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Xie Y, Liu F, Wu Y, Zhu Y, Jiang Y, Wu Q, Dong Z, Liu K. Inflammation in cancer: therapeutic opportunities from new insights. Mol Cancer 2025; 24:51. [PMID: 39994787 PMCID: PMC11849313 DOI: 10.1186/s12943-025-02243-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/20/2025] [Indexed: 02/26/2025] Open
Abstract
As one part of the innate immune response to external stimuli, chronic inflammation increases the risk of various cancers, and tumor-promoting inflammation is considered one of the enabling characteristics of cancer development. Recently, there has been growing evidence on the role of anti-inflammation therapy in cancer prevention and treatment. And researchers have already achieved several noteworthy outcomes. In the review, we explored the underlying mechanisms by which inflammation affects the occurrence and development of cancer. The pro- or anti-tumor effects of these inflammatory factors such as interleukin, interferon, chemokine, inflammasome, and extracellular matrix are discussed. Since FDA-approved anti-inflammation drugs like aspirin show obvious anti-tumor effects, these drugs have unique advantages due to their relatively fewer side effects with long-term use compared to chemotherapy drugs. The characteristics make them promising candidates for cancer chemoprevention. Overall, this review discusses the role of these inflammatory molecules in carcinogenesis of cancer and new inflammation molecules-directed therapeutic opportunities, ranging from cytokine inhibitors/agonists, inflammasome inhibitors, some inhibitors that have already been or are expected to be applied in clinical practice, as well as recent discoveries of the anti-tumor effect of non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs. The advantages and disadvantages of their application in cancer chemoprevention are also discussed.
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Affiliation(s)
- Yifei Xie
- Department of Pathology and Forensic Medicine, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China
| | - Fangfang Liu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China
| | - Yunfei Wu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yuer Zhu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yanan Jiang
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China
| | - Qiong Wu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China
| | - Zigang Dong
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China.
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China.
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China.
| | - Kangdong Liu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China.
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China.
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China.
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Hadebe B, Harry L, Gabela L, Nxasana T, Ndlovu N, Pillay V, Masikane S, Patel M, Mpanya D, Buccimaza I, Msimang M, Aldous C, Sathekge M, Vorster M. Comparing 68Ga-Pentixafor, 18F-FDG PET/CT and Chemokine Receptor 4 Immunohistochemistry Staining in Breast Cancer: A Prospective Cross Sectional Study. Cancers (Basel) 2025; 17:763. [PMID: 40075611 PMCID: PMC11898970 DOI: 10.3390/cancers17050763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/11/2025] [Accepted: 02/12/2025] [Indexed: 03/14/2025] Open
Abstract
Background. CXCR4 is a chemokine receptor that is frequently overexpressed in invasive breast cancer and plays a major role in tumor proliferation, aggressiveness and metastasis. The aim of this prospective study was to establish the value of CXCR4-directed PET imaging in patients with breast cancer using the novel CXCR4-targeted PET probe 68Ga-Pentixafor by comparing it with 18F-FDG PET/CT (n = 40). Materials and methods. In this prospective cross-sectional study, fifty-one patients with breast cancer aged 36-81 (median (Q1-Q3) 51 (42.5-63)), n = 47 (92%) with initially diagnosed and n = 4 (8%) patients with recurrent breast cancer, underwent CXCR4-targeted PET imaging using 68Ga-Pentixafor. Maximum standardized uptake values (SUVmax), total lesion glycolysis (TLG) or total lesion uptake (TLU), metabolic tumor volume (MTV) and tumor-to-background ratios (TBR) of tumor lesions were measured and correlated with pathological prognostic factors, molecular subtypes and CXCR4 immunohistochemistry (IHC) staining. 18F-FDG PET/CT images were available in 40 of 51 cases (82%) and were compared semi-quantitatively. The patients were followed up for a median of 11 months (range 4-80 months) to determine whether CXCR4 expression correlated with survival. Results. 68Ga-Pentixafor-PET/CT was visually positive in 49/51 (96%) of the cases; in addition, [18F]FDG demonstrated a higher SUVmax compared to 68Ga-Pentixafor. The mean SUVmax was 7.26 ± 2.84 and 18.8 ± 9.1 for 68Ga-Pentixafor and [18F]FDG, respectively. Thirty-seven percent (18/51) of patients had triple-negative breast cancer and 25/51 (49%) had estrogen receptor (ER+) disease. There was a statistically significant correlation between tumor grade, proliferative index (Ki-67) and SUVmax obtained from 68Ga-Pentixafor PET p = 0.002. There was no correlation between the SUVmax obtained from 68Ga-Pentixafor and PET molecular subtypes, estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2) status; however, triple-negative breast cancers had more avid 68Ga-Pentixafor accumulation compared to luminals A and B. The median (Q1-Q3) 68Ga-Pentixafor TLU was significantly higher in HIV-positive (376 (219-881)) compared to HIV-negative (174 (105-557)) breast cancer patients. Conclusions. In conclusion, 68Ga-Pentixafor had a sensitivity of 96% and a specificity of 100% for detecting primary breast cancer; in addition, 68Ga-Pentixafor exhibited significantly higher uptake in patients with higher tumor grade, high proliferative index and triple-negative breast cancer (TNBC), as well as HIV-infected breast cancer patients, highlighting the potential clinical utility and prognostic role of CXCR4-targeted PET imaging in aggressive breast cancer. Notably, 68Ga-Pentixafor complements 18F-FDG by detecting more metastasis in the brain and the skull where FDG has limitations, while 18F-FDG remains superior for detecting skeletal metastasis. Future research should further explore the potential of CXCR4-targeted PET imaging in selecting patients with triple-negative breast cancer and high-grade breast cancer who may benefit from CXCR4-targeted therapies, particularly in the context of HIV co-infection.
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Affiliation(s)
- Bawinile Hadebe
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Lerwine Harry
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Lerato Gabela
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Thembelihle Nxasana
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Nontobeko Ndlovu
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Venesen Pillay
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Siphelele Masikane
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Maryam Patel
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Dineo Mpanya
- Department of Nuclear Medicine, School of Medicine, Faculty of Health Sciences, Sefako Makgatho Health Sciences University, Pretoria 0208, South Africa
| | - Ines Buccimaza
- Department of Surgery, University of KwaZulu Natal, Durban 4001, South Africa
| | - Mpumelelo Msimang
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
- Department of Anatomical Pathology, National Health Laboratory Service, Durban 4001, South Africa
| | - Colleen Aldous
- Department of Genetics, College of Health Sciences, University of KwaZulu Natal, Durban 4001, South Africa
| | - Mike Sathekge
- Department of Nuclear Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa
| | - Mariza Vorster
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
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Frederick MI, Abdesselam D, Clouvel A, Croteau L, Hassan S. Leveraging PARP-1/2 to Target Distant Metastasis. Int J Mol Sci 2024; 25:9032. [PMID: 39201718 PMCID: PMC11354653 DOI: 10.3390/ijms25169032] [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: 07/22/2024] [Revised: 08/14/2024] [Accepted: 08/14/2024] [Indexed: 09/03/2024] Open
Abstract
Poly (ADP-Ribose) Polymerase (PARP) inhibitors have changed the outcomes and therapeutic strategy for several cancer types. As a targeted therapeutic mainly for patients with BRCA1/2 mutations, PARP inhibitors have commonly been exploited for their capacity to prevent DNA repair. In this review, we discuss the multifaceted roles of PARP-1 and PARP-2 beyond DNA repair, including the impact of PARP-1 on chemokine signalling, immune modulation, and transcriptional regulation of gene expression, particularly in the contexts of angiogenesis and epithelial-to-mesenchymal transition (EMT). We evaluate the pre-clinical role of PARP inhibitors, either as single-agent or combination therapies, to block the metastatic process. Efficacy of PARP inhibitors was demonstrated via DNA repair-dependent and independent mechanisms, including DNA damage, cell migration, invasion, initial colonization at the metastatic site, osteoclastogenesis, and micrometastasis formation. Finally, we summarize the recent clinical advancements of PARP inhibitors in the prevention and progression of distant metastases, with a particular focus on specific metastatic sites and PARP-1 selective inhibitors. Overall, PARP inhibitors have demonstrated great potential in inhibiting the metastatic process, pointing the way for greater use in early cancer settings.
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Affiliation(s)
- Mallory I. Frederick
- Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3T5, Canada; (M.I.F.); (D.A.); (L.C.)
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), l’Institut de Cancer de Montreal, Montreal, QC H2X 0A9, Canada;
| | - Djihane Abdesselam
- Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3T5, Canada; (M.I.F.); (D.A.); (L.C.)
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), l’Institut de Cancer de Montreal, Montreal, QC H2X 0A9, Canada;
| | - Anna Clouvel
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), l’Institut de Cancer de Montreal, Montreal, QC H2X 0A9, Canada;
| | - Laurent Croteau
- Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3T5, Canada; (M.I.F.); (D.A.); (L.C.)
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), l’Institut de Cancer de Montreal, Montreal, QC H2X 0A9, Canada;
| | - Saima Hassan
- Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3T5, Canada; (M.I.F.); (D.A.); (L.C.)
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), l’Institut de Cancer de Montreal, Montreal, QC H2X 0A9, Canada;
- Division of Surgical Oncology, Department of Surgery, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC H2X 0C1, Canada
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Chen CY, Yang SH, Chang PY, Chen SF, Nieh S, Huang WY, Lin YC, Lee OKS. Cancer-Associated-Fibroblast-Mediated Paracrine and Autocrine SDF-1/CXCR4 Signaling Promotes Stemness and Aggressiveness of Colorectal Cancers. Cells 2024; 13:1334. [PMID: 39195225 PMCID: PMC11352219 DOI: 10.3390/cells13161334] [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: 05/25/2024] [Revised: 07/20/2024] [Accepted: 08/01/2024] [Indexed: 08/29/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide, and cancer-associated fibroblasts (CAFs) play a major role in the tumor microenvironment (TME), which facilitates the progression of CRC. It is critical to understand how CAFs promote the progression of CRC for the development of novel therapeutic approaches. The purpose of this study was to understand how CAF-derived stromal-derived factor-1 (SDF-1) and its interactions with the corresponding C-X-C motif chemokine receptor 4 (CXCR4) promote CRC progression. Our study focused on their roles in promoting tumor cell migration and invasion and their effects on the characteristics of cancer stem cells (CSCs), which ultimately impact patient outcomes. Here, using in vivo approaches and clinical histological samples, we analyzed the influence of secreted SDF-1 on CRC progression, especially in terms of tumor cell behavior and stemness. We demonstrated that CAF-secreted SDF-1 significantly enhanced CRC cell migration and invasion through paracrine signaling. In addition, the overexpression of SDF-1 in CRC cell lines HT29 and HCT-116 triggered these cells to generate autocrine SDF-1 signaling, which further enhanced their CSC characteristics, including those of migration, invasion, and spheroid formation. An immunohistochemical study showed a close relationship between SDF-1 and CXCR4 expression in CRC tissue, and this significantly affected patient outcomes. The administration of AMD3100, an inhibitor of CXCR4, reversed the entire phenomenon. Our results strongly suggest that targeting this signaling axis in CRC is a feasible approach to attenuating tumor progression, and it may, therefore, serve as an alternative treatment method to improve the prognosis of patients with CRC, especially those with advanced, recurrent, or metastatic CRC following standard therapy.
