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Yilihamu Y, Wang L, Ma T, Zhao T, Wang Y, Sun G. The Effects of Preoperative Serum Carcinoembryonic Antigen, Cancer Antigen 15-3 and Cancer Antigen 125 on the Prognosis of Breast Cancer Patients With Different Molecular Subtypes. J Clin Med Res 2024; 16:491-502. [PMID: 39544329 PMCID: PMC11557502 DOI: 10.14740/jocmr5237] [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: 06/13/2024] [Accepted: 09/25/2024] [Indexed: 11/17/2024] Open
Abstract
Background The aim of the study was to investigate the relationship between serum carcinoembryonic antigen (CEA), cancer antigen 15-3 (CA15-3), and cancer antigen 125 (CA125) levels and traditional clinicopathological factors in patients with early invasive breast cancer in Xinjiang, and the influence of those serum markers on the prognosis of patients with different molecular subtypes. Methods We conducted a retrospective study based on the clinical data of 2,940 invasive breast cancer patients who were diagnosed and treated at the Affiliated Cancer Hospital of Xinjiang Medical University from 2015 to 2019. Firstly, in this study, preoperative serum CEA, CA15-3, and CA125 levels were divided into elevated and normal groups based on the optimal cut-off values. Secondly, Chi-square test was used to analyze the correlation between the elevated and normal groups of CEA, CA15-3, and CA125 and traditional clinicopathological factors. Finally, Cox regression model was also used to evaluate the effect of preoperative CEA, CA15-3, and CA125 elevated groups on the prognosis of patients with different molecular subtypes compared with normal groups. Results The optimal cut-off values for preoperative CEA, CA15-3, and CA125 were 4.32 ng/mL, 23.10 U/mL and 29.80 U/mL, respectively. The elevated group of preoperative CEA, CA15-3, and CA125 patients usually had larger tumors (tumor size: T2-4), later clinical staging (TNM stage: II-III), and higher histological grading (histological grade: II-III). Univariate analysis showed that the overall survival (OS) of preoperative CEA, CA15-3, and CA125 patients in the elevated group was lower than that in the normal group (P < 0.0001), the 5-year OS was 76.63% vs. 95.35%, 74.34% vs. 95.60%, and 83.73% vs. 94.71%, respectively. Multivariate analysis revealed that for the luminal A, compared with the normal group, the hazard ratios (HRs) of preoperative CEA, CA15-3, and CA125 elevated groups were 6.475 (95% confidence interval (CI): 1.850 - 22.66), 5.192 (95% CI: 1.153 - 23.38), and 7.294 (95% CI: 1.152 - 46.18), respectively. However, for the luminal B, elevated levels of CEA, CA15-3, and CA125 were not independent prognostic factors for OS. For the human epidermal growth factor receptor-2 (HER2)-enriched, the HR of preoperative CA15-3 elevated group was 3.155 (95% CI: 1.325 - 7.509). Additionally, for the triple-negative breast cancer, the HR of preoperative CEA elevated group was 2.390 (95% CI: 1.247 - 4.583). Conclusions High levels of CEA, CA15-3, and CA125 were positively correlated with increased tumor load. Preoperative CEA, CA15-3, and CA125 levels may have different prognostic effects on patients with different molecular subtypes. Particularly, preoperative elevated levels of CEA have a significant adverse impact on the prognosis of luminal A and triple-negative patients, while preoperative elevated levels of CA15-3 have an adverse effect on the prognosis of luminal A and HER-positive patients.
