is sufficient to reproduce nearly all of these inhibitory effects. Conclusions This work sheds light on the interactions between breast cancer cells and lymphatic endothelium during vascular escape and reveals an inhibitory role for the lymphatic endothelium in breast tumor invasion and escape. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-022-00745-9.
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Affiliation(s)
- Alex J. Seibel
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Owen M. Kelly
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Yoseph W. Dance
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Celeste M. Nelson
- Department of Chemical and Biological Engineering, Princeton University, 303 Hoyt Laboratory, 25 William Street, Princeton, NJ 08544 USA
- Department of Molecular Biology, Princeton University, Princeton, NJ USA
| | - Joe Tien
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
- Division of Materials Science and Engineering, Boston University, Boston, MA USA
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16
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Maurya SK, Khan P, Rehman AU, Kanchan RK, Perumal N, Mahapatra S, Chand HS, Santamaria-Barria JA, Batra SK, Nasser MW. Rethinking the chemokine cascade in brain metastasis: Preventive and therapeutic implications. Semin Cancer Biol 2022; 86:914-930. [PMID: 34968667 PMCID: PMC9234104 DOI: 10.1016/j.semcancer.2021.12.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 01/27/2023]
Abstract
Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.
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Affiliation(s)
- Shailendra Kumar Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Asad Ur Rehman
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Hitendra S Chand
- Department of Immunology and Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | | | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA.
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17
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Sharma G, Pothuraju R, Kanchan RK, Batra SK, Siddiqui JA. Chemokines network in bone metastasis: Vital regulators of seeding and soiling. Semin Cancer Biol 2022; 86:457-472. [PMID: 35124194 PMCID: PMC9744380 DOI: 10.1016/j.semcancer.2022.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/20/2022] [Accepted: 02/01/2022] [Indexed: 02/07/2023]
Abstract
Chemokines are well equipped with chemo-attractive signals that can regulate cancer cell trafficking to specific organ sites. Currently, updated concepts have revealed the diverse role of chemokines in the biology of cancer initiation and progression. Genomic instabilities and alterations drive tumor heterogeneity, providing more options for the selection and metastatic progression to cancer cells. Tumor heterogeneity and acquired drug resistance are the main obstacles in managing cancer therapy and the primary root cause of metastasis. Studies emphasize that multiple chemokine/receptor axis are involved in cancer cell-mediated organ-specific distant metastasis. One of the persuasive mechanisms for heterogeneity and subsequent events is sturdily interlinked with the crosstalk between chemokines and their receptors on cancer cells and tissue-specific microenvironment. Among different metastatic niches, skeletal metastasis is frequently observed in the late stages of prostate, breast, and lung cancer and significantly reduces the survival of cancer patients. Therefore, it is crucial to elucidate the role of chemokines and their receptors in metastasis and bone remodeling. Here, we review the potential chemokine/receptor axis in tumorigenesis, tumor heterogeneity, metastasis, and vicious cycle in bone microenvironment.
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Affiliation(s)
- Gunjan Sharma
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ranjana Kumari Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Alrumaihi F. The Multi-Functional Roles of CCR7 in Human Immunology and as a Promising Therapeutic Target for Cancer Therapeutics. Front Mol Biosci 2022; 9:834149. [PMID: 35874608 PMCID: PMC9298655 DOI: 10.3389/fmolb.2022.834149] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
An important hallmark of the human immune system is to provide adaptive immunity against pathogens but tolerance toward self-antigens. The CC-chemokine receptor 7 (CCR7) provides a significant contribution in guiding cells to and within lymphoid organs and is important for acquiring immunity and tolerance. The CCR7 holds great importance in establishing thymic architecture and function and naïve and regulatory T-cell homing in the lymph nodes. Similarly, the receptor is a key regulator in cancer cell migration and the movement of dendritic cells. This makes the CCR7 an important receptor as a drug and prognostic marker. In this review, we discussed several biological roles of the CCR7 and its importance as a drug and prognostic marker.
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Affiliation(s)
- Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
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Jeong J, Tanaka M, Iwakiri Y. Hepatic lymphatic vascular system in health and disease. J Hepatol 2022; 77:206-218. [PMID: 35157960 PMCID: PMC9870070 DOI: 10.1016/j.jhep.2022.01.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/13/2022] [Accepted: 01/31/2022] [Indexed: 02/07/2023]
Abstract
In recent years, significant advances have been made in the study of lymphatic vessels with the identification of their specific markers and the development of research tools that have accelerated our understanding of their role in tissue homeostasis and disease pathogenesis in many organs. Compared to other organs, the lymphatic system in the liver is understudied despite its obvious importance for hepatic physiology and pathophysiology. In this review, we describe fundamental aspects of the hepatic lymphatic system and its role in a range of liver-related pathological conditions such as portal hypertension, ascites formation, malignant tumours, liver transplantation, congenital liver diseases, non-alcoholic fatty liver disease, and hepatic encephalopathy. The article concludes with a discussion regarding the modulation of lymphangiogenesis as a potential therapeutic strategy for liver diseases.
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Affiliation(s)
- Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Masatake Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.
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20
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Roberts LM, Perez MJ, Balogh KN, Mingledorff G, Cross JV, Munson JM. Myeloid Derived Suppressor Cells Migrate in Response to Flow and Lymphatic Endothelial Cell Interaction in the Breast Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14123008. [PMID: 35740673 PMCID: PMC9221529 DOI: 10.3390/cancers14123008] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/26/2022] [Accepted: 06/07/2022] [Indexed: 12/07/2022] Open
Abstract
At the site of the tumor, myeloid derived suppressor cells (MDSCs) infiltrate and interact with elements of the tumor microenvironment in complex ways. Within the invading tumor, MDSCs are exposed to interstitial fluid flow (IFF) that exists within the chronic inflammatory tumor microenvironment at the tumor-lymphatic interface. As drivers of cell migration and invasion, the link between interstitial fluid flow, lymphatics, and MDSCs have not been clearly established. Here, we hypothesized that interstitial fluid flow and cells within the breast tumor microenvironment modulate migration of MDSCs. We developed a novel 3D model to mimic the breast tumor microenvironment and incorporated MDSCs harvested from 4T1-tumor bearing mice. Using live imaging, we found that sorted GR1+ splenocytes had reduced chemotactic index compared to the unsorted population, but their speed and displacement were similar. Using our adapted tissue culture insert assay, we show that interstitial fluid flow promotes MDSC invasion, regardless of absence or presence of tumor cells. Coordinating with lymphatic endothelial cells, interstitial fluid flow further enhanced invasion of MDSCs in the presence of 4T1 cells. We also show that VEGFR3 inhibition reduced both MDSC and 4T1 flow response. Together, these findings indicate a key role of interstitial fluid flow in MDSC migration as well as describe a tool to explore the immune microenvironment in breast cancer.
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Affiliation(s)
- LaDeidra Monét Roberts
- Department of Biomedical Engineering and Mechanics, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA 24016, USA;
| | - Matthew J. Perez
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904, USA;
| | - Kristen N. Balogh
- Department of Pathology, University of Virginia, Charlottesville, VA 22904, USA; (K.N.B.); (J.V.C.)
| | - Garnett Mingledorff
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22904, USA;
| | - Janet V. Cross
- Department of Pathology, University of Virginia, Charlottesville, VA 22904, USA; (K.N.B.); (J.V.C.)
| | - Jennifer M. Munson
- Department of Biomedical Engineering and Mechanics, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA 24016, USA;
- Correspondence:
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21
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Masih M, Agarwal S, Kaur R, Gautam PK. Role of chemokines in breast cancer. Cytokine 2022; 155:155909. [PMID: 35597171 DOI: 10.1016/j.cyto.2022.155909] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 05/02/2022] [Accepted: 05/09/2022] [Indexed: 02/06/2023]
Abstract
Chemokines belong to a family of chemoattractant cytokines and are well known to have an essential role in various cancer aetiologies. Multiplesubsets of immune cells are recruited and enrolled into the tumor microenvironment through interactions between chemokines and their specific receptors. These populations and their interactions have a distinct impact on tumor growth, progression, and treatment outcomes. While it is clear that many chemokines and their cognate receptors can be detected in breast and other cancers, the role of each chemokine and receptor has yet to be determined. This review focuses on the main chemokines that play a crucial role in the tumor microenvironment, emphasizing breast cancer. We have also discussed the techniques used to identify the chemokines and their future implication in the early diagnosis of cancer. In-depth knowledge of chemokines and their role in breast cancer progression can provide specific targets for breast cancer biotherapy.