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Affiliation(s)
- Chao-Yang Chen
- Division of Colon and Rectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Shih-Hsien Yang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan;
- Office of General Affairs and Occupational Safety, National Defense Medical Center, Taipei 11490, Taiwan
| | - Ping-Ying Chang
- Division of Hematology-Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Su-Feng Chen
- Department of Dentistry, School of Dentistry, China Medical University, Taichung 40433, Taiwan;
| | - Shin Nieh
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Wen-Yen Huang
- Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Yu-Chun Lin
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Oscar Kuang-Sheng Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei 11211, Taiwan
- Department of Orthopedics, China Medical University Hospital, Taichung 40402, Taiwan
- Center for Translational Genomics & Regenerative Medicine Research, China Medical University Hospital, Taichung 40402, Taiwan
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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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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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Zhao F, Zhao C, Xu T, Lan Y, Lin H, Wu X, Li X. Single-cell and bulk RNA sequencing analysis of B cell marker genes in TNBC TME landscape and immunotherapy. Front Immunol 2023; 14:1245514. [PMID: 38111587 PMCID: PMC10725955 DOI: 10.3389/fimmu.2023.1245514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 11/13/2023] [Indexed: 12/20/2023] Open
Abstract
Objective This study amied to investigate the prognostic characteristics of triple negative breast cancer (TNBC) patients by analyzing B cell marker genes based on single-cell and bulk RNA sequencing. Methods Utilizing single-cell sequencing data from TNBC patients, we examined tumor-associated B cell marker genes. Transcriptomic data from The Cancer Genome Atlas (TCGA) database were used as the foundation for predictive modeling. Independent validation set was conducted using the GSE58812 dataset. Immune cell infiltration into the tumor was assessed through various, including XCELL, TIMER, QUANTISEQ, CIBERSORT, CIBERSORT-ABS, and ssGSEA. The TIDE score was utilized to predict immunotherapy outcomes. Additional investigations were conducted on the immune checkpoint blockade gene, tumor mutational load, and the GSEA enrichment analysis. Results Our analysis encompassed 22,106 cells and 20,556 genes in cancerous tissue samples from four TNBC patients, resulting in the identification of 116 B cell marker genes. A B cell marker gene score (BCMG score) involving nine B cell marker genes (ZBP1, SEL1L3, CCND2, TNFRSF13C, HSPA6, PLPP5, CXCR4, GZMB, and CCDC50) was developed using TCGA transcriptomic data, revealing statistically significant differences in survival analysis (P<0.05). Functional analysis demonstrated that marker genes were predominantly associated with immune-related pathways. Notably, substantial differences between the higher and lower- BCMG score groups were observed in terms of immune cell infiltration, immune cell activity, tumor mutational burden, TIDE score, and the expression of immune checkpoint blockade genes. Conclusion This study has established a robust model based on B-cell marker genes in TNBC, which holds significant potential for predicting prognosis and response to immunotherapy in TNBC patients.
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Affiliation(s)
- Fangrui Zhao
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chen Zhao
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tangpeng Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yanfang Lan
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Huiqing Lin
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaofei Wu
- Department of Neurology, Central War Zone General Hospital of the Chinese People's Liberation Army, Wuhan, Hubei, China
| | - Xiangpan Li
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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8
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Hjazi A, Nasir F, Noor R, Alsalamy A, Zabibah RS, Romero-Parra RM, Ullah MI, Mustafa YF, Qasim MT, Akram SV. The pathological role of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC) progression; special focus on molecular mechanisms and possible therapeutics. Pathol Res Pract 2023; 248:154616. [PMID: 37379710 DOI: 10.1016/j.prp.2023.154616] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/07/2023] [Accepted: 06/10/2023] [Indexed: 06/30/2023]
Abstract
Colorectal cancer (CRC) is comprised of transformed cells and non-malignant cells including cancer-associated fibroblasts (CAF), endothelial vasculature cells, and tumor-infiltrating cells. These nonmalignant cells, as well as soluble factors (e.g., cytokines), and the extracellular matrix (ECM), form the tumor microenvironment (TME). In general, the cancer cells and their surrounding TME can crosstalk by direct cell-to-cell contact and via soluble factors, such as cytokines (e.g., chemokines). TME not only promotes cancer progression through growth-promoting cytokines but also provides resistance to chemotherapy. Understanding the mechanisms of tumor growth and progression and the roles of chemokines in CRC will likely suggest new therapeutic targets. In this line, a plethora of reports has evidenced the critical role of chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis in CRC pathogenesis. In the current review, we take a glimpse into the role of the CXCR4/CXCL12 axis in CRC growth, metastasis, angiogenesis, drug resistance, and immune escape. Also, a summary of recent reports concerning targeting CXCR4/CXCL12 axis for CRC management and therapy has been delivered.
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Affiliation(s)
- Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Rabia Noor
- Amna Inayat Medical College, Lahore, Pakistan
| | - Ali Alsalamy
- College of Medical Technique, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 75471, Aljouf, Saudi Arabia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Shaik Vaseem Akram
- Uttaranchal Institute of Technology, Division of Research & Innovation, Uttaranchal University, Dehradun 248007, India
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9
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Mamonto L, Nelwan BJ, Sungowati NK, Miskad UA, Cangara MH, Zainuddin AA. Association of chemokine (CXC motif) receptor 4 expression with lymphovascular invasion and lymph node metastasis of invasive breast cancer. Breast Dis 2023; 41:447-453. [PMID: 36617771 DOI: 10.3233/bd-229003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND The histological tumor grade influences the prognosis of breast cancer. In metastatic breast cancer, stromal cells produce chemokine (CXC motif) ligand 12 or stromal cell-derived factor-1 as a chemoattractant, which binds to chemokine (CXC motif) receptor 4 (CXCR4) expressed by breast cancer cells. OBJECTIVE This study aimed to determine the expression of CXCR4 in invasive breast cancer in relation to lymphovascular invasion (LVI) and lymph node metastasis. METHODS This observational study retrospectively investigated a paraffin block archived sample diagnosed with invasive breast cancer. The results of immunohistochemical staining with CXCR4 antibody and expression analysis were evaluated using light microscopy. The data were statistically analyzed using the chi-square test and presented in a table using SPSS version 18. P-values of <0.05 were considered statistically significant. RESULTS The expression of CXCR4 was significantly associated with the incidence of LVI and lymph node metastasis in invasive breast cancer (both p = 0.001). CONCLUSIONS The results show that the expression of CXCR4 varies and support its decisive role in the incidence of LVI and lymph node metastasis in invasive breast cancer.
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Affiliation(s)
- Lidya Mamonto
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Berti J Nelwan
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Ni Ketut Sungowati
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Upik A Miskad
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Muh Husni Cangara
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Andi Alfian Zainuddin
- Department of Public Health and Community Medicine Science, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
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10
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González-Moles MÁ, Keim-del Pino C, Ramos-García P. Hallmarks of Cancer Expression in Oral Lichen Planus: A Scoping Review of Systematic Reviews and Meta-Analyses. Int J Mol Sci 2022; 23:13099. [PMID: 36361889 PMCID: PMC9658487 DOI: 10.3390/ijms232113099] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 09/05/2023] Open
Abstract
Oral lichen planus (OLP) is a common chronic inflammatory disease of unknown etiology and likely autoimmune nature that is currently considered an oral potentially malignant disorder, implying that patients suffering from this process are at risk of developing oral cancer in their lifetime. The molecular alterations that develop in OLP and that make the affected oral epithelium predisposed to malignancy are unknown, although, as in other autoimmune diseases (ulcerative colitis, primary biliary cirrhosis, etc.), they may be linked to oncogenesis-promoting effects mediated by the inflammatory infiltrate. So far there is no in-depth knowledge on how these hallmarks of cancer are established in the cells of the oral epithelium affected by OLP. In this scoping review of systematic reviews and meta-analyses the state of evidence based knowledge in this field is presented, to point out gaps of evidence and to indicate future lines of research. MEDLINE, Embase, Cochrane Library and Dare were searched for secondary-level studies published before October 2022. The results identified 20 systematic reviews and meta-analyses critically appraising the hallmarks tumor-promoting inflammation (n = 17, 85%), sustaining proliferative signaling (n = 2, 10%), and evading growth suppressors (n = 1, 5%). No evidence was found for the other hallmarks of cancer in OLP. In conclusion, OLP malignization hypothetically derives from the aggressions of the inflammatory infiltrate and a particular type of epithelial response based on increased epithelial proliferation, evasion of growth-suppressive signals and lack of apoptosis. Future evidence-based research is required to support this hypothesis.
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Affiliation(s)
- Miguel Ángel González-Moles
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Carmen Keim-del Pino
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Pablo Ramos-García
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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11
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Zhang R, Zhang G, Li B, Wang J, Wang J, Che J, Wang X, Zhang Z. Analysis of LINC01314 and miR-96 Expression in Colorectal Cancer Patients via Tissue Microarray-Based Fluorescence In Situ Hybridization. DISEASE MARKERS 2022; 2022:5378963. [PMID: 36246563 PMCID: PMC9568347 DOI: 10.1155/2022/5378963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 09/27/2022] [Indexed: 11/23/2022]
Abstract
Methods A tissue microarray (TMA) containing 76 individual colorectal tumor samples and 28 adjacent normal samples was constructed, and the expression levels of LINC01314 and miR-96 were detected by fluorescence in situ hybridization. Results The expression levels of both LINC01314 and miR-96 were upregulated in CRC tissues and were associated with vascular metastasis (p < 0.05). A significantly positive correlation was observed between LINC01314 and miR-96 expression in tumor tissues (p < 0.001, r = 0.870). Dominant expression of LINC01314 was a risk factor for both blood vessel invasion (p < 0.05) and poor 5-year survival (p = 0.001, hazard ratio = 4.144). The Kaplan-Meier analysis indicated that patients with LINC01314-dominant expression exhibited worse 5-year survival rates than those with miR-96-dominant expression (p < 0.05). Conclusion The expression patterns of both LINC01314 and miR-96 may be diagnostic of, and prognostic for, CRC. These findings will facilitate further exploration of the molecular mechanism of lncRNAs in CRC.
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Affiliation(s)
- Runan Zhang
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Genhua Zhang
- Department of Pathology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Baohua Li
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Juan Wang
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jvfang Wang
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jia Che
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaojun Wang
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhen Zhang
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
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12
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Clinical Evaluation of Nuclear Imaging Agents in Breast Cancer. Cancers (Basel) 2022; 14:cancers14092103. [PMID: 35565232 PMCID: PMC9101155 DOI: 10.3390/cancers14092103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/16/2022] [Accepted: 04/20/2022] [Indexed: 12/07/2022] Open
Abstract
Precision medicine is the customization of therapy for specific groups of patients using genetic or molecular profiling. Noninvasive imaging is one strategy for molecular profiling and is the focus of this review. The combination of imaging and therapy for precision medicine gave rise to the field of theranostics. In breast cancer, the detection and quantification of therapeutic targets can help assess their heterogeneity, especially in metastatic disease, and may help guide clinical decisions for targeted treatments. Positron emission tomography (PET) or single-photon emission tomography (SPECT) imaging has the potential to play an important role in the molecular profiling of therapeutic targets in vivo for the selection of patients who are likely to respond to corresponding targeted therapy. In this review, we discuss the state-of-the-art nuclear imaging agents in clinical research for breast cancer. We reviewed 17 clinical studies on PET or SPECT agents that target 10 different receptors in breast cancer. We also discuss the limitations of the study designs and of the imaging agents in these studies. Finally, we offer our perspective on which imaging agents have the highest potential to be used in clinical practice in the future.