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Affiliation(s)
- Yipala Yilihamu
- Country College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Lei Wang
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Tao Ma
- Country College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Ting Zhao
- Department of Medical Record Management, The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yan Wang
- Department of Tumor Control and Research, The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Gang Sun
- Department of Breast and Thyroid Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Key Laboratory of Oncology of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
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Goggins E, Mironchik Y, Kakkad S, Jacob D, Wildes F, Bhujwalla ZM, Krishnamachary B. Reprogramming of VEGF-mediated extracellular matrix changes through autocrine signaling. Cancer Biol Ther 2023; 24:2184145. [PMID: 37389973 PMCID: PMC10012930 DOI: 10.1080/15384047.2023.2184145] [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: 08/16/2022] [Revised: 01/20/2023] [Accepted: 01/30/2023] [Indexed: 03/11/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) plays key roles in angiogenesis, vasculogenesis, and wound healing. In cancers, including triple negative breast cancer (TNBC), VEGF has been associated with increased invasion and metastasis, processes that require cancer cells to traverse through the extracellular matrix (ECM) and establish angiogenesis at distant sites. To further understand the role of VEGF in modifying the ECM, we characterized VEGF-mediated changes in the ECM of tumors derived from TNBC MDA-MB-231 cells engineered to overexpress VEGF. We established that increased VEGF expression by these cells resulted in tumors with reduced collagen 1 (Col1) fibers, fibronectin, and hyaluronan. Molecular characterization of tumors identified an increase of MMP1, uPAR, and LOX, and a decrease of MMP2, and ADAMTS1. α-SMA, a marker of cancer associated fibroblasts (CAFs), increased, and FAP-α, a marker of a subset of CAFs associated with immune suppression, decreased with VEGF overexpression. Analysis of human data from The Cancer Genome Atlas Program confirmed mRNA differences for several molecules when comparing TNBC with high and low VEGF expression. We additionally characterized enzymatic changes induced by VEGF overexpression in three different cancer cell lines that clearly identified autocrine-mediated changes, specifically uPAR, in these enzymes. Unlike the increase of Col1 fibers and fibronectin mediated by VEGF during wound healing, in the TNBC model, VEGF significantly reduced key protein components of the ECM. These results further expand our understanding of the role of VEGF in cancer progression and identify potential ECM-related targets to disrupt this progression.
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Affiliation(s)
- Eibhlin Goggins
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yelena Mironchik
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Samata Kakkad
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Desmond Jacob
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Flonne Wildes
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zaver M. Bhujwalla
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Balaji Krishnamachary
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Romano F, Di Porzio A, Iaccarino N, Riccardi G, Di Lorenzo R, Laneri S, Pagano B, Amato J, Randazzo A. G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting. Expert Opin Ther Pat 2023; 33:745-773. [PMID: 37855085 DOI: 10.1080/13543776.2023.2271168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 10/11/2023] [Indexed: 10/20/2023]
Abstract
INTRODUCTION Guanine-rich DNA sequences can fold into four-stranded noncanonical secondary structures called G-quadruplexes (G4s) which are widely distributed in functional regions of the human genome, such as telomeres and gene promoter regions. Compelling evidence suggests their involvement in key genome functions such as gene expression and genome stability. Notably, the abundance of G4-forming sequences near transcription start sites suggests their potential involvement in regulating oncogenes. AREAS COVERED This review provides an overview of current knowledge on G4s in human oncogene promoters. The most representative G4-binding ligands have also been documented. The objective of this work is to present a comprehensive overview of the most promising targets for the development of novel and highly specific anticancer drugs capable of selectively impacting the expression of individual or a limited number of genes. EXPERT OPINION Modulation of G4 formation by specific ligands has been proposed as a powerful new tool to treat cancer through the control of oncogene expression. Actually, most of G4-binding small molecules seem to simultaneously target a range of gene promoter G4s, potentially influencing several critical driver genes in cancer, thus producing significant therapeutic benefits.