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Affiliation(s)
- Marilyn Masih
- Department of Biochemistry, AIIMS, New Delhi -110029, India.
| | - Sonam Agarwal
- Department of Biochemistry, AIIMS, New Delhi -110029, India.
| | - Rupinder Kaur
- Department of Biochemistry, AIIMS, New Delhi -110029, India.
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22
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Shokati Eshkiki Z, Khayer N, Talebi A, Karbalaei R, Akbari A. Novel insight into pancreatic adenocarcinoma pathogenesis using liquid association analysis. BMC Med Genomics 2022; 15:30. [PMID: 35180880 PMCID: PMC8855560 DOI: 10.1186/s12920-022-01174-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 02/01/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with a poor prognosis. High-throughput disease-related-gene expression data provide valuable information on gene interaction, which consequently lead to deeper insight about pathogenesis. The co-expression analysis is a common approach that is used to investigate gene interaction. However, such an approach solely is inadequate to reveal the complexity of the gene interaction. The three-way interaction model is known as a novel approach applied to decode the complex relationship between genes. METHODS In the current study, the liquid association method was used to capture the statistically significant triplets involved in the PDAC pathogenesis. Subsequently, gene set enrichment and gene regulatory network analyses were performed to trace the biological relevance of the statistically significant triplets. RESULTS The results of the current study suggest that "response to estradiol" and "Regulation of T-cell proliferation" are two critical biological processes that may be associated with the PDAC pathogenesis. Additionally, we introduced six switch genes, namely Lamc2, Klk1, Nqo1, Aox1, Tspan1, and Cxcl12, which might be involved in PDAC triggering. CONCLUSION In the current study, for the first time, the critical genes and pathways involved in the PDAC pathogenesis were investigated using the three-way interaction approach. As a result, two critical biological processes, as well as six potential biomarkers, were suggested that might be involved in the PDAC triggering. Surprisingly, strong evidence for the biological relevance of our results can be found in the literature.
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Affiliation(s)
- Zahra Shokati Eshkiki
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Nasibeh Khayer
- Skull Base Research Center, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran.
| | - Atefeh Talebi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Karbalaei
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA, USA
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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23
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C-C Chemokine Receptor 7 in Cancer. Cells 2022; 11:cells11040656. [PMID: 35203305 PMCID: PMC8870371 DOI: 10.3390/cells11040656] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/01/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
C-C chemokine receptor 7 (CCR7) was one of the first two chemokine receptors that were found to be upregulated in breast cancers. Chemokine receptors promote chemotaxis of cells and tissue organization. Since under homeostatic conditions, CCR7 promotes migration of immune cells to lymph nodes, questions immediately arose regarding the ability of CCR7 to direct migration of cancer cells to lymph nodes. The literature since 2000 was examined to determine to what extent the expression of CCR7 in malignant tumors promoted migration to the lymph nodes. The data indicated that in different cancers, CCR7 plays distinct roles in directing cells to lymph nodes, the skin or to the central nervous system. In certain tumors, it may even serve a protective role. Future studies should focus on defining mechanisms that differentially regulate the unfavorable or beneficial role that CCR7 plays in cancer pathophysiology, to be able to improve outcomes in patients who harbor CCR7-positive cancers.
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24
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Hayasaka H, Yoshida J, Kuroda Y, Nishiguchi A, Matsusaki M, Kishimoto K, Nishimura H, Okada M, Shimomura Y, Kobayashi D, Shimazu Y, Taya Y, Akashi M, Miyasaka M. CXCL12 promotes CCR7 ligand-mediated breast cancer cell invasion and migration toward lymphatic vessels. Cancer Sci 2022; 113:1338-1351. [PMID: 35133060 PMCID: PMC8990860 DOI: 10.1111/cas.15293] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/20/2022] [Accepted: 01/25/2022] [Indexed: 12/03/2022] Open
Abstract
Chemokines are a family of cytokines that mediate leukocyte trafficking and are involved in tumor cell migration, growth, and progression. Although there is emerging evidence that multiple chemokines are expressed in tumor tissues and that each chemokine induces receptor‐mediated signaling, their collaboration to regulate tumor invasion and lymph node metastasis has not been fully elucidated. In this study, we examined the effect of CXCL12 on the CCR7‐dependent signaling in MDA‐MB‐231 human breast cancer cells to determine the role of CXCL12 and CCR7 ligand chemokines in breast cancer metastasis to lymph nodes. CXCL12 enhanced the CCR7‐dependent in vitro chemotaxis and cell invasion into collagen gels at suboptimal concentrations of CCL21. CXCL12 promoted CCR7 homodimer formation, ligand binding, CCR7 accumulation into membrane ruffles, and cell response at lower concentrations of CCL19. Immunohistochemistry of MDA‐MB‐231–derived xenograft tumors revealed that CXCL12 is primarily located in the pericellular matrix surrounding tumor cells, whereas the CCR7 ligand, CCL21, mainly associates with LYVE‐1+ intratumoral and peritumoral lymphatic vessels. In the three‐dimensional tumor invasion model with lymph networks, CXCL12 stimulation facilitates breast cancer cell migration to CCL21‐reconstituted lymphatic networks. These results indicate that CXCL12/CXCR4 signaling promotes breast cancer cell migration and invasion toward CCR7 ligand–expressing intratumoral lymphatic vessels and supports CCR7 signaling associated with lymph node metastasis.
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Affiliation(s)
- Haruko Hayasaka
- Faculty of Science & Engineering, Department of Science, Graduate School of Science and Engineering, Kindai University
| | - Junichi Yoshida
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University
| | - Yasutaka Kuroda
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University
| | - Akihiro Nishiguchi
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University
| | - Michiya Matsusaki
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University
| | - Kei Kishimoto
- Faculty of Science & Engineering, Department of Science, Graduate School of Science and Engineering, Kindai University
| | - Hitoshi Nishimura
- Faculty of Science & Engineering, Department of Science, Graduate School of Science and Engineering, Kindai University
| | - Mari Okada
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University
| | - Yuki Shimomura
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University
| | - Daichi Kobayashi
- Niigata University Graduate School of Medical and Dental Sciences
| | - Yoshihito Shimazu
- Department of Life and Food Science, School of Life and Environmental Science, Azabu University
| | - Yuji Taya
- Life Dentistry at Tokyo, The Nippon Dental University
| | - Mitsuru Akashi
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University
| | - Masayuki Miyasaka
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University.,MediCity Research Laboratory, University of Turku, Finland
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25
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Fuss CT, Other K, Heinze B, Landwehr LS, Wiegering A, Kalogirou C, Hahner S, Fassnacht M. Expression of the Chemokine Receptor CCR7 in the Normal Adrenal Gland and Adrenal Tumors and Its Correlation with Clinical Outcome in Adrenocortical Carcinoma. Cancers (Basel) 2021; 13:5693. [PMID: 34830848 PMCID: PMC8616506 DOI: 10.3390/cancers13225693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/19/2021] [Accepted: 11/04/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. METHODS CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. RESULTS CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients' survival. CONCLUSION We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis.
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Affiliation(s)
- Carmina Teresa Fuss
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany; (C.T.F.); (K.O.); (B.H.); (L.-S.L.); (S.H.)
| | - Katharina Other
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany; (C.T.F.); (K.O.); (B.H.); (L.-S.L.); (S.H.)
| | - Britta Heinze
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany; (C.T.F.); (K.O.); (B.H.); (L.-S.L.); (S.H.)
| | - Laura-Sophie Landwehr
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany; (C.T.F.); (K.O.); (B.H.); (L.-S.L.); (S.H.)
| | - Armin Wiegering
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, 97080 Würzburg, Germany;
- Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Charis Kalogirou
- Department of Urology, University Hospital Würzburg, 97080 Würzburg, Germany;
| | - Stefanie Hahner
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany; (C.T.F.); (K.O.); (B.H.); (L.-S.L.); (S.H.)
| | - Martin Fassnacht
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany; (C.T.F.); (K.O.); (B.H.); (L.-S.L.); (S.H.)