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13
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Braga M, Leow CH, Gil JH, Teh JH, Carroll L, Long NJ, Tang MX, Aboagye EO. Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach. PLoS One 2021; 16:e0260186. [PMID: 34793563 PMCID: PMC8601444 DOI: 10.1371/journal.pone.0260186] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/03/2021] [Indexed: 11/19/2022] Open
Abstract
The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [18F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [18F]MCFB showed a marked difference in tumor uptake at 40-60 min post-injection between the two tumor models (p<0.05). Ex vivo analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvessel density and CXCR4 expression in the vasculature was comparable between U2932 and SuDHL8 tumors. In conclusion, we successfully developed a T140-MB that can be used for imaging CXCR4 expression in the tumor vasculature.
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Affiliation(s)
- Marta Braga
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Chee Hau Leow
- Department of Bioengineering, Faculty of Engineering, Imperial College London, London, United Kingdom
| | - Javier Hernandez Gil
- Department of Chemistry, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
| | - Jin H. Teh
- Department of Chemistry, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
| | - Laurence Carroll
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Nicholas J. Long
- Department of Chemistry, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
| | - Meng-Xing Tang
- Department of Bioengineering, Faculty of Engineering, Imperial College London, London, United Kingdom
| | - Eric O. Aboagye
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
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14
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Li J, Luco AL, Camirand A, St-Arnaud R, Kremer R. Vitamin D Regulates CXCL12/CXCR4 and Epithelial-to-Mesenchymal Transition in a Model of Breast Cancer Metastasis to Lung. Endocrinology 2021; 162:6164379. [PMID: 33693593 PMCID: PMC8183495 DOI: 10.1210/endocr/bqab049] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Indexed: 12/31/2022]
Abstract
Vitamin D deficiency is associated with poor cancer outcome in humans, and administration of vitamin D or its analogs decreases tumor progression and metastasis in animal models. Using the mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) model of mammary cancer, we previously demonstrated a significant acceleration of carcinogenesis in animals on a low vitamin D diet and a reduction in spontaneous lung metastases when mice received vitamin D through perfusion. We investigate here the action mechanism for vitamin D in lung metastasis in the same non-immunodeficient model and demonstrate that it involves the control of epithelial to mesenchymal transition as well as interactions between chemokine C-X-C motif chemokine 12 (CXCL12) and its receptor C-X-C chemokine receptor type 4 (CXCR4). In vitro, 10-9M vitamin D treatment modifies the phenotype of MMTV-PyMT primary mammary tumor cells and significantly decreases their invasiveness and mammosphere formation capacity by 40% and 50%, respectively. Vitamin D treatment also inhibits phospho-signal transducer and activator of transcription 3 (p-STAT3), zinc finger E-box-binding homeobox 1 (Zeb1), and vimentin by 52%, 75%, and 77%, respectively, and increases E-cadherin by 87%. In vivo, dietary vitamin D deficiency maintains high levels of Zeb1 and p-STAT3 in cells from primary mammary tumors and increases CXCL12 expression in lung stroma by 64%. In lung metastases, vitamin D deficiency increases CXCL12/CXCR4 co-localization by a factor of 2.5. These findings indicate an involvement of vitamin D in mammary cancer "seed" (primary tumor cell) and "soil" (metastatic site) and link vitamin D deficiency to epithelial-to-mesenchymal transition (EMT), CXCL12/CXCR4 signaling, and accelerated metastasis, suggesting vitamin D repleteness in breast cancer patients could enhance the efficacy of co-administered therapies in preventing spread to distant organs.
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Affiliation(s)
- Jiarong Li
- Department of Medicine, McGill University Health Centre, Glen Site, Montréal, QC, Canada
| | - Aimée-Lee Luco
- Department of Medicine, McGill University Health Centre, Glen Site, Montréal, QC, Canada
| | - Anne Camirand
- Department of Medicine, McGill University Health Centre, Glen Site, Montréal, QC, Canada
| | - René St-Arnaud
- Department of Orthopaedic Surgery, Faculty of Dentistry, Shriners Hospital, Montréal, QC, Canada
| | - Richard Kremer
- Department of Medicine, McGill University Health Centre, Glen Site, Montréal, QC, Canada
- Correspondence: Richard Kremer, Department of Medicine, McGill University Health Centre, Glen site E-M1.3221, 1001 Décarie Blvd, Montréal, QC, Canada, H4A 3J1.
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15
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Fang H, Cavaliere A, Li Z, Huang Y, Marquez-Nostra B. Preclinical Advances in Theranostics for the Different Molecular Subtypes of Breast Cancer. Front Pharmacol 2021; 12:627693. [PMID: 33986665 PMCID: PMC8111013 DOI: 10.3389/fphar.2021.627693] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/22/2021] [Indexed: 12/29/2022] Open
Abstract
Breast cancer is the most common cancer in women worldwide. The heterogeneity of breast cancer and drug resistance to therapies make the diagnosis and treatment difficult. Molecular imaging methods with positron emission tomography (PET) and single-photon emission tomography (SPECT) provide useful tools to diagnose, predict, and monitor the response of therapy, contributing to precision medicine for breast cancer patients. Recently, many efforts have been made to find new targets for breast cancer therapy to overcome resistance to standard of care treatments, giving rise to new therapeutic agents to offer more options for patients with breast cancer. The combination of diagnostic and therapeutic strategies forms the foundation of theranostics. Some of these theranostic agents exhibit high potential to be translated to clinic. In this review, we highlight the most recent advances in theranostics of the different molecular subtypes of breast cancer in preclinical studies.
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Affiliation(s)
- Hanyi Fang
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States.,Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Alessandra Cavaliere
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States
| | - Ziqi Li
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States.,Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiyun Huang
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States
| | - Bernadette Marquez-Nostra
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States
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16
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Matossian MD, Elliott S, Rhodes LV, Martin EC, Hoang VT, Burks HE, Zuercher WJ, Drewry DH, Collins-Burow BM, Burow ME. Application of a small molecule inhibitor screen approach to identify CXCR4 downstream signaling pathways that promote a mesenchymal and fulvestrant-resistant phenotype in breast cancer cells. Oncol Lett 2021; 21:380. [PMID: 33777204 PMCID: PMC7988660 DOI: 10.3892/ol.2021.12641] [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: 03/07/2020] [Accepted: 11/30/2020] [Indexed: 12/27/2022] Open
Abstract
Chemokine receptor 4 (CXCR4) and its ligand stromal-derived factor 1 (SDF-1) have well-characterized functions in cancer metastasis; however, the specific mechanisms through which CXCR4 promotes a metastatic and drug-resistant phenotype remain widely unknown. The aim of the present study was to demonstrate the application of a phenotypic screening approach using a small molecule inhibitor library to identify potential CXCR4-mediated signaling pathways. The present study demonstrated a new application of the Published Kinase Inhibitor Set (PKIS), a library of small molecule inhibitors from diverse chemotype series with varying levels of selectivity, in a phenotypic medium-throughput screen to identify potential mechanisms to pursue. Crystal violet staining and brightfield microscopy were employed to evaluate relative cell survival and changes to cell morphology in the screens. ‘Hits’ or lead active compounds in the first screen were PKIS inhibitors that reversed mesenchymal morphologies in CXCR4-activated breast cancer cells without the COOH-terminal domain (MCF-7-CXCR4-ΔCTD) and in the phenotypically mesenchymal triple-negative breast cancer cells (MDA-MB-231, BT-549 and MDA-MB-157), used as positive controls. In a following screen, the phenotypic and cell viability screen was used with a positive control that was both morphologically mesenchymal and had acquired fulvestrant resistance. Compounds within the same chemotype series were identified that exhibited biological activity in the screens, the ‘active’ inhibitors, were compared with inactive compounds. Relative kinase activity was obtained using published datasets to discover candidate kinase targets responsible for CXCR4 activity. MAP4K4 and MINK reversed both the mesenchymal and drug-resistant phenotypes, NEK9 and DYRK2 only reversed the mesenchymal morphology, and kinases, including ROS, LCK, HCK and LTK, altered the fulvestrant-resistant phenotype. Oligoarray experiments revealed pathways affected in CXCR4-activated cells, and these pathways were compared with the present screening approach to validate our screening tool. The oligoarray approach identified the integrin-mediated, ephrin B-related, RhoA, RAC1 and ErbB signaling pathways to be upregulated in MCF-7-CXCR4-ΔCTD cells, with ephrin B signaling also identified in the PKIS phenotypic screen. The present screening tool may be used to discover potential mechanisms of targeted signaling pathways in solid cancers.
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Affiliation(s)
- Margarite D Matossian
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Steven Elliott
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Lyndsay V Rhodes
- Department of Biology, Florida Gulf Coast University, Fort Myers, FL 33965, USA
| | - Elizabeth C Martin
- Department of Biological and Agricultural Engineering Biology, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Van T Hoang
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hope E Burks
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - William J Zuercher
- Structural Genomics Consortium, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
| | - David H Drewry
- Structural Genomics Consortium, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Bridgette M Collins-Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Matthew E Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA
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17
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Lu G, Qiu Y, Su X. Targeting CXCL12-CXCR4 Signaling Enhances Immune Checkpoint Blockade Therapy Against Triple Negative Breast Cancer. Eur J Pharm Sci 2021; 157:105606. [PMID: 33131745 DOI: 10.1016/j.ejps.2020.105606] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 06/21/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022]
Abstract
Insufficient T cell infiltration in triple-negative breast cancer (TNBC) has limited its response rate to immune checkpoint blockade (ICB) therapies and motivated the development of immunostimulatory approaches to enhance the ICB therapy. CXCR4 is a chemokine receptor highly upregulated both on cell surface and cytoplasm in tumor tissues. Activating CXCR4 has been associated with increased immunosuppression in the tumor microenvironment. Here, we developed a CXCR4-targeted liposomal formulation (Liposomal-AMD3100) to enhance therapeutic efficacy of AMD3100, a CXCR4 antagonist. Particularly, AMD3100 is not only encapsulated into the liposome but coated on the surface of the formulation to serve as a targeting moiety and a dual blocker capable of inhibiting CXCR4 activation extracellularly and intracellularly. The Liposomal-AMD3100 remodeled both immune and stromal microenvironment more efficiently compared with free AMD3100, indicating better pharmacodynamic profile of AMD3100 achieved by liposomal formulation. The combination of anti-PD-L1 with Liposomal-AMD3100 formulation exhibited an increased antitumor effect and prolonged survival time compared with monotherapies in a murine TNBC model (4T1). This work proves that immune activation via liposomal delivery of CXCR4 inhibitors has a great potential to expand ICB therapies to originally ICB-insensitive cancer types.
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Affiliation(s)
- Guowen Lu
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China.
| | - Yier Qiu
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China
| | - Xiaobao Su
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China
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18
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Portella L, Bello AM, Scala S. CXCL12 Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1302:51-70. [PMID: 34286441 DOI: 10.1007/978-3-030-62658-7_5] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tumor microenvironment (TME) is the local environment of tumor, composed of tumor cells and blood vessels, extracellular matrix (ECM), immune cells, and metabolic and signaling molecules. Chemokines and their receptors play a fundamental role in the crosstalk between tumor cells and TME, regulating tumor-related angiogenesis, specific leukocyte infiltration, and activation of the immune response and directly influencing tumor cell growth, invasion, and cancer progression. The chemokine CXCL12 is a homeostatic chemokine that regulates physiological and pathological process such as inflammation, cell proliferation, and specific migration. CXCL12 activates CXCR4 and CXCR7 chemokine receptors, and the entire axis has been shown to be dysregulated in more than 20 different tumors. CXCL12 binding to CXCR4 triggers multiple signal transduction pathways that regulate intracellular calcium flux, chemotaxis, transcription, and cell survival. CXCR7 binds with high-affinity CXCL12 and with lower-affinity CXCL11, which binds also CXCR3. Although CXCR7 acts as a CXCL12 scavenger through ligand internalization and degradation, it transduces the signal mainly through β-arrestin with a pivotal role in endothelial and neural cells. Recent studies demonstrate that TME rich in CXCL12 leads to resistance to immune checkpoint inhibitors (ICI) therapy and that CXCL12 axis inhibitors sensitize resistant tumors to ICI effect. Thus targeting the CXCL12-mediated axis may control tumor and tumor microenvironment exerting an antitumor dual action. Herein CXCL12 physiology, role in cancer biology and in composite TME, prognostic role, and the relative inhibitors are addressed.