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Affiliation(s)
- Francesca Romano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Anna Di Porzio
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Nunzia Iaccarino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | | | - Sonia Laneri
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Bruno Pagano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Jussara Amato
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Antonio Randazzo
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
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Chen XY, Long ZQ, Huang HY, Wen W, Lin F, Guo L, Lin HX. Predicting Survival of Patients with Nonmetastatic Breast Cancer Based on Fibrinogen-to-Albumin Ratio and Lymphocyte-to-Monocyte Ratio: A Nomogram-Based Assessment. Breast Care (Basel) 2023; 18:374-389. [PMID: 37901049 PMCID: PMC10601685 DOI: 10.1159/000531939] [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: 02/28/2022] [Accepted: 05/30/2023] [Indexed: 10/31/2023] Open
Abstract
Background Parameters of systemic inflammation have received attention as prognostic surrogates in various malignant tumors. Fibrinogen-to-albumin ratio (FAR) and lymphocyte-to-monocyte ratio (LMR) correlate with tumor growth and dissemination. We aimed to bring the combination of FAR and LMR (FAR-LMR) together to establish novel nomograms for survival and recurrence in nonmetastatic breast cancer patients. Methods We retrospectively recruited 461 female patients with nonmetastatic breast cancer from January 2011 to December 2013 in our hospital and randomly assigned them into the training cohort (N = 318) and the validation cohort (N = 143). The potential predictive factors for overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Cox proportional hazards models and log-rank test. Results Elevated FAR was associated with poor OS (p < 0.001) and DMFS (p = 0.02), whereas increased LMR was associated with satisfactory OS (p = 0.01) and LRFS (p = 0.01). High FAR combined with low LMR was associated with less favorable OS (p = 0.001), LRFS (p = 0.005), and DMFS (p = 0.003) Based on multivariate analysis, FAR-LMR, tumor size, lymph node metastasis, age, and pathologic status contributed to prognostic nomograms of OS, DMFS, and LRFS. Nomograms presented exceptional performance for 3-, 5-, and 8-year OS, DMFS, and LRFS prediction compared with clinical TNM stage. The C-index was significantly higher than that of TNM stage, either of FAR or LMR (3-year: 0.709 vs. 0.621 vs. 0.544 vs. 0.641, 5-year: 0.761 vs. 0.597 vs. 0.605 vs. 0.677, 8-year: 0.84 vs. 0.62 vs. 0.539 vs. 0.623). Conclusions We developed and validated a convenient predictive model for the survival outcomes of patients with nonmetastatic breast cancer. The nomograms can be utilized as auxiliary tools to provide prognostic information.
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Affiliation(s)
- Xiao-Yu Chen
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Zhi-Qing Long
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Han-Ying Huang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Wen Wen
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Fei Lin
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Ling Guo
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Huan-Xin Lin
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, PR China
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Ismail MMF, Shawer TZ, Ibrahim RS, Allam RM, Ammar YA. Novel quinoxaline-based VEGFR-2 inhibitors to halt angiogenesis. Bioorg Chem 2023; 139:106735. [PMID: 37531818 DOI: 10.1016/j.bioorg.2023.106735] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/27/2023] [Accepted: 07/11/2023] [Indexed: 08/04/2023]
Abstract
Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancer. This study was aimed at exploring the VEGFR-2 inhibitory activity of a novel library of quinoxalin-2-one derivatives such as 3-furoquinoxaline carboxamides, 3-pyrazolylquinoxalines, and 3-pyridopyrimidyl-quinoxalines. Among them, 6c, 7a, and 7d-f produced remarkable cytotoxicity against HCT-116 (IC50's 4.28-9.31 µM) and MCF-7 (IC50's 3.57-7.57 µM) cell lines using the MTT assay and doxorubicin (DOX) as a reference standard. Interestingly, results of cytotoxicity towards the human fibroblast cell line WI38 revealed that these hits demonstrated higher selectivity indices towards both HCT-116 (SI 8.69-23.19) and MCF-7 (SI 9.48-27.80) than DOX, SI 0.72 and 0.90, respectively. Then, these hits were subjected to a mechanistic study; they showed direct inhibition of VEGFR-2. Impressively, compound 7f displayed 1.2 times the VEGFR-2 inhibitory activity of sorafenib. The antiangiogenic potential of 7f was proved via lowering the level of VEGF-A, than that of control. It as well, exhibited scratch closure percent of 61.8%, compared with 74.5% of control at 48 hrs, indicating the potential anti-migratory effect of the compound 7f. It significantly increased the expression of tumor suppressor gene (p53) on MCF-7 cells by almost 18 folds and upregulated the caspase-3 level by 10.7 folds, compared to the control. Cell cycle analysis revealed cell cycle arrest at G2/M together with a PreG increase which indicated apoptosis induction potential. Annexin V-FITC apoptosis results proposed the two modes of cell death (apoptosis and necrosis) as an inherent mechanism of cytotoxicity of compound 7f. Molecular docking further supported the mechanism showing the affinity of target compounds for VEGFR-2 active site. Moreover, physicochemical and drug-like properties were assessed from the ADME properties.