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26
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Sentinel Lymph Node Metastasis on Clinically Negative Patients: Preliminary Results of a Machine Learning Model Based on Histopathological Features. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app112110372] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The reported incidence of node metastasis at sentinel lymph node biopsy is generally low, so that the majority of women underwent unnecessary invasive axilla surgery. Although the sentinel lymph node biopsy is time consuming and expensive, it is still the intra-operative exam with the highest performance, but sometimes surgery is achieved without a clear diagnosis and also with possible serious complications. In this work, we developed a machine learning model to predict the sentinel lymph nodes positivity in clinically negative patients. Breast cancer clinical and immunohistochemical features of 907 patients characterized by a clinically negative lymph node status were collected. We trained different machine learning algorithms on the retrospective collected data and selected an optimal subset of features through a sequential forward procedure. We found comparable performances for different classification algorithms: on a hold-out training set, the logistics regression classifier with seven features, i.e., tumor diameter, age, histologic type, grading, multiplicity, in situ component and Her2-neu status reached an AUC value of 71.5% and showed a better trade-off between sensitivity and specificity (69.4 and 66.9%, respectively) compared to other two classifiers. On the hold-out test set, the performance dropped by five percentage points in terms of accuracy. Overall, the histological characteristics alone did not allow us to develop a support tool suitable for actual clinical application, but it showed the maximum informative power contained in the same for the resolution of the clinical problem. The proposed study represents a starting point for future development of predictive models to obtain the probability for lymph node metastases by using histopathological features combined with other features of a different nature.
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27
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Wang X, Liu Z, Sun J, Song X, Bian M, Wang F, Yan F, Yu Z. Inhibition of NADPH oxidase 4 attenuates lymphangiogenesis and tumor metastasis in breast cancer. FASEB J 2021; 35:e21531. [PMID: 33769605 DOI: 10.1096/fj.202002533r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/14/2021] [Accepted: 03/01/2021] [Indexed: 12/11/2022]
Abstract
Lymphangiogenesis is thought to contribute to promote tumor cells to enter lymphatic vessels and plant at a secondary site. Endothelial cells are the cornerstone of the generation of new lymphatic vessels. NADPH oxidase 4 (Nox4) is the most abundant one of NADPH oxidases in endothelial cells and the most studied one in relevance with cancer. Our purpose is to analyze the relationship between Nox4 and lymphangiogenesis and find out whether the newborn lymphatic vessels lead to cancer metastasis. We first explored the expression of Nox4 in lymphatic endothelial cells of primary invasive breast tumors and human normal mammary glands using GEO databases and found that Nox4 was upregulated in primary invasive breast tumors samples. In addition, its high expression correlated with lymph node metastasis in breast cancer patients. Nox4 could increase the tube formation and lymphatic vessel sprouting in a three-dimensional setting. In vivo, inhibition of Nox4 in 4T1 tumor-bearing mice could significantly decrease the tumor lymphangiogenesis and metastasis. Nox4 may increase tumor lymphangiogenesis via ROS/ERK/CCL21 pathway and attract CCR7-positive breast cancer cells to entry lymphatic vessels and distant organs. In conclusion, our results show that Nox4 is a factor that promotes lymphangiogenesis and is a potential target of antitumor metastasis.
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Affiliation(s)
- Xinzhao Wang
- Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.,Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Zhaoyun Liu
- Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.,Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Jujie Sun
- Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Xiang Song
- Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Mengxue Bian
- Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Fukai Wang
- Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Feng Yan
- Department of Emergency Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.,Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Zhiyong Yu
- Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
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28
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Contribution of Heparan Sulphate Binding in CCL21-Mediated Migration of Breast Cancer Cells. Cancers (Basel) 2021; 13:cancers13143462. [PMID: 34298676 PMCID: PMC8306094 DOI: 10.3390/cancers13143462] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/29/2021] [Accepted: 07/02/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. Chemokine receptor CCR7 and its ligand CCL21 are implicated in the metastasis of breast cancer to the lymph nodes. Chemokine function is dependent upon binding to their specific chemokine receptors and negatively charged molecules on the cell surface (heparan sulphate). The role of heparan sulphate in CCR7-mediated lymph node metastasis was investigated by creating a non-heparan sulphate binding mutant chemokine CCL21. Mutant-CCL21 was tested in vitro in a range of assays, including cell migration, calcium flux and surface plasmon resonance spectroscopy. Mutant-CCL21 induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration of breast cancer cells. A murine model was used to assess the potential of mutant-CCL21 to prevent lymph node metastasis in vivo. Lymph node metastasis was significantly reduced by the administration of mutant-CCL21 compared to the control. Targeting chemokine–heparan sulphate interactions may be a promising approach to inhibit chemokine activity and metastasis. Abstract Chemokine receptor CCR7 is implicated in the metastasis of breast cancer to the lymph nodes. Chemokine function is dependent upon their binding to both cell-surface heparan sulphate (HS) and to their specific receptors; thus, the role of HS in CCR7-mediated lymph node metastasis was investigated by creating a non-HS binding chemokine CCL21 (mut-CCL21). Mut-CCL21 (Δ103–134) induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration of PBMCs (p < 0.001) and 4T1-Luc cells (p < 0.01). Furthermore, the effect of heparin and HS on the chemotactic properties of wild-type (WT) and mut-CCL21 was examined. Interestingly, heparin and HS completely inhibit the chemotaxis mediated by WT-CCL21 at 250 and 500 µg/mL, whereas minimal effect was seen with mut-CCL21. This difference could potentially be attributed to reduced HS binding, as surface plasmon resonance spectroscopy showed that mut-CCL21 did not significantly bind HS compared to WT-CCL21. A murine model was used to assess the potential of mut-CCL21 to prevent lymph node metastasis in vivo. Mice were injected with 4T1-Luc cells in the mammary fat pad and treated daily for a week with 20 µg mut-CCL21. Mice were imaged weekly with IVIS and sacrificed on day 18. Luciferase expression was significantly reduced in lymph nodes from mice that had been treated with mut-CCL21 compared to the control (p = 0.0148), suggesting the potential to target chemokine binding to HS as a therapeutic option.
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29
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Fu J, Xie Y, Fu T, Qiu F, Yu F, Qu W, Yao X, Zhang A, Yang Z, Shao G, Meng Q, Shi X, Huang Y, Gu W, Wang F. [ 99mTc]Tc-Galacto-RGD 2 integrin α vβ 3-targeted imaging as a surrogate for molecular phenotyping in lung cancer: real-world data. EJNMMI Res 2021; 11:59. [PMID: 34121134 PMCID: PMC8200335 DOI: 10.1186/s13550-021-00801-x] [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: 02/23/2021] [Accepted: 06/09/2021] [Indexed: 12/18/2022] Open
Abstract
Background Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are beneficial in patients with lung cancer. We explored the clinical value of [99mTc]Tc-Galacto-RGD2 single-photon emission computed tomography (SPECT/CT) in patients with lung cancer, integrin αvβ3 expression, and neovascularization in lung cancer subtypes was also addressed. Methods A total of 185 patients with lung cancer and 25 patients with benign lung diseases were enrolled in this prospective study from January 2013 to December 2016. All patients underwent [99mTc]Tc-Galacto-RGD2 imaging. The region of interest was drawn around each primary lesion, and tumour uptake of [99mTc]Tc-Galacto-RGD2 was expressed as the tumour/normal tissue ratio(T/N). The diagnostic efficacy was evaluated by receiver operating characteristic curve analysis. Tumour specimens were obtained from 66 patients with malignant diseases and 7 with benign disease. Tumour expression levels of αvβ3, CD31, Ki-67, and CXCR4 were further analysed for the evaluation of biological behaviours. Results The lung cancer patients included 22 cases of small cell lung cancer (SCLC), 48 squamous cell carcinoma (LSC), 97 adenocarcinoma (LAC), and 18 other types of lung cancer. The sensitivity, specificity, and accuracy of [99mTc]Tc-Galacto-RGD2 SPECT/CT using a cut-off value of T/N ratio at 2.5 were 91.89%, 48.0%, and 86.67%, respectively. Integrin αvβ3 expression was higher in non-SCLC compared with SCLC, while LSC showed denser neovascularization and higher integrin αvβ3 expression. Integrin αvβ3 expression levels were significantly higher in advanced (III, IV) than early stages (I, II). However, there was no significant correlation between tumour uptake and αvβ3 expression. Conclusions [99mTc]Tc-Galacto-RGD2 SPECT/CT has high sensitivity but limited specificity for detecting primary lung cancer, integrin expression in the tumour vessel and tumour cell membrane contributes to the tumour uptake.