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Affiliation(s)
- Luigi Portella
- Microenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy
| | - Anna Maria Bello
- Microenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy
| | - Stefania Scala
- Microenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy.
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19
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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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20
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“Star” miR-34a and CXCR4 antagonist based nanoplex for binary cooperative migration treatment against metastatic breast cancer. J Control Release 2020; 326:615-627. [DOI: 10.1016/j.jconrel.2020.07.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 01/14/2023]
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21
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Ariyarathna H, Thomson N, Aberdein D, Munday JS. Chemokine gene expression influences metastasis and survival time of female dogs with mammary carcinoma. Vet Immunol Immunopathol 2020; 227:110075. [PMID: 32590239 DOI: 10.1016/j.vetimm.2020.110075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 04/25/2020] [Accepted: 05/15/2020] [Indexed: 01/02/2023]
Abstract
Chemokines are signaling proteins secreted by immune cells which regulate leukocyte trafficking. The aberrant expression of chemokines and their receptors by neoplastic cells influences the behaviour of many human cancers. This study evaluated gene-expression of the chemokines: CCL5, CXCL10, CXCL12 and the chemokine receptors: CXCR3, CXCR4, CXCR7, CCR4, CCR9 in 41 histologically-malignant, outcome-known, canine mammary tumours. These chemokines and chemokine receptors were selected as all were previously shown to influence the behaviour of human breast cancers. The expression of chemokines CCL5 and CXCL12 were significantly higher in tumours which subsequently metastasised than tumours that did not metastasise (p < 0.05). Increased expression of these chemokines was also correlated with shorter survival times of the dogs (CCL5: rs = -0.40, p = 0.02, CXCL12: rs = -0.40, p = 0.03) while CCL5 was independently prognostic of survival times (p = 0.026). A significantly higher proportion of tumours that subsequently metastasised expressed CXCR3 (p = 0.037), CXCR4 (p = 0.026), CXCR7 (p = 0.025) and CCR9 (p = 0.039) receptors while the survival times of the dogs with tumours that expressed CXCR4 (p = 0.045) and CCR9 (p = 0.039) receptors were significantly shorter than dogs with tumours that did not express these receptors. Chemokine and chemokine receptor gene-expression has not been previously correlated with disease outcome of canine mammary tumours. These findings indicate that altered expression of chemokines and their receptors influences the behaviour of canine mammary tumours suggesting a potential role of them as prognostic markers or therapeutic targets.
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Affiliation(s)
- Harsha Ariyarathna
- School of Veterinary Science, Massey University, Palmerston North, 4442, New Zealand.
| | - Neroli Thomson
- School of Veterinary Science, Massey University, Palmerston North, 4442, New Zealand
| | - Danielle Aberdein
- School of Veterinary Science, Massey University, Palmerston North, 4442, New Zealand
| | - John S Munday
- School of Veterinary Science, Massey University, Palmerston North, 4442, New Zealand
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22
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New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM. Vaccines (Basel) 2020; 8:vaccines8020164. [PMID: 32260318 PMCID: PMC7349554 DOI: 10.3390/vaccines8020164] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 03/30/2020] [Accepted: 03/31/2020] [Indexed: 12/16/2022] Open
Abstract
Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom's macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.
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23
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Heo GS, Zhao Y, Sultan D, Zhang X, Detering L, Luehmann HP, Zhang X, Li R, Choksi A, Sharp S, Levingston S, Reichert DE, Sun G, Razani B, Li S, Weilbaecher KN, Dehdashti F, Wooley KL, Liu Y. Assessment of Copper Nanoclusters for Accurate in Vivo Tumor Imaging and Potential for Translation. ACS APPLIED MATERIALS & INTERFACES 2019; 11:19669-19678. [PMID: 31074257 PMCID: PMC7811435 DOI: 10.1021/acsami.8b22752] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Nanoparticles have been widely used for preclinical cancer imaging. However, their successful clinical translation is largely hampered by potential toxicity, unsatisfactory detection of malignancy at early stages, inaccurate diagnosis of tumor biomarkers, and histology for imaging-guided treatment. Herein, a targeted copper nanocluster (CuNC) is reported with high potential to address these challenges for future translation. Its ultrasmall structure enables efficient renal/bowel clearance, minimized off-target effects in nontargeted organs, and low nonspecific tumor retention. The pH-dependent in vivo dissolution of CuNCs affords minimal toxicity and potentially selective drug delivery to tumors. The intrinsic radiolabeling through the direct addition of 64Cu to CuNC (64Cu-CuNCs-FC131) synthesis offers high specific activity for sensitive and accurate detection of CXCR4 via FC131-directed targeting in novel triple negative breast cancer (TNBC) patient-derived xenograft mouse models and human TNBC tissues. In summary, this study not only reveals the potential of CXCR4-targeted 64Cu-CuNCs for TNBC imaging in clinical settings, but also provides a useful strategy to design and assess the translational potential of nanoparticles for cancer theranostics.
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Affiliation(s)
- Gyu Seong Heo
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
| | - Yongfeng Zhao
- Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS 39217, United States
| | - Deborah Sultan
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
| | - Xiaohui Zhang
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
| | - Lisa Detering
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
| | - Hannah P. Luehmann
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
| | - Xiangyu Zhang
- Department of Medicine, Washington University, St. Louis, MO 63110, United States
| | - Richen Li
- Department of Chemistry, Department of Chemical Engineering, Department of Materials Science & Engineering, and Laboratory for Synthetic-Biologic Interactions, Texas A&M University, College Station, TX 77842, United States
| | - Ankur Choksi
- University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | | | - Sidney Levingston
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
| | - David E. Reichert
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
| | - Guorong Sun
- Department of Chemistry, Department of Chemical Engineering, Department of Materials Science & Engineering, and Laboratory for Synthetic-Biologic Interactions, Texas A&M University, College Station, TX 77842, United States
| | - Babak Razani
- Department of Medicine, Washington University, St. Louis, MO 63110, United States
| | - Shunqiang Li
- Department of Medicine, Washington University, St. Louis, MO 63110, United States
| | | | - Farrokh Dehdashti
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
| | - Karen L. Wooley
- Department of Chemistry, Department of Chemical Engineering, Department of Materials Science & Engineering, and Laboratory for Synthetic-Biologic Interactions, Texas A&M University, College Station, TX 77842, United States
| | - Yongjian Liu
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
- Corresponding Author:
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24
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Yin X, Liu Z, Zhu P, Wang Y, Ren Q, Chen H, Xu J. CXCL12/CXCR4 promotes proliferation, migration, and invasion of adamantinomatous craniopharyngiomas via PI3K/AKT signal pathway. J Cell Biochem 2018; 120:9724-9736. [PMID: 30582214 DOI: 10.1002/jcb.28253] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 10/22/2018] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Adamantinomatous craniopharyngiomas (adaCP) accounts for 5.6% to 15% of intracranial tumors. High expression of chemokine (C-X-C motif) ligand 12 (CXCL12, also known as stromal cell-derived factor 1 [SDF1]) and its receptor CXC receptor type 4 (CXCR4) are widespread in various malignancy via multiple signal transduction pathways. This study aims to investigate the mechanism of CXCL12/CXCR4 promoting proliferation, migration, and invasion of adaCP. METHODS Quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry were used to evaluate the expression of CXCL12/CXCR4 mRNA and protein in 10 human adaCP tissues. Three successfully primary cell lines were obtained from native mainly solid tumor specimens, and confirmed by the means of inverted contrast microscope directly and following hematoxylin and eosin staining. Immunofluorescence was used to detect protein expression in vivo for the verification of primary cell line. Proliferation, migration, and invasion assays were performed to assess the biological functional role of CXCL12/CXCR4 in adaCP. The signal pathways involved in the action of CXCL12/CXCR4 in adaCP were also evaluated. RESULTS CXCL12 and CXCR4 were highly expressed in human adaCP samples. Primary adaCP cells were isolated and detected by the means of immunofluorescence for the detection of pan cytokeratin (pan-CK) and vimentin (VIM). Overexpression of CXCL12/CXCR4 significantly promoted the proliferation, migration, and invasion of primary adaCP cells. Moreover, cancer-promoting activity of CXCL12/CXCR4 is partially through its facilitation of PI3K/AKT signal pathway. CONCLUSIONS Our data showed that CXCL12/CXCR4 promotes adaCP proliferation, migration, and invasion through PI3K/AKT signal pathway. These findings suggested that therapeutic strategies regulating CXCL12/CXCR4 expression may provide an effective treatment of adaCP.
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Affiliation(s)
- Xiaohong Yin
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.,Department of Neurosurgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Zhiyong Liu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Pan Zhu
- Department of Clinical Laboratory, Taihe Hospital (Affiliated Hubei University of Medicine), Shiyan, Hubei, People's Republic of China
| | - Yuelong Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qingqing Ren
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hongxu Chen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
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25
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Shim B, Jin MS, Moon JH, Park IA, Ryu HS. High Cytoplasmic CXCR4 Expression Predicts Prolonged Survival in Triple-Negative Breast Cancer Patients Treated with Adjuvant Chemotherapy. J Pathol Transl Med 2018; 52:369-377. [PMID: 30269472 PMCID: PMC6250928 DOI: 10.4132/jptm.2018.09.19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 09/18/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Chemokine receptor CXC chemokine receptor type 4 (CXCR4) and its ligand CXC motif chemokine 12 (CXCL12; stromal cell-derived factor-1) are implicated in tumor growth, metastasis, and tumor cell-microenvironment interaction. A number of studies have reported that increased CXCR4 expression is associated with worse prognosis in triple-negative breast cancer (TNBC), but its prognostic significance has not been studied in TNBC patients treated with adjuvant chemotherapy. METHODS Two hundred eighty-three TNBC patients who received adjuvant chemotherapy were retrospectively analyzed. Tissue microarray was constructed from formalinfixed, paraffin-embedded tumor tissue and immunohistochemistry for CXCR4 and CXCL12 was performed. Expression of each marker was compared with clinicopathologic characteristics and outcome. RESULTS High cytoplasmic CXCR4 expression was associated with younger age (p = .008), higher histologic grade (p = .007) and lower pathologic stage (p = .045), while high CXCL12 expression was related to larger tumor size (p = .045), positive lymph node metastasis (p = .005), and higher pathologic stage (p = .017). The patients with high cytoplasmic CXCR4 experienced lower distant recurrence (p = .006) and better recurrence-free survival (RFS) (log-rank p = .020) after adjuvant chemotherapy. Cytoplasmic CXCR4 expression remained an independent factor of distant recurrence (p = .019) and RFS (p = .038) after multivariate analysis. CONCLUSIONS High cytoplasmic CXCR4 expression was associated with lower distant recurrence and better RFS in TNBC patients treated with adjuvant chemotherapy. This is the first study to correlate high CXCR4 expression to better TNBC prognosis, and the underlying mechanism needs to be elucidated in further studies.