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Affiliation(s)
- Magda M F Ismail
- Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), 11754 Al-Azhar University, Cairo, Egypt.
| | - Taghreed Z Shawer
- Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), 11754 Al-Azhar University, Cairo, Egypt
| | - Rabab S Ibrahim
- Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), 11754 Al-Azhar University, Cairo, Egypt
| | - Rasha M Allam
- Department of Pharmacology, Medical and Clinical Research Institute, National Research Centre, 12622, Dokki, Cairo, Egypt
| | - Yousry A Ammar
- Department of Chemistry, Faculty of Science, 11754 Al-Azhar University, Cairo, Egypt
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Pappas-Gogos G, Tepelenis K, Goussia A, Tellis C, Fousekis F, Glantzounis GK, Vlachos K. Plasma VEGF and Leptin Values in Patients With Gastric Intestinal Metaplasia and Metabolic Syndrome. Front Oncol 2022; 12:905168. [PMID: 35712481 PMCID: PMC9194502 DOI: 10.3389/fonc.2022.905168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/29/2022] [Indexed: 11/25/2022] Open
Abstract
Intestinal metaplasia of the stomach (IM) is considered a pre-cancerous lesion and is a potential precursor to adenocarcinoma. Metabolic syndrome (MetS) has been associated with lesions to the gastrointestinal tract such as the risk of developing Barett esophagus. Vascular endothelial growth factor and leptin have been associated with either gastrointestinal tract carcinogenesis or MetS. In this context, this study was designed to analyze plasma levels of VEGF and leptin in patients with IM and MetS. Four groups of 137 participants (a control group and three patient groups, IM, MetS and IM- MetS) were created. Inclusion criteria for the presence of IM were endoscopic findings and histological confirmation, while for MetS the ATP III and IDF guidelines. Levels of plasma vascular endothelial growth factor (VEGF) and leptin (Leptin) were determined. VEGF levels were increased in IM (IM vs Control, p=0,011) and IM-MetS groups (IM-MetS vs Control, p <0.001 and IM-MetS vs MetS, p=0.001). Leptin levels were found to be increased in the MetS group (MetS vs. Control, p <0.001 and MetS vs IM, p <0.001) and in IM-MetS (IM-MetS vs Control, p = 0.002, IM-MetS vs IM, p=0.033). Patients with intestinal metaplasia and metabolic syndrome (I M - Me t S g r o u p) have elevated levels of VEGF, while leptin levels were associated predominantly with MetS and not with IM.
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Affiliation(s)
- George Pappas-Gogos
- Department of Surgery, Ioannina University Hospital, Ioannina, Greece
- *Correspondence: George Pappas-Gogos,
| | - Kostas Tepelenis
- Department of Surgery, Ioannina University Hospital, Ioannina, Greece
| | - Anna Goussia
- Department of Pathology, Ioannina University Hospital, Ioannina, Greece
- School of Medicine, University of Ioannina, Ioannina, Greece
| | - Constantinos Tellis
- Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece
| | - Fotis Fousekis
- Department of Gastroenterology, Ioannina University Hospital, Ioannina, Greece
| | - Georgios K. Glantzounis
- Department of Surgery, Ioannina University Hospital, Ioannina, Greece
- School of Medicine, University of Ioannina, Ioannina, Greece
| | - Konstantinos Vlachos
- Department of Surgery, Ioannina University Hospital, Ioannina, Greece
- School of Medicine, University of Ioannina, Ioannina, Greece
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Li J, Yan Z, Ma J, Chu Z, Li H, Guo J, Zhang Q, Zhao H, Li Y, Wang T. ZKSCAN5 Activates VEGFC Expression by Recruiting SETD7 to Promote the Lymphangiogenesis, Tumour Growth, and Metastasis of Breast Cancer. Front Oncol 2022; 12:875033. [PMID: 35600335 PMCID: PMC9117617 DOI: 10.3389/fonc.2022.875033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/15/2022] [Indexed: 12/28/2022] Open
Abstract