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Affiliation(s)
- Jingjing Fu
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Yan Xie
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Tong Fu
- Department of Imaging, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Fan Qiu
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Fei Yu
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Wei Qu
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Xiaochen Yao
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Aiping Zhang
- Department of Thoracic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Zhenhua Yang
- Department of Respiratory, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Guoqiang Shao
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Qingle Meng
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Xiumin Shi
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Yue Huang
- Department of Pathology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China.
| | - Wei Gu
- Department of Respiratory, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China.
| | - Feng Wang
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China.
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Chai H, Zhou X, Zhang Z, Rao J, Zhao H, Yang Y. Integrating multi-omics data through deep learning for accurate cancer prognosis prediction. Comput Biol Med 2021; 134:104481. [PMID: 33989895 DOI: 10.1016/j.compbiomed.2021.104481] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 05/06/2021] [Accepted: 05/06/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Genomic information is nowadays widely used for precise cancer treatments. Since the individual type of omics data only represents a single view that suffers from data noise and bias, multiple types of omics data are required for accurate cancer prognosis prediction. However, it is challenging to effectively integrate multi-omics data due to the large number of redundant variables but relatively small sample size. With the recent progress in deep learning techniques, Autoencoder was used to integrate multi-omics data for extracting representative features. Nevertheless, the generated model is fragile from data noises. Additionally, previous studies usually focused on individual cancer types without making comprehensive tests on pan-cancer. Here, we employed the denoising Autoencoder to get a robust representation of the multi-omics data, and then used the learned representative features to estimate patients' risks. RESULTS By applying to 15 cancers from The Cancer Genome Atlas (TCGA), our method was shown to improve the C-index values over previous methods by 6.5% on average. Considering the difficulty to obtain multi-omics data in practice, we further used only mRNA data to fit the estimated risks by training XGboost models, and found the models could achieve an average C-index value of 0.627. As a case study, the breast cancer prognosis prediction model was independently tested on three datasets from the Gene Expression Omnibus (GEO), and shown able to significantly separate high-risk patients from low-risk ones (C-index>0.6, p-values<0.05). Based on the risk subgroups divided by our method, we identified nine prognostic markers highly associated with breast cancer, among which seven genes have been proved by literature review. CONCLUSION Our comprehensive tests indicated that we have constructed an accurate and robust framework to integrate multi-omics data for cancer prognosis prediction. Moreover, it is an effective way to discover cancer prognosis-related genes.
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Affiliation(s)
- Hua Chai
- School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou, 510000, China
| | - Xiang Zhou
- School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou, 510000, China
| | - Zhongyue Zhang
- School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou, 510000, China
| | - Jiahua Rao
- School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou, 510000, China
| | - Huiying Zhao
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510000, China.
| | - Yuedong Yang
- School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou, 510000, China; Key Laboratory of Machine Intelligence and Advanced Computing (MOE), Sun Yat-sen University, Guangzhou, 510000, China.
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31
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He M, He Q, Cai X, Chen Z, Lao S, Deng H, Liu X, Zheng Y, Liu X, Liu J, Xie Z, Yao M, Liang W, He J. Role of lymphatic endothelial cells in the tumor microenvironment-a narrative review of recent advances. Transl Lung Cancer Res 2021; 10:2252-2277. [PMID: 34164274 PMCID: PMC8182726 DOI: 10.21037/tlcr-21-40] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background As lymphatic vessel is a major route for solid tumor metastasis, they are considered an essential part of tumor drainage conduits. Apart from forming the walls of lymphatic vessels, lymphatic endothelial cells (LECs) have been found to play multiple other roles in the tumor microenvironment, calling for a more in-depth review. We hope that this review may help researchers gain a detailed understanding of this fast-developing field and shed some light upon future research. Methods To achieve an informative review of recent advance, we carefully searched the Medline database for English literature that are openly published from the January 1995 to December 2020 and covered the topic of LEC or lymphangiogenesis in tumor progression and therapies. Two different authors independently examined the literature abstracts to exclude possible unqualified ones, and 310 papers with full texts were finally retrieved. Results In this paper, we discussed the structural and molecular basis of tumor-associated LECs, together with their roles in tumor metastasis and drug therapy. We then focused on their impacts on tumor cells, tumor stroma, and anti-tumor immunity, and the molecular and cellular mechanisms involved. Special emphasis on lung cancer and possible therapeutic targets based on LECs were also discussed. Conclusions LECs can play a much more complex role than simply forming conduits for tumor cell dissemination. Therapies targeting tumor-associated lymphatics for lung cancer and other tumors are promising, but more research is needed to clarify the mechanisms involved.
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Affiliation(s)
- Miao He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qihua He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiuyu Cai
- Department of VIP Region, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zisheng Chen
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Respiratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China
| | - Shen Lao
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hongsheng Deng
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiwen Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yongmei Zheng
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoyan Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jun Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhanhong Xie
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Maojin Yao
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenhua Liang
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,The First People Hospital of Zhaoqing, Zhaoqing, China
| | - Jianxing He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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32
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Yu T, Wang C, Xie M, Zhu C, Shu Y, Tang J, Guan X. Heterogeneity of CTC contributes to the organotropism of breast cancer. Biomed Pharmacother 2021; 137:111314. [PMID: 33581649 DOI: 10.1016/j.biopha.2021.111314] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/11/2021] [Accepted: 01/21/2021] [Indexed: 02/08/2023] Open
Abstract
Circulating tumor cells (CTCs) are viewed as pro-metastasis precursors shed from primary tumors or metastatic sites. The phenotypic and molecular heterogeneity of CTCs is associated with breast cancer progression and prognosis. Therefore, we divided CTCs into several subtypes according to their differences in biomarker status, epithelial/mesenchymal phenotype, aggregation status, and other factors to summarize their characteristics. Considering that the organ-specific metastasis is a hallmark of breast cancer, we adopted the "seed and soil" model to further analyze the relationship between the heterogeneity of CTCs and the organotropism of breast cancer. We speculated that CTCs might not only develop their genetic potential but communicate with surroundings, including chemokine systems, hemocytes, and extracellular matrix components, to regulate the organ-specific metastases of breast cancer.
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Affiliation(s)
- Tao Yu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People's Republic of China
| | - Cenzhu Wang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People's Republic of China
| | - Mengyan Xie
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People's Republic of China
| | - Chengjun Zhu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People's Republic of China
| | - Yongqian Shu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People's Republic of China
| | - Jinhai Tang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People's Republic of China.
| | - Xiaoxiang Guan
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People's Republic of China.
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33
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Predicting of Sentinel Lymph Node Status in Breast Cancer Patients with Clinically Negative Nodes: A Validation Study. Cancers (Basel) 2021; 13:cancers13020352. [PMID: 33477893 PMCID: PMC7833376 DOI: 10.3390/cancers13020352] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Sentinel lymph node biopsy procedure is time consuming and expensive, but it is still the intra-operative exam capable of the best performance. However, sometimes, surgery is achieved without a clear diagnosis, so clinical decision support systems developed with artificial intelligence techniques are essential to assist current diagnostic procedures. In this work, we evaluated the usefulness of a CancerMath tool in the sentinel lymph nodes positivity prediction for clinically negative patients. We tested it on 993 patients referred to our institute characterized by sentinel lymph node status, tumor size, age, histologic type, grading, expression of estrogen receptor, progesterone receptor, HER2, and Ki-67. By training the CancerMath (CM) model on our dataset, we reached a sensitivity value of 72%, whereas the online one was 46%, despite a specificity reduction. It was found the addiction of the prognostic factors Her2 and Ki67 could help improve performances on the classification of particular types of patients. Abstract In the absence of lymph node abnormalities detectable on clinical examination or imaging, the guidelines provide for the dissection of the first axillary draining lymph nodes during surgery. It is not always possible to arrive at surgery without diagnostic doubts, and machine learning algorithms can support clinical decisions. The web calculator CancerMath (CM) allows you to estimate the probability of having positive lymph nodes valued on the basis of tumor size, age, histologic type, grading, expression of estrogen receptor, and progesterone receptor. We collected 993 patients referred to our institute with clinically negative results characterized by sentinel lymph node status, prognostic factors defined by CM, and also human epidermal growth factor receptor 2 (HER2) and Ki-67. Area Under the Curve (AUC) values obtained by the online CM application were comparable with those obtained after training its algorithm on our database. Nevertheless, by training the CM model on our dataset and using the same feature, we reached a sensitivity median value of 72%, whereas the online one was equal to 46%, despite a specificity reduction. We found that the addition of the prognostic factors Her2 and Ki67 could help improve performances on the classification of particular types of patients with the aim of reducing as much as possible the false positives that lead to axillary dissection. As showed by our experimental results, it is not particularly suitable for use as a support instrument for the prediction of metastatic lymph nodes on clinically negative patients.