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Affiliation(s)
- Bobae Shim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Min-Sun Jin
- Department of Pathology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Ji Hye Moon
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Ae Park
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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Chen G, Wang Y, Wu P, Zhou Y, Yu F, Zhu C, Li Z, Hang Y, Wang K, Li J, Sun M, Oupicky D. Reversibly Stabilized Polycation Nanoparticles for Combination Treatment of Early- and Late-Stage Metastatic Breast Cancer. ACS NANO 2018; 12:6620-6636. [PMID: 29985577 DOI: 10.1021/acsnano.8b01482] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Metastatic breast cancer is a major cause of cancer-related female mortality worldwide. The signal transducer and activator of transcription 3 (STAT3) and the chemokine receptor CXCR4 are involved in the metastatic spread of breast cancer. The goal of this study was to develop nanomedicine treatment based on combined inhibition of STAT3 and CXCR4. We synthesized a library of CXCR4-inhibiting polymers with a combination of beneficial features that included PEGylation, fluorination, and bioreducibility to achieve systemic delivery of siRNA to silence STAT3 expression in the tumors. An in vivo structure-activity relationship study in an experimental lung metastasis model revealed superior antimetastatic activity of bioreducible fluorinated polyplexes when compared with nonreducible controls despite similar CXCR4 antagonism and the ability to inhibit in vitro cancer cell invasion. When compared with nonreducible and nonfluorinated polyplexes, improved siRNA delivery was observed with the bioreducible fluorinated polyplexes. The improvement was ascribed to a combination of enhanced physical stability, decreased serum destabilization, and improved intracellular trafficking. Pharmacokinetic analysis showed that fluorination decreased the rate of renal clearance of the polyplexes and contributed to enhanced accumulation in the tumors. Therapeutic efficacy of the polyplexes with STAT3 siRNA was assessed in early stage breast cancer and late-stage metastatic breast cancer with primary tumor resection. Strong inhibition of the primary tumor growth and pronounced antimetastatic effects were observed in both models of metastatic breast cancer. Mechanistic studies revealed multifaceted mechanism of action of the combined STAT3 and CXCR4 inhibition by the developed polyplexes relying both on local and systemic effects.
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Affiliation(s)
- Gang Chen
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
| | - Yixin Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
| | - Pengkai Wu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
| | - Yiwen Zhou
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
| | - Fei Yu
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Chenfei Zhu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
| | - Zhaoting Li
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
| | - Yu Hang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Kaikai Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
| | - Jing Li
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Minjie Sun
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
| | - David Oupicky
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , Nanjing 210009 , China
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
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Graham N, Qian BZ. Mesenchymal Stromal Cells: Emerging Roles in Bone Metastasis. Int J Mol Sci 2018; 19:E1121. [PMID: 29642534 PMCID: PMC5979535 DOI: 10.3390/ijms19041121] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/25/2018] [Accepted: 03/29/2018] [Indexed: 12/13/2022] Open
Abstract
Bone metastasis is the most advanced stage of many cancers and indicates a poor prognosis for patients due to resistance to anti-tumor therapies. The establishment of metastasis within the bone is a multistep process. To ensure survival within the bone marrow, tumor cells must initially colonize a niche in which they can enter dormancy. Subsequently, reactivation permits the proliferation and growth of the tumor cells, giving rise to a macro-metastasis displayed clinically as a bone metastatic lesion. Here, we review the evidences that suggest mesenchymal stromal cells play an important role in each of these steps throughout the development of bone metastasis. Similarities between the molecular mechanisms implicated in these processes and those involved in the homeostasis of the bone indicate that the metastatic cells may exploit the homeostatic processes to their own advantage. Identifying the molecular interactions between the mesenchymal stromal cells and tumor cells that promote tumor development may offer insight into potential therapeutic targets that could be utilized to treat bone metastasis.
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Affiliation(s)
- Nicola Graham
- Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
| | - Bin-Zhi Qian
- Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
- Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh EH4 2XR, UK.
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Zhang X, You L, Chen S, Gao M, Guo Z, Du J, Lu J, Zhang X. Development of a novel 99m Tc-labeled small molecular antagonist for CXCR4 positive tumor imaging. J Labelled Comp Radiopharm 2018; 61:438-446. [PMID: 29370457 DOI: 10.1002/jlcr.3608] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/11/2018] [Accepted: 01/13/2018] [Indexed: 12/18/2022]
Abstract
The chemokine receptor 4 (CXCR4) has been an attractive molecular target for tumor imaging, because it is overexpressed in many tumor types and involved in tumor progression and metastasis. The purpose of this study is to examine the CXCR4 targeting properties of 99m Tc-labeled AMD3465, a small molecule antagonist of CXCR4. 99m Tc-AMD3465 was prepared in high yield (>95%) and stable in mice serum at least for 4 hours. In vitro cell binding experiments were performed with Chinese hamster ovary (CHO), MCF-7 (breast cancer), and CHO-CXCR4 (CHO stably transfected to express CXCR4) cell lines. Small animal single photon emission computed tomography/computed tomography imaging studies in nude mice bearing MCF-7 and CHO xenografts showed that the uptakes of the radiotracer in MCF-7 tumors were significantly higher than those in the CXCR4-negative CHO tumors (P < 0.05), and the MCF-7 tumors uptake could be blocked with an excess of unlabeled AMD3465 (P < 0.05). These results suggested that 99m Tc-AMD3465 could be a potential single photon emission computed tomography radiotracer for CXCR4 imaging.
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Affiliation(s)
- Xuran Zhang
- Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education; College of Chemistry, Beijing Normal University, Beijing, PR China
- Department of Isotope, China Institute of Atomic Energy, Beijing, China
| | - Linyi You
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian, PR China
| | - Shuting Chen
- Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education; College of Chemistry, Beijing Normal University, Beijing, PR China
| | - Mengna Gao
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian, PR China
| | - Zhide Guo
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian, PR China
| | - Jin Du
- Department of Isotope, China Institute of Atomic Energy, Beijing, China
| | - Jie Lu
- Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education; College of Chemistry, Beijing Normal University, Beijing, PR China
| | - Xianzhong Zhang
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian, PR China
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Rovito D, Gionfriddo G, Barone I, Giordano C, Grande F, De Amicis F, Lanzino M, Catalano S, Andò S, Bonofiglio D. Ligand-activated PPARγ downregulates CXCR4 gene expression through a novel identified PPAR response element and inhibits breast cancer progression. Oncotarget 2018; 7:65109-65124. [PMID: 27556298 PMCID: PMC5323141 DOI: 10.18632/oncotarget.11371] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 08/11/2016] [Indexed: 12/26/2022] Open
Abstract
Stromal Derived Factor-1α (SDF-1α) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) γ, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPARγ-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPARγ downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPARγ agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPARγ-mediated, since it was reversed in the presence of the PPARγ antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1α, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPARγ in inhibiting breast cancer progression and further highlight the utility of PPARγ ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.
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Affiliation(s)
- Daniela Rovito
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.,Centro Sanitario, University of Calabria, Rende (CS), Italy
| | - Giulia Gionfriddo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | | | - Fedora Grande
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Marilena Lanzino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.,Centro Sanitario, University of Calabria, Rende (CS), Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
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30
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Mukherjee D, Lu H, Yu L, He C, Lahiri SK, Li T, Zhao J. Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis. Oncotarget 2018; 7:23552-68. [PMID: 26993780 PMCID: PMC5029647 DOI: 10.18632/oncotarget.8083] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 02/25/2016] [Indexed: 02/04/2023] Open
Abstract
Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels, as determined by quantitative real-time PCR and immunoblotting. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Interestingly, a CXCR4-dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8-overexpressing, but not KLF8 deficient cells. This activation of FAK in turn induced a further increase in KLF8 expression. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. These results collectively suggest a critical role for a previously unidentified feed-forward signaling wheel made of KLF8, CXCR4 and FAK in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies.
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Affiliation(s)
- Debarati Mukherjee
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
| | - Heng Lu
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
| | - Lin Yu
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
| | - Chunjiang He
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Satadru K Lahiri
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
| | - Tianshu Li
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.,Current address: Cleveland Clinic, Cleveland, OH, USA
| | - Jihe Zhao
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
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31
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Song ZY, Wang F, Cui SX, Qu XJ. Knockdown of CXCR4 Inhibits CXCL12-Induced Angiogenesis in HUVECs through Downregulation of the MAPK/ERK and PI3K/AKT and the Wnt/β-Catenin Pathways. Cancer Invest 2018; 36:10-18. [PMID: 29381400 DOI: 10.1080/07357907.2017.1422512] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
CXCL12 is an extracellular chemokine binding to cell surface receptor CXCR4. We found that activation of CXCL12/CXCR4 axis stimulated angiogenesis in endothelial cells. Knockdown of CXCR4 in endothelial cells prevented the branch points of angiogenesis. Endothelial cells exposed to CXCL12 presented high level of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and matrix metalloproteinase MMP-2, but not in CXCR4 knockdown cells. Further studies revealed that activation of CXCL12/CXCR4 axis in vascular endothelial cells stimulates the angiogenesis through upregulation of the MAPK/ERK and PI3K/AKT and Wnt/β-catenin pathways. Conclusion, downregulation of CXCR4 could inhibit angiogenesis in cancer tissues.
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Affiliation(s)
- Zhi-Yu Song
- a Department of Pharmacology, School of Basic Medical Sciences , Capital Medical University , Beijing , China
| | - Feng Wang
- b Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , China
| | - Shu-Xiang Cui
- b Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , China
| | - Xian-Jun Qu
- a Department of Pharmacology, School of Basic Medical Sciences , Capital Medical University , Beijing , China
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32
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Jamaludin SYN, Azimi I, Davis FM, Peters AA, Gonda TJ, Thompson EW, Roberts-Thomson SJ, Monteith GR. Assessment of CXC ligand 12-mediated calcium signalling and its regulators in basal-like breast cancer cells. Oncol Lett 2018. [PMID: 29541196 PMCID: PMC5835901 DOI: 10.3892/ol.2018.7827] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
CXC ligand (L)12 is a chemokine implicated in the migration, invasion and metastasis of cancer cells via interaction with its receptors CXC chemokine receptor (CXCR)4 and CXCR7. In the present study, CXCL12-mediated Ca2+ signalling was compared with two basal-like breast cancer cell lines, MDA-MB-231 and MDA-MB-468, which demonstrate distinct metastatic potential. CXCL12 treatment induced Ca2+ responses in the more metastatic MDA-MB-231 cells but not in the less metastatic MDA-MB-468 cells. Assessment of mRNA levels of CXCL12 receptors and their potential modulators in both cell lines revealed that CXCR4 and CXCR7 levels were increased in MDA-MB-231 cells compared with MDA-MB-468 cells. Cluster of differentiation (CD)24, the negative regulator of CXCL12 responses, demonstrated increased expression in MDA-MB-468 cells compared with MDA-MB-231 cells, and the two cell lines expressed comparable levels of hypoxia-inducible factor (HIF)2α, a CXCR4 regulator. Induction of epithelial-mesenchymal transition (EMT) by epidermal growth factor exhibited opposite effects on CXCR4 mRNA levels compared with hypoxia-induced EMT. Neither EMT inducer exhibited an effect on CXCR7 expression, however hypoxia increased HIF2α expression levels in MDA-MB-468 cells. Analysis of the gene expression profiles of breast tumours revealed that the highest expression levels of CXCR4 and CXCR7 were in the Claudin-Low molecular subtype, which is markedly associated with EMT features.