The growth of lymphatic vessels (lymphangiogenesis) plays a pivotal role in breast cancer progression and metastasis and the immune response. Vascular endothelial growth factor C (VEGFC) has been demonstrated to accelerate cancer metastasis and modulate the immune system by enhancing lymphangiogenesis. However, it remains largely unclear how transcription factors physically regulate VEGFC expression by interacting with histone-modifying enzymes. Like many histone-modifying enzymes, SETD7 plays a key role in cell proliferation and inhibits tumour cell differentiation. In this study, we identified the role of the transcription factor zinc finger with KRAB and SCAN domains 5 (ZKSCAN5) in interacting with histone methyltransferase SETD7 and mediating VEGFC transcription and tumour lymphangiogenesis. ZKSCAN5 interacts with and recruits SETD7 to the VEGFC promoter. By regulating breast cancer-secreted VEGFC, ZKSCAN5 could induce the tube formation of lymph endothelial cells, which promotes tumour proliferation, migration, and metastasis. Clinically, the expression of ZKSCAN5 was frequently upregulated in patients with breast cancer and positively correlated with the expression of VEGFC and the number of lymphatic microvessels. ZKSCAN5 is a poor prognostic factor for patients with breast cancer. Our results characterise the role of ZKSCAN5 in regulating VEGFC transcription and predict ZKSCAN5 as a breast cancer therapeutic target.
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Affiliation(s)
- Jingtong Li
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhifeng Yan
- Department of Obstetrics and Gynecology, Seventh Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Jianli Ma
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhong Chu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Huizi Li
- Department of Nutrition, People’s Liberation Army (PLA) Rocket Force Characteristic Medical Center, Beijing, China
| | - Jingjing Guo
- Department of Oncology, Fourth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Qingyuan Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Qingyuan Zhang, ; Hui Zhao, ; Ying Li, ; Tao Wang,
| | - Hui Zhao
- Department of Oncology, Fourth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Qingyuan Zhang, ; Hui Zhao, ; Ying Li, ; Tao Wang,
| | - Ying Li
- Department of Oncology, Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Qingyuan Zhang, ; Hui Zhao, ; Ying Li, ; Tao Wang,
| | - Tao Wang
- Department of Oncology, Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Qingyuan Zhang, ; Hui Zhao, ; Ying Li, ; Tao Wang,
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Association of XRCC3, XRCC4, BAX, and BCL-2 Polymorphisms with the Risk of Breast Cancer. Int J Breast Cancer 2022; 2022:5817841. [PMID: 35320970 PMCID: PMC8938079 DOI: 10.1155/2022/5817841] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 12/06/2021] [Accepted: 12/20/2021] [Indexed: 11/23/2022] Open
Abstract
Background Breast cancer is the most common malignancy in women. Genetic risk factors associated with breast cancer incidence have been identified. Aims This study is aimed at determining the association of XRCC3 Thr241Met (rs861539), XRCC4 G(-1394) T (rs6869366) DNA repair and BAX G(-248) A (rs4645878), and BCL2 C(-938) A (rs2279115) apoptotic gene polymorphisms with breast cancer. Materials and Methods Genetic analysis was performed using peripheral blood samples. Gene polymorphisms were detected by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. 175 patients and 158 healthy controls were enrolled in the study. Results Breast cancer risk was 5.43 times more in individuals with AA genotype of Bax G(-248) A (rs4645878) (P = 0.002). The risk of metastasis was 11 times with this genotype. It was associated with 6 times more risk of having a tumor larger than 2 cm. The risk of breast cancer was 2.77 times more in individuals carrying the Met/Met genotype of XRCC3 Thr241Met (rs861539) (P = 0.009). The risk of having advanced clinical stage (stage III+IV) with the Met/Met genotype was 4 times more increased. No relationship with breast cancer was found with XRCC4 G(-1394) T (rs6869366) and BCL2 C(-938) A (rs2279115) gene polymorphisms. Conclusion Multicenter trials using subjects with genetic variations are needed to establish the relationship between breast cancer and single gene polymorphism.