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34
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Salem A, Alotaibi M, Mroueh R, Basheer HA, Afarinkia K. CCR7 as a therapeutic target in Cancer. Biochim Biophys Acta Rev Cancer 2020; 1875:188499. [PMID: 33385485 DOI: 10.1016/j.bbcan.2020.188499] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/24/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023]
Abstract
The CCR7 chemokine axis is comprised of chemokine ligand 21 (CCL21) and chemokine ligand 19 (CCL19) acting on chemokine receptor 7 (CCR7). This axis plays two important but apparently opposing roles in cancer. On the one hand, this axis is significantly engaged in the trafficking of a number of effecter cells involved in mounting an immune response to a growing tumour. This suggests therapeutic strategies which involve potentiation of this axis can be used to combat the spread of cancer. On the other hand, the CCR7 axis plays a significant role in controlling the migration of tumour cells towards the lymphatic system and metastasis and can thus contribute to the expansion of cancer. This implies that therapeutic strategies which involve decreasing signaling through the CCR7 axis would have a beneficial effect in preventing dissemination of cancer. This dichotomy has partly been the reason why this axis has not yet been exploited, as other chemokine axes have, as a therapeutic target in cancer. Recent report of a crystal structure for CCR7 provides opportunities to exploit this axis in developing new cancer therapies. However, it remains unclear which of these two strategies, potentiation or antagonism of the CCR7 axis, is more appropriate for cancer therapy. This review brings together the evidence supporting both roles of the CCR7 axis in cancer and examines the future potential of each of the two different therapeutic approaches involving the CCR7 axis in cancer.
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Affiliation(s)
- Anwar Salem
- Institute of Cancer Therapeutics, University of Bradford; Bradford BD7 1DP, United Kingdom
| | - Mashael Alotaibi
- Institute of Cancer Therapeutics, University of Bradford; Bradford BD7 1DP, United Kingdom
| | - Rima Mroueh
- Institute of Cancer Therapeutics, University of Bradford; Bradford BD7 1DP, United Kingdom
| | - Haneen A Basheer
- Faculty of Pharmacy, Zarqa University, PO Box 132222, Zarqa 13132, Jordan
| | - Kamyar Afarinkia
- Institute of Cancer Therapeutics, University of Bradford; Bradford BD7 1DP, United Kingdom.
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35
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DeNies MS, Smrcka AV, Schnell S, Liu AP. β-arrestin mediates communication between plasma membrane and intracellular GPCRs to regulate signaling. Commun Biol 2020; 3:789. [PMID: 33339901 PMCID: PMC7749148 DOI: 10.1038/s42003-020-01510-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 11/16/2020] [Indexed: 01/14/2023] Open
Abstract
It has become increasingly apparent that G protein-coupled receptor (GPCR) localization is a master regulator of cell signaling. However, the molecular mechanisms involved in this process are not well understood. To date, observations of intracellular GPCR activation can be organized into two categories: a dependence on OCT3 cationic channel-permeable ligands or the necessity of endocytic trafficking. Using CXC chemokine receptor 4 (CXCR4) as a model, we identified a third mechanism of intracellular GPCR signaling. We show that independent of membrane permeable ligands and endocytosis, upon stimulation, plasma membrane and internal pools of CXCR4 are post-translationally modified and collectively regulate EGR1 transcription. We found that β-arrestin-1 (arrestin 2) is necessary to mediate communication between plasma membrane and internal pools of CXCR4. Notably, these observations may explain that while CXCR4 overexpression is highly correlated with cancer metastasis and mortality, plasma membrane localization is not. Together these data support a model where a small initial pool of plasma membrane-localized GPCRs are capable of activating internal receptor-dependent signaling events. DeNies et al. identify a new mechanism of intracellular GPCR signalling. Using CXC chemokine receptor 4 (CXCR4) as a model, they show that upon stimulation with receptor agonists that not only plasma membrane-localized receptors, but also intracellular CXCR4 molecules are post-translationally modified and regulate transcription. This study suggests that a small pool of plasma membrane-localized GPCRs can activate internal receptor-dependent signaling, and that β-arrestin-1 mediates this activation.
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Affiliation(s)
- Maxwell S DeNies
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA
| | - Alan V Smrcka
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Santiago Schnell
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.,Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Computational Medicine & Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Allen P Liu
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA. .,Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, USA. .,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. .,Department of Biophysics, University of Michigan, Ann Arbor, MI, USA.
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36
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To B, Isaac D, Andrechek ER. Studying Lymphatic Metastasis in Breast Cancer: Current Models, Strategies, and Clinical Perspectives. J Mammary Gland Biol Neoplasia 2020; 25:191-203. [PMID: 33034778 DOI: 10.1007/s10911-020-09460-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 09/24/2020] [Indexed: 03/23/2023] Open
Abstract
Breast cancer is the most commonly diagnosed cancer in women and the second most common cause of cancer-related deaths in the United States. Although early detection has significantly decreased breast cancer mortality, patients diagnosed with distant metastasis still have a very poor prognosis. The most common site that breast cancer spreads to are local lymph nodes. Therefore, the presence of lymph node metastasis remains one of most important prognostic factors in breast cancer patients. Given its significant clinical implications, increased efforts have been dedicated to better understand the molecular mechanism governing lymph node metastasis in breast cancer. The identification of lymphatic-specific biomarkers, including podoplanin and LYVE-1, has propelled the field of lymphatic metastasis forward. In addition, several animal models such as cell line-derived xenografts, patient-derived xenografts, and spontaneous tumor models have been developed to recreate the process of lymphatic metastasis. Moreover, the incorporation of various -omic platforms have provided further insight into the genetic drivers facilitating lymphatic metastasis, as well as potential biomarkers and therapeutic targets. Here, we highlight various models of lymphatic metastasis, their potential pitfalls, and other tools available to study lymphatic metastasis including imaging modalities and -omic studies.
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Affiliation(s)
- Briana To
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Daniel Isaac
- Division of Hematology and Oncology, MSU Breslin Cancer Center, Lansing, MI, USA
| | - Eran R Andrechek
- Department of Physiology, Michigan State University, East Lansing, MI, USA.
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37
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The CXCR4-Dependent LASP1-Ago2 Interaction in Triple-Negative Breast Cancer. Cancers (Basel) 2020; 12:cancers12092455. [PMID: 32872485 PMCID: PMC7564666 DOI: 10.3390/cancers12092455] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 08/20/2020] [Accepted: 08/26/2020] [Indexed: 12/28/2022] Open
Abstract
The CXCR4-LASP1 axis is an emerging target in the field of breast cancer metastasis. C-X-C chemokine receptor type 4 (CXCR4) mediates directed cell migration when activated by its cognate ligand CXCL12. LIM and SH3 Protein 1 (LASP1) is a critical node in the CXCR4 signaling pathway, as its deficiency blocks CXCR4-dependent Matrigel invasion. The mechanism by which LASP1 facilitates this invasive ability of tumor cells when CXCR4 is activated is unknown. Our previous proteomics work had revealed several components of the RNA interference (RNAi) machinery as being potential LASP1 interacting proteins. Here we report that argonaute 2 (Ago2), a protein with central involvement in RNAi, associates with LASP1 in triple-negative breast cancer (TNBC) cells. We demonstrate that LASP1 co-immunoprecipitates with Ago2 endogenously in a CXCL12-dependent manner, with further confirmation of this interaction by proximity ligation assay. Furthermore, this association is specific to CXCR4 as it can be abrogated by the CXCR4 antagonist, AMD3465. By GST-pulldown approach, we identify that LASP1 directly binds to Ago2 through its LIM and SH3 domains, and that this binding is dictated by the S146 and Y171 phosphorylation sites of LASP1. Additionally, the phosphorylation status of LASP1 affected tumor suppressor microRNA (miRNA) Let-7a-guided Ago2 activity. Levels of several endogenous targets of Let-7a were found to be altered including C-C chemokine receptor type 7 (CCR7), which is another critical chemokine receptor involved in metastasis to lymph nodes. Our results suggest a novel role for the LASP1-Ago2 module in shaping the RNAi landscape, functionally impacting the invasive ability of cancer cells.