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Affiliation(s)
- S Y N Jamaludin
- School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland 4102, Australia.,Faculty of Medicine, Universiti Sultan Zainal Abidin, 20400 Kuala Terengganu, Terengganu, Malaysia
| | - I Azimi
- School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland 4102, Australia.,Mater Research Institute, The University of Queensland, Brisbane, Queensland 4102, Australia.,The Translational Research Institute, Brisbane, Queensland 4102, Australia
| | - F M Davis
- School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland 4102, Australia.,Mater Research Institute, The University of Queensland, Brisbane, Queensland 4102, Australia
| | - A A Peters
- School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland 4102, Australia.,Mater Research Institute, The University of Queensland, Brisbane, Queensland 4102, Australia.,The Translational Research Institute, Brisbane, Queensland 4102, Australia
| | - T J Gonda
- School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland 4102, Australia
| | - E W Thompson
- The Translational Research Institute, Brisbane, Queensland 4102, Australia.,Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia.,University of Melbourne Department of Surgery, St Vincent's Hospital, Melbourne, Victoria 3065, Australia
| | - S J Roberts-Thomson
- School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland 4102, Australia
| | - G R Monteith
- School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland 4102, Australia.,Mater Research Institute, The University of Queensland, Brisbane, Queensland 4102, Australia.,The Translational Research Institute, Brisbane, Queensland 4102, Australia
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33
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Teixidó J, Martínez-Moreno M, Díaz-Martínez M, Sevilla-Movilla S. The good and bad faces of the CXCR4 chemokine receptor. Int J Biochem Cell Biol 2017; 95:121-131. [PMID: 29288743 DOI: 10.1016/j.biocel.2017.12.018] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/14/2017] [Accepted: 12/19/2017] [Indexed: 11/18/2022]
Abstract
Chemokines are chemotactic cytokines that promote cell migration and activation under homeostatic and inflammatory conditions. Chemokines bind to seven transmembrane-spanning receptors that are coupled to heterotrimeric guanine nucleotide-binding (G) proteins, which are the responsible for intracellularly transmitting the activating signals for cell migration. Hematopoiesis, vascular development, lymphoid organ morphogenesis, cardiogenesis and neural differentiation are amongst the processes involving chemokine function. In addition, immune cell trafficking from bone marrow to blood circulation, and from blood and lymph to lymphoid and inflamed tissues, is tightly regulated by chemokines both under physiological conditions and also in autoimmune diseases. Furthermore, chemokine binding to their receptors stimulate trafficking to and positioning of cancer cells into target tissues and organs during tumour dissemination. The CXCL12 chemokine (also known as stromal-cell derived factor-1α, SDF-1α) plays key roles in hematopoiesis and lymphoid tissue architecture, in cardiogenesis, vascular formation and neurogenesis, as well as in the trafficking of solid and hematological cancer cell types. CXCL12 binds to the CXCR4 receptor, a multi-facetted molecule which tightly mirrors CXCL12 functions in homeostasis and disease. This review addresses the important roles of the CXCR4-CXCL12 axis in homeostasis, specially focusing in hematopoiesis, as well as it provides a picture of CXCR4 as mediator of cancer cell spreading, and a view of the available CXCR4 antagonists in different cancer types.
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Affiliation(s)
- Joaquin Teixidó
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), 28040 Madrid, Spain.
| | - Mónica Martínez-Moreno
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), 28040 Madrid, Spain
| | - Marta Díaz-Martínez
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), 28040 Madrid, Spain
| | - Silvia Sevilla-Movilla
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), 28040 Madrid, Spain
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34
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A fully human CXCR4 antibody demonstrates diagnostic utility and therapeutic efficacy in solid tumor xenografts. Oncotarget 2017; 7:12344-58. [PMID: 26848769 PMCID: PMC4914289 DOI: 10.18632/oncotarget.7111] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 01/15/2016] [Indexed: 12/27/2022] Open
Abstract
For physiologically important cancer therapeutic targets, use of non-invasive imaging for therapeutic guidance and monitoring may improve outcomes for treated patients. The CXC chemokine receptor 4 (CXCR4) is overexpressed in many cancers including non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). CXCR4 overexpression contributes to tumor growth, progression and metastasis. There are several CXCR4-targeted therapeutic agents currently in clinical trials. Since CXCR4 is also crucial for normal biological functions, its prolonged inhibition could lead to unwanted toxicities. While CXCR4-targeted imaging agents and inhibitors have been reported and evaluated independently, there are currently no studies demonstrating CXCR4-targeted imaging for therapeutic guidance. Monoclonal antibodies (mAbs) are commonly used for cancer therapy and imaging. Here, an 89Zr-labeled human CXCR4-mAb (89Zr-CXCR4-mAb) was evaluated for detection of CXCR4 expression with positron emission tomography (PET) while its native unmodified analogue was evaluated for therapy in relevant models of NSCLC and TNBC. In vitro and in vivo evaluation of 89Zr-CXCR4-mAb showed enhanced uptake in NSCLC xenografts with a high expression of CXCR4. It also had the ability to detect lymph node metastases in an experimental model of metastatic TNBC. Treatment of high and low CXCR4 expressing NSCLC and TNBC xenografts with CXCR4-mAb demonstrated a therapeutic response correlating with the expression of CXCR4. Considering the key role of CXCR4 in normal biological functions, our results suggest that combination of 89Zr-CXCR4-mAb-PET with non-radiolabeled mAb therapy may provide a precision medicine approach for selecting patients with tumors that are likely to be responsive to this treatment.
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35
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Serum SDF-1 levels are a reliable diagnostic marker of feline mammary carcinoma, discriminating HER2-overexpressing tumors from other subtypes. Oncotarget 2017; 8:105775-105789. [PMID: 29285291 PMCID: PMC5739678 DOI: 10.18632/oncotarget.22398] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 10/25/2017] [Indexed: 02/07/2023] Open
Abstract
The feline mammary carcinoma (FMC) is the third most common tumor in cat, sharing many clinicopathological features with human breast cancer and thus, considered a suitable model for comparative oncology. Due to its poor prognosis, further studies are required to improve the diagnostic accuracy and treatment of cats with spontaneous mammary carcinoma. Recently, it was reported that the overexpression of stromal cell-derived factor-1 (SDF-1) has great value in human breast cancer diagnosis, suggesting that diagnostic tools and therapies targeting the SDF-1 ligand can improve the clinical outcome. In this study, we aimed to evaluate if serum SDF-1 levels can also be used as a biomarker of mammary carcinoma in cats and to analyze if serum SDF-1 levels are associated with clinicopathological features, linked to a specific FMC subtype or correlated with the tumor expression of SDF-1 receptor, the chemokine C-X-C motif receptor 4 (CXCR4). Results showed that cats with mammary carcinoma had significantly higher serum SDF-1 levels than healthy controls (p=0.035) and ROC analysis revealed that the best cut-off value to differentiate sick from healthy animals was 2 ng/ml (specificity: 80%; sensitivity: 57%; AUC=0.715). Significant associations were also found between cats with elevated serum SDF-1 concentrations (≥ 2 ng/ml) and HER2-overexpressing mammary carcinomas (Luminal B-like and HER2-positive subtypes, p<0.0001), CXCR4-negative mammary carcinomas (p=0.027), mammary carcinomas with small size (<3 cm, p=0.027) and tumors with low Ki-67 expression (p=0.012). No statistical associations were found between serum SDF-1 levels and overall or disease-free survival. In summary, our results show that serum SDF-1 levels can be used as a biomarker of feline mammary carcinoma, especially in cats with HER2-overexpressing mammary tumors. Data suggest that targeted therapies against the SDF-1 ligand and/or its CXC4 receptor may be effective for the treatment of FMC, as described for human breast cancer, strengthening the concept that spontaneous feline mammary carcinoma is a suitable model for comparative oncology.
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36
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Abstract
The global incidence of thyroid cancer is increasing, and metastatic spread to the lymph nodes is common in papillary thyroid carcinoma. The metastatic course of thyroid carcinoma is an intricate process involving invasion, angiogenesis, cell trafficking, extravasation, organ specific homing, and growth. A key aspect in this process involves a multitude of interactions between chemokines and their receptors. Chemokines are a group of small proteins, which act to elicit normal physiologic and immune responses principally through recruitment of specific cell populations to the site of infection or malignancy. Thyroid cancer cells, like other tumors, possess the ability to corrupt the chemokine system to their advantage by altering cell movement into the tumor microenvironment and affecting all aspects of thyroid cancer progression.
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Affiliation(s)
- Sharinie Yapa
- 1 Department of Otolaryngology and Head and Neck Surgery, Castle Hill Hospital , Cottingham, United Kingdom
| | - Omar Mulla
- 1 Department of Otolaryngology and Head and Neck Surgery, Castle Hill Hospital , Cottingham, United Kingdom
| | - Victoria Green
- 2 School of Life Sciences, University of Hull , Hull, United Kingdom
| | - James England
- 1 Department of Otolaryngology and Head and Neck Surgery, Castle Hill Hospital , Cottingham, United Kingdom
| | - John Greenman
- 2 School of Life Sciences, University of Hull , Hull, United Kingdom
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37
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Phattarataratip E, Dhanuthai K. Expression of C-X-C motif chemokine receptors 4 and 7 in salivary gland neoplasms. Arch Oral Biol 2017; 83:136-144. [DOI: 10.1016/j.archoralbio.2017.07.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/18/2017] [Accepted: 07/19/2017] [Indexed: 12/29/2022]
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38
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39
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Yang QL, Zhang LY, Wang HF, Li Y, Wang YY, Chen TT, Dai MF, Wu HH, Chen SL, Wang WR, Wu Q, Chen CJ, Zhou CZ. The N-terminal polypeptide derived from viral macrophage inflammatory protein II reverses breast cancer epithelial-to-mesenchymal transition via a PDGFRα-dependent mechanism. Oncotarget 2017; 8:37448-37463. [PMID: 28415580 PMCID: PMC5514921 DOI: 10.18632/oncotarget.16394] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 03/01/2017] [Indexed: 01/22/2023] Open
Abstract
NT21MP, a 21-residue peptide derived from the viral macrophage inflammatory protein II, competed effectively with the natural ligand of CXC chemokine receptor 4 (CXCR4), stromal cell-derived factor 1-alpha, to induce apoptosis and inhibit growth in breast cancer. Its role in tumor epithelial-to-mesenchymal transition (EMT) regulation remains unknown. In this study, we evaluated the reversal of EMT upon NT21MP treatment and examined its role in the inhibition of EMT in breast cancer. The parental cells of breast cancer (SKBR-3 and MCF-7) and paclitaxel-resistant (SKBR-3 PR and MCF-7 PR) cells were studied in vitro and in combined immunodeficient mice. The mice injected with SKBR-3 PR cells were treated with NT21MP through the tail vein or intraperitoneally with paclitaxel or saline. Sections from tumors were evaluated for tumor weight and EMT markers based on Western blot. In vitro, the effects of NT21MP, CXCR4 and PDGFRα on tumor EMT were assessed by relative quantitative real-time reverse transcription-polymerase chain reaction, western blot and biological activity in breast cancer cell lines expressing high or low levels of CXCR4. Our results illustrated that NT21MP could reverse the phenotype of EMT in paclitaxel-resistant cells. Furthermore, we found that NT21MP governed PR-mediated EMT partly due to controlling platelet-derived growth factors A and B (PDGFA and PDGFB) and their receptor (PDGFRα). More importantly, NT21MP down-regulated AKT and ERK1/2 activity, which were activated by PDGFRα, and eventually reversed the EMT. Together, these results indicated that CXCR4 overexpression drives acquired paclitaxel resistance, partly by activating the PDGFA and PDGFB/PDGFRα autocrine signaling loops that activate AKT and ERK1/2. Inhibition of the oncogenic EMT process by targeting CXCR4/PDGFRα-mediated pathways using NT21MP may provide a novel therapeutic approach towards breast cancer.