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38
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Rizeq B, Malki MI. The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression. Cancers (Basel) 2020; 12:E1036. [PMID: 32340161 PMCID: PMC7226115 DOI: 10.3390/cancers12041036] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/01/2020] [Accepted: 04/11/2020] [Indexed: 12/14/2022] Open
Abstract
Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. It is generally accepted that the pattern of breast cancer metastasis is largely determined by the interaction between the chemokine receptors on cancer cells and the chemokines expressed at the sites of metastatic disease. Chemokine receptors belong to the G-protein-coupled receptors (GPCRs) family that appear to be implicated in inflammatory diseases, tumor growth and metastasis. One of its members, C-C Chemokine receptor 7 (CCR7), binds chemokines CCL19 and CCL21, which are important for tissue homeostasis, immune surveillance and tumorigenesis. These receptors have been shown to induce the pathobiology of breast cancer due to their ability to induce cellular proliferation and migration upon the binding of the cognate chemokine receptors. The underlying signaling pathways and exact cellular interactions within this biological system are not fully understood and need further insights. Thus, in this review, we summarize the essential roles of CCR7 and its receptors in breast cancer progression. Furthermore, we discuss the mechanisms of regulation that may lead to novel opportunities for therapeutic intervention. Despite the enormous advances in our knowledge of the nature of the chemokines in breast cancer metastasis, research about the involvement of CCR7 in cancer progression is still limited. Therefore, further studies are essential to illustrate the distinct roles of CCR7 in cancer progression and validate its potential as a preventive bio-factor for human breast cancer metastasis by targeting chemokine receptor genes.
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Affiliation(s)
| | - Mohammed Imad Malki
- College of Medicine, QU Health, Qatar University, P. O. Box. 2713, Doha, Qatar;
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39
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Liu H, Yang Z, Lu W, Chen Z, Chen L, Han S, Wu X, Cai T, Cai Y. Chemokines and chemokine receptors: A new strategy for breast cancer therapy. Cancer Med 2020; 9:3786-3799. [PMID: 32253815 PMCID: PMC7286460 DOI: 10.1002/cam4.3014] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/19/2020] [Accepted: 03/07/2020] [Indexed: 12/24/2022] Open
Abstract
Chemokines and chemokine receptors not only participate in the development of tissue differentiation, hematopoiesis, inflammation, and immune regulation but also play an important role in the process of tumor development. The role of chemokines and chemokine receptors in tumors has been emphasized in recent years. More and more studies have shown that chemokines and chemokine receptors are closely related to the occurrence, angiogenesis, metastasis, drug resistance, and immunity of breast cancer. Here, we review recent progression on the roles of chemokines and chemokine receptors in breast cancer, and discuss the possible mechanism in breast cancer that might facilitate the development of new therapies by targeting chemokines as well as chemokine receptors. Chemokines and chemokine receptors play an important role in the occurrence and development of breast cancer. In-depth study of chemokines and chemokine receptors can provide intervention targets for breast cancer biotherapy. The regulation of chemokines and chemokine receptors may become a new strategy for breast cancer therapy.
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Affiliation(s)
- Hui Liu
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Zhenjiang Yang
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Wenping Lu
- Guangan' Men Hospital China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhen Chen
- Department of Integrative Oncology, Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lianyu Chen
- Department of Integrative Oncology, Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shuyan Han
- Department of Integration of Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaoyu Wu
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
| | - Tiange Cai
- College of Life Sciences, Liaoning University, Shenyang, China
| | - Yu Cai
- College of Pharmacy, Jinan University, Guangzhou, China.,Cancer Research Institute of Jinan University, Guangzhou, China.,International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, Guangzhou, China
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40
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Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy. Cells 2020; 9:cells9030762. [PMID: 32244922 PMCID: PMC7140636 DOI: 10.3390/cells9030762] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/13/2020] [Accepted: 03/18/2020] [Indexed: 12/24/2022] Open
Abstract
Metastasis is the primary cause of cancer-related mortality. Cancer cells primarily metastasize via blood and lymphatic vessels to colonize lymph nodes and distant organs, leading to worse prognosis. Thus, strategies to limit blood and lymphatic spread of cancer have been a focal point of cancer research for several decades. Resistance to FDA-approved anti-angiogenic therapies designed to limit blood vessel growth has emerged as a significant clinical challenge. However, there are no FDA-approved drugs that target tumor lymphangiogenesis, despite the consequences of metastasis through the lymphatic system. This review highlights several of the key resistance mechanisms to anti-angiogenic therapy and potential challenges facing anti-lymphangiogenic therapy. Blood and lymphatic vessels are more than just conduits for nutrient, fluid, and cancer cell transport. Recent studies have elucidated how these vasculatures often regulate immune responses. Vessels that are abnormal or compromised by tumor cells can lead to immunosuppression. Therapies designed to improve lymphatic vessel function while limiting metastasis may represent a viable approach to enhance immunotherapy and limit cancer progression.
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41
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Mechanisms of Tumor-Lymphatic Interactions in Invasive Breast and Prostate Carcinoma. Int J Mol Sci 2020; 21:ijms21020602. [PMID: 31963450 PMCID: PMC7013901 DOI: 10.3390/ijms21020602] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/10/2020] [Accepted: 01/15/2020] [Indexed: 12/31/2022] Open
Abstract
During the last few years, diverse studies have shown that tumors can actively interact with the lymphatic system and promote metastases development. In order to examine the molecular mechanisms involved in this interaction, we co-cultured tumor and lymphatic endothelial cells (LEC) and subsequently analyzed the molecular alterations of LECs. Therefore, LECs were co-cultivated with either a highly or weakly metastatic breast cancer cell line using contact (mixture) and non-contact (transwell) co-cultures. mRNA profiles from LECs were subsequently analyzed for genes specifically induced by highly metastatic tumor cells (“metastatic specific”). Among the up-regulated “metastatic specific” genes, we found candidates involved in cell cycle, cell adhesion and motility (BST2, E-selectin, and HMMR), cytokines (CCL7, CXCL6, CXCL1, and CSF2) and factors of the complement system (C1R, C3, and CFB). Among the down-regulated genes, we detected the hyaluronan receptor STAB2, angiogenic factor apelin receptor (APLNR), and the glycosylation enzyme MAN1A1. In an additional prostate cancer co-culture model, we could confirm a “metastatic specific” upregulation of E-selectin and CCL7 in LECs after interaction with the prostate cancer cell lines LNCAP (highly metastatic) and DU145 (weakly metastatic). These data allowed us to identify a set of genes regulated in LECs during in vitro communication with cancer cells, which might subsequently facilitate lymphatic metastasis.
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Garnier L, Gkountidi AO, Hugues S. Tumor-Associated Lymphatic Vessel Features and Immunomodulatory Functions. Front Immunol 2019; 10:720. [PMID: 31024552 PMCID: PMC6465591 DOI: 10.3389/fimmu.2019.00720] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 03/18/2019] [Indexed: 12/21/2022] Open
Abstract
The lymphatic system comprises a network of lymphoid tissues and vessels that drains the extracellular compartment of most tissues. During tumor development, lymphatic endothelial cells (LECs) substantially expand in response to VEGFR-3 engagement by VEGF-C produced in the tumor microenvironment, a process known as tumor-associated lymphangiogenesis. Lymphatic drainage from the tumor to the draining lymph nodes consequently increases, powering interstitial flow in the tumor stroma. The ability of a tumor to induce and activate lymphatic growth has been positively correlated with metastasis. Much effort has been made to identify genes responsible for tumor-associated lymphangiogenesis. Inhibition of lymphangiogenesis with soluble VEGFR-3 or with specific monoclonal antibodies decreases tumor spread to LNs in rodent models. Importantly, tumor-associated lymphatics do not only operate as tumor cell transporters but also play critical roles in anti-tumor immunity. Therefore, metastatic as well as primary tumor progression can be affected by manipulating tumor-associated lymphatic remodeling or function. Here, we review and discuss our current knowledge on the contribution of LECs immersed in the tumor microenvironment as immunoregulators, as well as a possible functional remodeling of LECs subsets depending on the organ microenvironment.