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Affiliation(s)
- Qing-Ling Yang
- Hefei National Laboratory for Physical Sciences at Microscale and the Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 233030, China
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Ling-Yu Zhang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Hai-Feng Wang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Yu Li
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Yue-Yue Wang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Tian-Tian Chen
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Meng-Fen Dai
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Hai-Hua Wu
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Su-Lian Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Wen-Rui Wang
- Department of Biotechnology, Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Qiong Wu
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Chang-Jie Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Cong-Zhao Zhou
- Hefei National Laboratory for Physical Sciences at Microscale and the Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 233030, China
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40
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Breast Carcinoma-associated Fibroblasts Share Similar Biomarker Profiles in Matched Lymph Node Metastasis. Appl Immunohistochem Mol Morphol 2017; 24:712-720. [PMID: 26808127 DOI: 10.1097/pai.0000000000000253] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
This study sought to understand the role of breast carcinoma-associated fibroblasts in the progression of cancer cells into lymph nodes. We compared fibroblasts of primary tumors and matched the involved lymph nodes to select fibroblast activation markers, namely α-smooth muscle actin (α-SMA), S100A4, and vimentin, as well as to determine the frequency of transforming growth factor β1, a pleiotropic cytokine that induces the differentiation of fibroblasts to myofibroblasts, and its downstream effectors: CXCR4 and p-AKT. We disposed samples of 80 primary invasive ductal carcinomas and matched the involved lymph nodes from 43 cases into 3 tissue microarrays, and analyzed stromal and tumor epithelial cells separately by immunohistochemistry. Control uninvolved lymph nodes were analyzed by whole-tissue sections. Cancer-associated fibroblast in lymph nodes with macrometastasis expressed similar profiles of vimentin, α-SMA, and S100A4 as those found in primary tumors. Cancer-associated fibroblast were uniformly estrogen receptor, progesterone receptor, HER-2, Ki-67, and p53 negative, but expressions of transforming growth factor β1 (TGFβ1), CXCR4, and p-AKT staining (62.3%, 52.4%, 65%, respectively) were equivalent between primary and lymph node metastasis (LNM) fibroblasts. A significant coexpression of TGFβ1 with p-AKT and CXCR4 in LNMs suggested the involvement of these proteins with TGFβ1 signaling. These biomarkers, including α-SMA and S100A4, were negative in fibroblasts of cancer-free lymph nodes, with the exception of vimentin. Our finding that expressions of biological markers were similar in fibroblasts of the primary tumors and in matched LNMs, but were absent in cancer-free lymph nodes, supports the assumption that the lymph node stroma mimics the microenvironment observed in primary tumors.
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41
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Lefort S, Thuleau A, Kieffer Y, Sirven P, Bieche I, Marangoni E, Vincent-Salomon A, Mechta-Grigoriou F. CXCR4 inhibitors could benefit to HER2 but not to triple-negative breast cancer patients. Oncogene 2017; 36:1211-1222. [PMID: 27669438 PMCID: PMC5340801 DOI: 10.1038/onc.2016.284] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 06/27/2016] [Accepted: 07/03/2016] [Indexed: 12/16/2022]
Abstract
The CXCR4 receptor and its ligand CXCL12 (also named stromal cell-derived factor 1, SDF1) have a critical role in chemotaxis and homing, key steps in cancer metastasis. Although myofibroblasts expressing CXCL12 are associated with the presence of axillary metastases in HER2 breast cancers (BC), the therapeutic interest of targeting CXCR4/CXCL12 axis in the different BC subtypes remains unclear. Here, we investigate this question by testing antitumor activity of CXCR4 inhibitors in patient-derived xenografts (PDX), which faithfully reproduce human tumor properties. We observed that two CXCR4 inhibitors, AMD3100 and TN14003, efficiently impair tumor growth and metastasis dissemination in both Herceptin-sensitive and Herceptin-resistant HER2 BC. Conversely, blocking CXCR4/CXCL12 pathway in triple-negative (TN) BC does not reduce tumor growth, and can even increase metastatic spread. Moreover, although CXCR4 inhibitors significantly reduce myofibroblast content in all BC subtypes, they decrease angiogenesis only in HER2 BC. Thus, our findings suggest that targeting CXCR4 could provide some therapeutic interest for HER2 BC patients, whereas it has no impact or could even be detrimental for TN BC patients.
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Affiliation(s)
- S Lefort
- Stress and Cancer Laboratory, LNCC Labelized Team, Institut Curie Research Department, 26 rue d'Ulm, 75248 Paris Cedex 05, France
- Inserm, U830, Genetics and Biology of Cancer, Paris, F-75248, France
| | - A Thuleau
- Laboratory of pre-clinical Investigation, Translational Research Department, Institut Curie Research Department, Paris, France
| | - Y Kieffer
- Stress and Cancer Laboratory, LNCC Labelized Team, Institut Curie Research Department, 26 rue d'Ulm, 75248 Paris Cedex 05, France
- Inserm, U830, Genetics and Biology of Cancer, Paris, F-75248, France
| | - P Sirven
- Stress and Cancer Laboratory, LNCC Labelized Team, Institut Curie Research Department, 26 rue d'Ulm, 75248 Paris Cedex 05, France
- Inserm, U830, Genetics and Biology of Cancer, Paris, F-75248, France
| | - I Bieche
- Service de Génétique, Unité de Pharmacogénétique, Institut Curie Hospital Group, Paris, France
| | - E Marangoni
- Laboratory of pre-clinical Investigation, Translational Research Department, Institut Curie Research Department, Paris, France
| | - A Vincent-Salomon
- Department of Pathology Institut Curie Hospital Group, Paris, France
| | - F Mechta-Grigoriou
- Stress and Cancer Laboratory, LNCC Labelized Team, Institut Curie Research Department, 26 rue d'Ulm, 75248 Paris Cedex 05, France
- Inserm, U830, Genetics and Biology of Cancer, Paris, F-75248, France
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Li RH, Huang WH, Wu JD, Du CW, Zhang GJ. EGFR expression is associated with cytoplasmic staining of CXCR4 and predicts poor prognosis in triple-negative breast carcinomas. Oncol Lett 2017; 13:695-703. [PMID: 28356948 PMCID: PMC5351258 DOI: 10.3892/ol.2016.5489] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 09/27/2016] [Indexed: 02/05/2023] Open
Abstract
The purpose of the present study was to investigate the significance of C-X-C motif chemokine receptor type 4 (CXCR4) and epidermal growth factor receptors (EGFRs) in triple-negative breast cancer (TNBC). CXCR4 and EGFR expression levels were immunohistochemically determined in 207 primary breast cancer specimens. The associations between receptor expression and clinicopathological characteristics were analyzed, and receptor expression was also assessed as a prognostic factor. In the human MDA-MB-231 TNBC cell line, CXCR4 or EGFR was stably knocked down by short hairpin RNA, and the biological behavior of the cells, including migration, invasion and tumorigenesis, was investigated. The results revealed that TNBC was associated with younger age, higher histological grade and an aggressive phenotype. CXCR4 and EGFR were highly expressed in patients with TNBC, and those with high CXCR4 or EGFR expression exhibited an unfavorable prognosis in terms of disease-free survival and overall survival. In MDA-MB-231 cells, the expression of CXCR4 protein was decreased following EGFR silencing, while CXCR4 knockdown also caused a decrease in EGFR protein levels. The migratory and invasive capabilities of MDA-MB-231 cells were decreased following the knockdown of CXCR4 or EGFR expression. A strong correlation between CXCR4 and EGFR expression was identified in patients with TNBC. The results suggest that elevated expression levels of these two receptors may serve as predictive factors for poor prognosis in patients with TNBC. In addition, tumor proliferation, migration, invasion and tumorigenesis are weakened in MDA-MB-231 cells following suppression of CXCR4 or EGFR expression. Therefore, EGFR and CXCR4 may be potential therapeutic targets for TNBC.
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Affiliation(s)
- Rong-Hui Li
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Chang Jiang Scholar's Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Wen-He Huang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Jun-Dong Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Cai-Wen Du
- Chang Jiang Scholar's Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Department of Breast Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Guo-Jun Zhang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Chang Jiang Scholar's Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment, Shantou, Guangdong 515041, P.R. China
- Correspondence to: Professor Guo-Jun Zhang, The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, Guangdong 515041, P.R. China, E-mail:
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43
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Kazanietz MG, Barrio-Real L, Casado-Medrano V, Baker MJ, Lopez-Haber C. The P-Rex1/Rac signaling pathway as a point of convergence for HER/ErbB receptor and GPCR responses. Small GTPases 2016; 9:297-303. [PMID: 27588611 DOI: 10.1080/21541248.2016.1221273] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Guanine nucleotide Exchange Factors (GEFs) are responsible for mediating GDP/GTP exchange for specific small G proteins, such as Rac. There has been substantial evidence for the involvement of Rac-GEFs in the control of cancer cell migration and metastatic progression. We have previously established that the Rac-GEF P-Rex1 is a mediator of actin cytoskeleton rearrangements and cell motility in breast cancer cells downstream of HER/ErbB receptors and the G-Protein Coupled Receptor (GPCR) CXCR4. P-Rex1 is highly expressed in luminal A and B breast cancer compared to normal mammary tissue, whereas expression is very low in basal breast cancer, and its expression correlates with the appearance of metastasis in patients. Here, we discuss the involvement of P-Rex1 as an effector of oncogenic/metastatic receptors in breast cancer and underscore its relevance in the convergence of receptor-triggered motile signals. In addition, we provide an overview of our recent findings describing a cross-talk between HER/ErbB receptors and CXCR4, and how this impacts on the activation of P-Rex1/Rac1 signaling, as well as highlight challenges that lie ahead. We propose a model in which P-Rex1 acts as a crucial node for the integration of upstream inputs from HER/ErbB receptors and CXCR4 in luminal breast cancer cells.
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Affiliation(s)
- Marcelo G Kazanietz
- a Department of Systems Pharmacology and Translational Therapeutics , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
| | - Laura Barrio-Real
- a Department of Systems Pharmacology and Translational Therapeutics , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
| | - Victoria Casado-Medrano
- a Department of Systems Pharmacology and Translational Therapeutics , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
| | - Martin J Baker
- a Department of Systems Pharmacology and Translational Therapeutics , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
| | - Cynthia Lopez-Haber
- a Department of Systems Pharmacology and Translational Therapeutics , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
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Adega F, Borges A, Chaves R. Cat Mammary Tumors: Genetic Models for the Human Counterpart. Vet Sci 2016; 3:vetsci3030017. [PMID: 29056725 PMCID: PMC5606576 DOI: 10.3390/vetsci3030017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 08/06/2016] [Accepted: 08/11/2016] [Indexed: 12/18/2022] Open
Abstract
The records are not clear, but Man has been sheltering the cat inside his home for over 12,000 years. The close proximity of this companion animal, however, goes beyond sharing the same roof; it extends to the great similarity found at the cellular and molecular levels. Researchers have found a striking resemblance between subtypes of feline mammary tumors and their human counterparts that goes from the genes to the pathways involved in cancer initiation and progression. Spontaneous cat mammary pre-invasive intraepithelial lesions (hyperplasias and neoplasias) and malignant lesions seem to share a wide repertoire of molecular features with their human counterparts. In the present review, we tried to compile all the genetics aspects published (i.e., chromosomal alterations, critical cancer genes and their expression) regarding cat mammary tumors, which support the cat as a valuable alternative in vitro cell and animal model (i.e., cat mammary cell lines and the spontaneous tumors, respectively), but also to present a critical point of view of some of the issues that really need to be investigated in future research.
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Affiliation(s)
- Filomena Adega
- Laboratory of Cytogenomics and Animal Genomics (CAG), Department of Genetics and Biotechnology (DGB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real 5001-801, Portugal.
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, Lisboa 1749-016, Portugal.
| | - Ana Borges
- Laboratory of Cytogenomics and Animal Genomics (CAG), Department of Genetics and Biotechnology (DGB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real 5001-801, Portugal.
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, Lisboa 1749-016, Portugal.
| | - Raquel Chaves
- Laboratory of Cytogenomics and Animal Genomics (CAG), Department of Genetics and Biotechnology (DGB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real 5001-801, Portugal.
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, Lisboa 1749-016, Portugal.
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Zhao Y, Detering L, Sultan D, Cooper ML, You M, Cho S, Meier SL, Luehmann H, Sun G, Rettig M, Dehdashti F, Wooley KL, DiPersio JF, Liu Y. Gold Nanoclusters Doped with (64)Cu for CXCR4 Positron Emission Tomography Imaging of Breast Cancer and Metastasis. ACS NANO 2016; 10:5959-70. [PMID: 27159079 PMCID: PMC5479491 DOI: 10.1021/acsnano.6b01326] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
As an emerging class of nanomaterial, nanoclusters hold great potential for biomedical applications due to their unique sizes and related properties. Herein, we prepared a (64)Cu doped gold nanocluster ((64)CuAuNC, hydrodynamic size: 4.2 ± 0.5 nm) functionalized with AMD3100 (or Plerixafor) for targeted positron emission tomography (PET) imaging of CXCR4, an up-regulated receptor on primary tumor and lung metastasis in a mouse 4T1 orthotopic breast cancer model. The preparation of targeted (64)CuAuNCs-AMD3100 (4.5 ± 0.4 nm) was done via one-step reaction with controlled conjugation of AMD3100 and specific activity, as well as improved colloid stability. In vivo pharmacokinetic evaluation showed favorable organ distribution and significant renal and fecal clearance within 48 h post injection. The expression of CXCR4 in tumors and metastasis was characterized by immunohistochemistry, Western blot, and reverse transcription polymerase chain reaction analysis. PET imaging with (64)CuAuNCs-AMD3100 demonstrated sensitive and accurate detection of CXCR4 in engineered tumors expressing various levels of the receptor, while competitive receptor blocking studies confirmed targeting specificity of the nanoclusters. In contrast to nontargeted (64)CuAuNCs and (64)Cu-AMD3100 alone, the targeted (64)CuAuNCs-AMD3100 detected up-regulated CXCR4 in early stage tumors and premetastatic niche of lung earlier and with greater sensitivity. Taken together, we believe that (64)CuAuNCs-AMD3100 could serve as a useful platform for early and accurate detection of breast cancer and metastasis providing an essential tool to guide the treatment.
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Affiliation(s)
- Yongfeng Zhao
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, 63110, United States
| | - Lisa Detering
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, 63110, United States
| | - Deborah Sultan
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, 63110, United States
| | - Matthew L Cooper
- Department of Medicine, Washington University, St. Louis, Missouri, 63110, United States
| | - Meng You
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, 63110, United States
| | - Sangho Cho
- Department of Chemistry, Department of Chemical Engineering, and Department of Materials Science and Engineering, Texas A&M University, College Station, TX 77842, United States
| | - Stephanie L. Meier
- Department of Medicine, Washington University, St. Louis, Missouri, 63110, United States
| | - Hannah Luehmann
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, 63110, United States
| | - Guorong Sun
- Department of Chemistry, Department of Chemical Engineering, and Department of Materials Science and Engineering, Texas A&M University, College Station, TX 77842, United States
| | - Michael Rettig
- Department of Medicine, Washington University, St. Louis, Missouri, 63110, United States
| | - Farrokh Dehdashti
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, 63110, United States
| | - Karen L. Wooley
- Department of Chemistry, Department of Chemical Engineering, and Department of Materials Science and Engineering, Texas A&M University, College Station, TX 77842, United States
| | - John F. DiPersio
- Department of Medicine, Washington University, St. Louis, Missouri, 63110, United States
| | - Yongjian Liu
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, 63110, United States
- Corresponding Author: Address correspondence to:
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Kim B, Kim YC, Park B. Pomolic acid inhibits metastasis of HER2 overexpressing breast cancer cells through inactivation of the ERK pathway. Int J Oncol 2016; 49:744-52. [DOI: 10.3892/ijo.2016.3568] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 06/01/2016] [Indexed: 11/05/2022] Open
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Khabar KSA. Hallmarks of cancer and AU-rich elements. WILEY INTERDISCIPLINARY REVIEWS-RNA 2016; 8. [PMID: 27251431 PMCID: PMC5215528 DOI: 10.1002/wrna.1368] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 05/05/2016] [Accepted: 05/09/2016] [Indexed: 12/14/2022]
Abstract
Post‐transcriptional control of gene expression is aberrant in cancer cells. Sustained stabilization and enhanced translation of specific mRNAs are features of tumor cells. AU‐rich elements (AREs), cis‐acting mRNA decay determinants, play a major role in the posttranscriptional regulation of many genes involved in cancer processes. This review discusses the role of aberrant ARE‐mediated posttranscriptional processes in each of the hallmarks of cancer, including sustained cellular growth, resistance to apoptosis, angiogenesis, invasion, and metastasis. WIREs RNA 2017, 8:e1368. doi: 10.1002/wrna.1368 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Khalid S A Khabar
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Wang F, Li S, Zhao Y, Yang K, Chen M, Niu H, Yang J, Luo Y, Tang W, Sheng M. Predictive role of the overexpression for CXCR4, C-Met, and VEGF-C among breast cancer patients: A meta-analysis. Breast 2016; 28:45-53. [PMID: 27214240 DOI: 10.1016/j.breast.2016.04.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Revised: 03/27/2016] [Accepted: 04/29/2016] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The overexpression of CXCR4, C-Met and VEGF-C present widely in breast tumors, they may be markers of resistance to treatment. However, the studies are still controversial. Thus, this meta-analysis aims to research the relationship between the overexpression of CXCR4, C-Met, VEGF-C and clinical prognosis among breast cancer patients. METHODS PubMed and EMBASE databases were searched for eligible literature. The outcomes of interest were progression-free survival (PFS), relapse-free survival (RFS) and overall survival (OS). All tests of statistical significance were two sided. RESULTS A total of 7830 patients from 28 eligible studies were assessed. The overexpression of the CXCR4 and C-Met both implied significantly worse PFS compared with normal expression [HR = 2.56, 95% CI = 1.34-4.91, P = 0.005; and HR = 1.63 95% CI = 1.20-2.22, P = 0.002]. Meanwhile, if patients had high expression of CXCR4, they would have worse OS [HR = 2.56 95% CI = 1.52-4.31, P = 0.000]. However, the overexpression of C-Met did not relate to OS for breast cancer patients [HR = 1.16, 95% CI = 0.69-1.95, P = 0.570]. Meanwhile, no statistically significant different was observed with respect to PFS and OS between VEGF-C overexpression and normal expression [HR = 0.99, 95% CI = 0.64-1.52, P = 0.968; and HR = 0.76, 95% CI = 0.43-1.33, P = 0.333]. CONCLUSIONS Our meta-analysis showed that CXCR4 and C-Met were efficient prognostic factors for breast cancer. Nevertheless, highly expressing VEGF-C was not related to progression-free survival and overall survival. Due to the small samples and insufficient date, further studies should be conducted to clarify the association between the overexpression of CXCR4 or C-Met or VEGF-C and the prognosis about breast cancer patients.
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Affiliation(s)
- Fang Wang
- Laboratory of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Shanshan Li
- Laboratory of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Yueguang Zhao
- Laboratory of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Kunxian Yang
- First People's Hospital of Yunnan Province, 157 Jinbi Road, Kunming, Yunnan 650032, China
| | - Minju Chen
- First People's Hospital of Yunnan Province, 157 Jinbi Road, Kunming, Yunnan 650032, China
| | - Heng Niu
- First People's Hospital of Yunnan Province, 157 Jinbi Road, Kunming, Yunnan 650032, China
| | - Jingyu Yang
- First People's Hospital of Yunnan Province, 157 Jinbi Road, Kunming, Yunnan 650032, China
| | - Ying Luo
- Laboratory of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Wenru Tang
- Laboratory of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China.
| | - Miaomiao Sheng
- Laboratory of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China.
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Kim B, Yoon J, Yoon SW, Park B. Onbaekwon Suppresses Colon Cancer Cell Invasion by Inhibiting Expression of the CXC Chemokine Receptor 4. Integr Cancer Ther 2016; 16:244-251. [PMID: 27160279 PMCID: PMC5739121 DOI: 10.1177/1534735416645182] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Cysteine X cysteine (CXC) chemokine receptor 4 (CXCR4) and C-X-C motif chemokine 12 (CXCL12) were originally identified as chemoattractants between immune cells and sites of inflammation. Since studies have validated an increased level of CXCL12 and its receptor in patients with colorectal cancers, CXCL12/CXCR4 axis has been considered as a valuable marker of cancer metastasis. Therefore, identification of CXCR4 inhibitors has great potential to abrogate tumor metastasis. Onbaekwon (OBW) is a complex herbal formula that is derived from the literature of traditional Korean medicine Dongeuibogam. In this study, we demonstrated that OBW suppressed CXCR4 expression in various cancer cell types in a concentration- and time-dependent manner. Both proteasomal and lysosomal inhibitors had no effect to prevent the OBW-induced suppression of CXCR4, suggesting that the inhibitory effect of OBW was not due to proteolytic degradation but occurred at the transcriptional level. Electrophoretic mobility shift assay further confirmed that OBW could block endogenous activation of nuclear factor kappa B, a key transcription factor that regulates the expression of CXCR4 in colon cancer cells. Consistent with the aforementioned molecular basis, OBW abolished cell invasion induced by CXCL12 in colon cancer cells. Together, our results suggest that OBW, as a novel inhibitor of CXCR4, could be a promising therapeutic agent contributing to cancer treatment.
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Affiliation(s)
- Buyun Kim
- 1 Keimyung University, Daegu, South Korea
| | | | - Seong Woo Yoon
- 2 Kyung Hee University Hospital at Gangdong, Seoul, Korea
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Symmetrical bis-tertiary amines as novel CXCR4 inhibitors. Eur J Med Chem 2016; 118:340-50. [PMID: 27179215 DOI: 10.1016/j.ejmech.2016.04.040] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 04/14/2016] [Accepted: 04/15/2016] [Indexed: 02/07/2023]
Abstract
CXCR4 inhibitors are promising agents for the treatment of cancer metastasis and inflammation. A series of novel tertiary amine derivatives targeting CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure-activity relationship. Seven compounds displayed much more potent activity than the reference drug, AMD3100, in both the binding affinity assay and the blocking of Matrigel invasion functional assay. These compounds exhibited effective concentration ranging from 1 to 100 nM in the binding affinity assay and inhibited invasion from 65.3% to 100% compared to AMD3100 at 100 nM. Compound IIn showed a 50% suppressive effect against carrageenan-induced paw inflammation in a mouse model, which was as effective as the peptidic antagonist, TN14003 (48%). These data demonstrate that symmetrical bis-tertiary amines are unique CXCR4 inhibitors with high potency.
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