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Affiliation(s)
- Laure Garnier
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Anastasia-Olga Gkountidi
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Stephanie Hugues
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Sun D, Zhong J, Wei W, Chen X, Liu J, Hu Z. Identification of microRNA expression in sentinel lymph nodes from patients with breast cancer via RNA sequencing for diagnostic accuracy. J Gene Med 2019; 21:e3075. [PMID: 30716792 DOI: 10.1002/jgm.3075] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 01/15/2019] [Accepted: 01/18/2019] [Indexed: 01/12/2023] Open
Affiliation(s)
- Desheng Sun
- Department of UltrasonographyPeking University Shenzhen Hospital Shenzhen Guangdong China
| | - Jieyu Zhong
- Department of UltrasonographyPeking University Shenzhen Hospital Shenzhen Guangdong China
| | - Wei Wei
- Department of Breast SurgeryPeking University Shenzhen Hospital Shenzhen Guangdong China
| | - Xiangmei Chen
- Department of UltrasonographyPeking University Shenzhen Hospital Shenzhen Guangdong China
| | - Jun Liu
- Department of PathologyPeking University Shenzhen Hospital Shenzhen Guangdong China
| | - Zhengming Hu
- Department of UltrasonographyPeking University Shenzhen Hospital Shenzhen Guangdong China
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Curcumae Radix Extract Decreases Mammary Tumor-Derived Lung Metastasis via Suppression of C-C Chemokine Receptor Type 7 Expression. Nutrients 2019; 11:nu11020410. [PMID: 30781353 PMCID: PMC6412318 DOI: 10.3390/nu11020410] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/11/2019] [Accepted: 02/11/2019] [Indexed: 12/29/2022] Open
Abstract
Curcumae radix is the dry root of Curcuma longa L. (turmeric) that can be used either as a spice or traditional medicine. The aim of this study was to investigate the survival benefits and the anti-metastatic activity of curcumae radix extract (CRE) in MCF7 cells and in MMTV-PyMT transgenic mice—a mouse model of breast cancer metastasis. In vitro wound scratch assay revealed that CRE treatment inhibited cell motility and cell migration in a dose-dependent manner. To investigate the effect of CRE in breast cancer metastasis, MMTV-PyMT transgenic female virgin mice were used and randomly divided into two groups. For survival curve analysis, CRE was administered in a dose of 50 mg/kg to 8–20-week-old mice. Interestingly, CRE treatment significantly increased the median and prolonged survival of MMTV-PyMT mice. Furthermore, CRE treatment decreased tumor burden and inhibited cell proliferation in primary breast tumor, and also suppressed mammary tumor-derived lung metastasis. The size of the lung metastases substantially decreased in the CRE-treated group compared with the ones in the control group. Curcumae radix extract showed anti-metastatic activity through regulating the expression of metastasis markers including C-C Chemokine Receptor Type 7, Matrix Metalloproteinase 9 and the proto-oncogenes c-fos and c-jun. We demonstrated that these metastatic regulators were decreased when CCR7 expression was suppressed in MCF7 cells transfected with CCR7 siRNA. The results of this study show that curcumae radix exerts antitumor and anti-metastatic activities, and we suggest that curcumae radix might be a potential supplement for the treatment and prevention of breast cancer metastasis.
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Del Molino Del Barrio I, Wilkins GC, Meeson A, Ali S, Kirby JA. Breast Cancer: An Examination of the Potential of ACKR3 to Modify the Response of CXCR4 to CXCL12. Int J Mol Sci 2018; 19:E3592. [PMID: 30441765 PMCID: PMC6274818 DOI: 10.3390/ijms19113592] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 11/02/2018] [Accepted: 11/08/2018] [Indexed: 12/22/2022] Open
Abstract
Upon binding with the chemokine CXCL12, the chemokine receptor CXCR4 has been shown to promote breast cancer progression. This process, however, can be affected by the expression of the atypical chemokine receptor ACKR3. Given ACKR3's ability to form heterodimers with CXCR4, we investigated how dual expression of both receptors differed from their lone expression in terms of their signalling pathways. We created single and double CXCR4 and/or ACKR3 Chinese hamster ovary (CHO) cell transfectants. ERK and Akt phosphorylation after CXCL12 stimulation was assessed and correlated with receptor internalization. Functional consequences in cell migration and proliferation were determined through wound healing assays and calcium flux. Initial experiments showed that CXCR4 and ACKR3 were upregulated in primary breast cancer and that CXCR4 and ACKR3 could form heterodimers in transfected CHO cells. This co-expression modified CXCR4's Akt activation after CXCL12's stimulation but not ERK phosphorylation (p < 0.05). To assess this signalling disparity, receptor internalization was assessed and it was observed that ACKR3 was recycled to the surface whilst CXCR4 was degraded (p < 0.01), a process that could be partially inhibited with a proteasome inhibitor (p < 0.01). Internalization was also assessed with the ACKR3 agonist VUF11207, which caused both CXCR4 and ACKR3 to be degraded after internalization (p < 0.05 and p < 0.001), highlighting its potential as a dual targeting drug. Interestingly, we observed that CXCR4 but not ACKR3, activated calcium flux after CXCL12 stimulation (p < 0.05) and its co-expression could increase cellular migration (p < 0.01). These findings suggest that both receptors can signal through ERK and Akt pathways but co-expression can alter their kinetics and internalization pathways.
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Affiliation(s)
- Irene Del Molino Del Barrio
- Applied Immunobiology and Transplantation Group, Institute of Cellular Medicine, Medical School, University of Newcastle Upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
| | - Georgina C Wilkins
- Applied Immunobiology and Transplantation Group, Institute of Cellular Medicine, Medical School, University of Newcastle Upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
| | - Annette Meeson
- Institute of Genetic Medicine, International Centre for Life, University of Newcastle Upon Tyne, Newcastle upon Tyne NE1 3BZ, UK.
| | - Simi Ali
- Applied Immunobiology and Transplantation Group, Institute of Cellular Medicine, Medical School, University of Newcastle Upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
| | - John A Kirby
- Applied Immunobiology and Transplantation Group, Institute of Cellular Medicine, Medical School, University of Newcastle Upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
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Widodo I, Dwianingsih EK, Utoro T, Anwar SL, Aryandono T, Soeripto S. Prognostic Value of Lymphangiogenesis Determinants in Luminal and Non-luminal Breast Carcinomas. Asian Pac J Cancer Prev 2018; 19:2461-2467. [PMID: 30255700 PMCID: PMC6249460 DOI: 10.22034/apjcp.2018.19.9.2461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background: Breast carcinomas (BCs) are sub-classified according to the molecular characteristics into luminal and non-luminal subtypes that clinically show different biological behavior, treatment and prognosis. BCs spread primarily through lymphatic vessels using cascade processes of lymphagiogenesis in which VEGF-C plays an important role during lymph node metastasis. Prognostic value of VEGF-C in luminal and non-luminal BC is still unclear and has not been studied thoroughly to clarify and define prognosis and therapeutic monitoring. Aim: To define the prognostic value of lymphangiogenesis on survival rates of luminal and non-luminal subtypes BC. Materials and Methods: This study applied prospective cohort design, using 130 patients of invasive duct carcinoma of the breast, stage I-IIIA, from Sardjito General Hospital, Indonesia and subsequent longitudinal follow-up. Immunohistochemical staining was carried out using anti-ER, -PR, -Her-2, VEGF-C, VEGFR-3 and D2-40 antibodies. The related clinicopathologic characteristics of BC patients and lymphangiogenesis determinants, including VEGF-C expression, were statistically analyzed. Results: In non-luminal BC subtypes, VEGF-C expression (HR=0.04; 95% CI=0.01-0.41), lymph node metastasis (HR=0.14; 95% CI=0.04-0.55) and stage (HR=0.30; 95% CI= 0.02-0.76) were determined as independent prognostic factors on survival rates. However, the lymphangiogenesis determinants were not associated with the survival rates of luminal BC subtypes. Conclusion: This study suggested that lymphangiogenesis affects survival rates of non-Luminal subtype rather than the luminal subtypes of BC.
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Wu J, Li L, Liu J, Wang Y, Wang Z, Wang Y, Liu W, Zhou Z, Chen C, Liu R, Yang R. CC chemokine receptor 7 promotes triple-negative breast cancer growth and metastasis. Acta Biochim Biophys Sin (Shanghai) 2018; 50:835-842. [PMID: 30032244 DOI: 10.1093/abbs/gmy077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 03/20/2018] [Indexed: 01/11/2023] Open
Abstract
Metastasis is the leading cause of breast cancer-related death. Chemokine (C-C motif) receptor 7 (CCR7) plays important roles in breast cancer metastasis. However, the role of CCR7 in triple-negative breast cancer (TNBC) has not been fully elucidated. In this study, we found that CCR7 is highly expressed in both TNBC cell lines and breast cancer tissues. CCR7 was knocked down by shRNA in 4T1 and MDA-MB-231, two TNBC cell lines, and we found that the depletion of CCR7 significantly decreased TNBC cell proliferation, migration and invasion in vitro. Furthermore, we confirmed that the knockdown of CCR7 reduced the distant metastasis of 4T1 cells in an orthotopic mouse model. Proteomic analysis in 4T1 cells indicated that several signaling pathways such as epithelial cell adhesion molecule might contribute to CCR7's function in breast cancer metastasis. Our results suggest that CCR7 promotes TNBC metastasis and may serve as a target for breast cancer diagnosis and treatment.
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Affiliation(s)
- Jiao Wu
- Second Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lu Li
- 2014 Grade of Queen Mary College of Medicine, Nanchang University, Nanchang, China
| | - Jianing Liu
- 2014 Grade of Queen Mary College of Medicine, Nanchang University, Nanchang, China
| | - Yang Wang
- Third Department of Internal Medicine, The Fifth People's Hospital of Puyang, Puyang, China
| | - Zehua Wang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Yangdan Wang
- Department of Oncology, The First Affiliated Hospital of Dali University, Dali, China
| | - Wenjing Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Zhongmei Zhou
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Runxiang Yang
- Second Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
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Schineis P, Runge P, Halin C. Cellular traffic through afferent lymphatic vessels. Vascul Pharmacol 2018; 112:31-41. [PMID: 30092362 DOI: 10.1016/j.vph.2018.08.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 06/26/2018] [Accepted: 08/01/2018] [Indexed: 12/15/2022]
Abstract
The lymphatic system has long been known to serve as a highway for migrating leukocytes from peripheral tissue to draining lymph nodes (dLNs) and back to circulation, thereby contributing to the induction of adaptive immunity and immunesurveillance. Lymphatic vessels (LVs) present in peripheral tissues upstream of a first dLN are generally referred to as afferent LVs. In contrast to migration through blood vessels (BVs), the detailed molecular and cellular requirements of cellular traffic through afferent LVs have only recently started to be unraveled. Progress in our ability to track the migration of lymph-borne cell populations, in combination with cutting-edge imaging technologies, nowadays allows the investigation and visualization of lymphatic migration of endogenous leukocytes, both at the population and at the single-cell level. These studies have revealed that leukocyte trafficking through afferent LVs generally follows a step-wise migration pattern, relying on the active interplay of numerous molecules. In this review, we will summarize and discuss current knowledge of cellular traffic through afferent LVs. We will first outline how the structure of the afferent LV network supports leukocyte migration and highlight important molecules involved in the migration of dendritic cells (DCs), T cells and neutrophils, i.e. the most prominent cell types trafficking through afferent LVs. Additionally, we will describe how tumor cells hijack the lymphatic system for their dissemination to draining LNs. Finally, we will summarize and discuss our current understanding of the functional significance as well as the therapeutic implications of cell traffic through afferent LVs.
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Affiliation(s)
| | - Peter Runge
- Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland
| | - Cornelia Halin
- Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
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Al-Awadhi FH, Gao B, Rezaei MA, Kwan JC, Li C, Ye T, Paul VJ, Luesch H. Discovery, Synthesis, Pharmacological Profiling, and Biological Characterization of Brintonamides A-E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium. J Med Chem 2018; 61:6364-6378. [PMID: 30015488 PMCID: PMC7341966 DOI: 10.1021/acs.jmedchem.8b00885] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Five novel modified linear peptides named brintonamides A-E (1-5) were discovered from a marine cyanobacterial sample collected from Brinton Channel, Florida Keys. The total synthesis of 1-5 in addition to two other structurally related analogues (6 and 7) was achieved, which provided more material to allow rigorous biological evaluation and SAR studies. Compounds were subjected to cancer-focused phenotypic cell viability and migration assays and orthogonal target-based pharmacological screening platforms to identify their protease and GPCR modulatory activity profiles. The cancer related serine protease kallikrein 7 (KLK7) was inhibited to similar extents with an IC50 near 20 μM by both representative members 1 and 4, which differed in the presence or lack of the N-terminal unit. In contrast to the biochemical protease profiling study, clear SAR was observed in the functional GPCR screens, where five GPCRs in antagonist mode (CCR10, OXTR, SSTR3, TACR2) and agonist mode (CXCR7) were modulated by compounds 1-7 to varying extents. Chemokine receptor type 10 (CCR10) was potently modulated by brintonamide D (4) with an IC50 of 0.44 μM. We performed in silico modeling to understand the structural basis underlying the differences in the antagonistic activity among brintonamides toward CCR10. Because of the significance of KLK7 and CCR10 in cancer progression and metastasis, we demonstrated the ability of brintonamide D (4) at 10 μM to significantly target downstream cellular substrates of KLK7 (Dsg-2 and E-cad) in vitro and to inhibit CCL27-induced CCR10-mediated proliferation and the migration of highly invasive breast cancer cells.
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Affiliation(s)
- Fatma H. Al-Awadhi
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait
| | - Bowen Gao
- State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen, 518055, China
| | - Mohammad A. Rezaei
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
- Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
| | - Jason C. Kwan
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
| | - Chenglong Li
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
| | - Tao Ye
- State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen, 518055, China
| | - Valerie J. Paul
- Smithsonian Marine Station, Fort Pierce, 701 Seaway Drive, Fort Pierce, Florida 34949, United States
| | - Hendrik Luesch
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
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50
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Hull-Ryde EA, Porter MA, Fowler KA, Kireev D, Li K, Simpson CD, Sassano MF, Suto MJ, Pearce KH, Janzen W, Coghill JM. Identification of Cosalane as an Inhibitor of Human and Murine CC-Chemokine Receptor 7 Signaling via a High-Throughput Screen. SLAS DISCOVERY 2018; 23:1083-1091. [PMID: 29958052 DOI: 10.1177/2472555218780917] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
CC-chemokine receptor 7 (CCR7) is a G protein-coupled receptor expressed on a variety of immune cells. CCR7 plays a critical role in the migration of lymphocytes into secondary lymphoid tissues. CCR7 expression, however, has been linked to numerous disease states. Due to its therapeutic relevance and absence of available CCR7 inhibitors, we undertook a high-throughput screen (HTS) to identify small-molecule antagonists of the receptor. Here, we describe a robust HTS approach using a commercially available β-galactosidase enzyme fragment complementation system and confirmatory transwell chemotaxis assays. This work resulted in the identification of several compounds with activity against CCR7. The most potent of these was subsequently determined to be cosalane, a cholesterol derivative previously designed as a therapeutic for human immunodeficiency virus. Cosalane inhibited both human and murine CCR7 in response to both CCL19 and CCL21 agonists at physiologic concentrations. Furthermore, cosalane produced durable inhibition of the receptor following a cellular incubation period with subsequent washout. Overall, our work describes the development of an HTS-compatible assay, completion of a large HTS campaign, and demonstration for the first time that cosalane is a validated CCR7 antagonist. These efforts could pave the way for new approaches to address CCR7-associated disease processes.
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Affiliation(s)
- Emily A Hull-Ryde
- 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,2 Marsico Lung Institute, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Melissa A Porter
- 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,3 Ribometrix, Inc., Durham, NC, USA
| | - Kenneth A Fowler
- 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Dmitri Kireev
- 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kelin Li
- 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Catherine D Simpson
- 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Maria F Sassano
- 2 Marsico Lung Institute, University of North Carolina School of Medicine, Chapel Hill, NC, USA.,5 Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA
| | - Mark J Suto
- 6 Southern Research Institute, Birmingham, AL, USA
| | - Kenneth H Pearce
- 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - William Janzen
- 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,7 Epizyme, Inc., Cambridge, MA, USA
| | - James M Coghill
- 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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