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10
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Ribatti D, Annese T, Tamma R. Controversial role of mast cells in breast cancer tumor progression and angiogenesis. Clin Breast Cancer 2021; 21:486-491. [PMID: 34580034 DOI: 10.1016/j.clbc.2021.08.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/16/2021] [Accepted: 08/26/2021] [Indexed: 10/20/2022]
Abstract
Breast cancer is a neoplastic disease and is a cause of cancer-related mortality for women. Among cellular and molecular regulators of the microenvironment, mast cells and vascular endothelial growth factor (VEGF), are correlated with tumor progression and prognosis in breast cancer. Clinical and experimental studies on breast cancer have revealed a marked correlation between increased angiogenesis, metastasization, and poorer prognosis. After a brief introduction on angiogenesis evidence and angiogenic factors role in different breast cancer subtypes, in this article, we have discerned the relationship between mast cell infiltration, angiogenesis, and tumor progression in human breast cancer with particular reference to the dual role of mast cells, in terms of both pro- or anti-tumoral activity and poor or good biomarker.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.
| | - Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
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Sobolewska A, Dunisławska A, Stadnicka K. Natural substances in cancer—do they work? PHYSICAL SCIENCES REVIEWS 2021. [DOI: 10.1515/psr-2019-0060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
Owing to anticancer properties of selected natural substances, it is assumed that they have potential to be used in oncological therapy. Here, the recently proven effects of the selected natural polyphenols, resveratrol and curcumin, are described. Secondly, the potential of probiotics and prebiotics in modulation of immunological response and/or enhancing the chemotherapeutic treatments is reported based on the recent clinical trials. Further, the chapter presents current knowledge regarding the targeted supplementation of the patient with probiotic bacteria and known efficacy of probiotics to support immunotherapy. The major clinical trials are listed, aiming to verify whether, and to which extent the manipulation of patient’s microbiome can improve the outcome of chemotherapies. In the end, a potential of natural substances and feed ingredients to pose epigenetic changes is highlighted. The chapter provides an insight into the scientific proofs about natural bioactive substances in relation to cancer treatment, leaded by the question – do they really work?
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Affiliation(s)
- Adrianna Sobolewska
- Department of Anatomy , Faculty of Medicine, Nicolaus Copernicus University in Torun, Ludwik Rydygier Collegium Medicum in Bydgoszcz , Bydgoszcz , Kujawsko-Pomorskie , Poland
| | - Aleksandra Dunisławska
- Department of Animal Biotechnology and Genetics , Faculty of Animal Breeding and Biology, UTP University of Science and Technology , Bydgoszcz , Kujawsko-Pomorskie , Poland
| | - Katarzyna Stadnicka
- Department of Animal Biotechnology and Genetics , Faculty of Animal Breeding and Biology, UTP University of Science and Technology , Bydgoszcz , Kujawsko-Pomorskie , Poland
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Annaratone L, Cascardi E, Vissio E, Sarotto I, Chmielik E, Sapino A, Berrino E, Marchiò C. The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas. Pathobiology 2020; 87:125-142. [PMID: 32325459 PMCID: PMC7265767 DOI: 10.1159/000507055] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/09/2020] [Indexed: 12/17/2022] Open
Abstract
Heterogeneity in breast carcinomas can be appreciated at various levels, from morphology to molecular alterations, and there are well-known genotypic-phenotypic correlations. Clinical decision-making is strictly focused on the evaluation of tumor cells and is based on the assessment of hormone receptors and of the HER2 status, by means of a combination of immunohistochemical and in situ hybridization techniques. The tumor microenvironment (TME) also shows a multifaceted nature stemming from the different actors populating the intratumoral and the peritumoral stroma of breast carcinomas. Of note, we have now evidence that tumor-infiltrating lymphocytes (TILs) are clinically meaningful as their quantification in the intratumoral stroma strongly correlates with good prognosis, in particular in triple-negative and HER2-positive breast cancer patients. Nevertheless, TILs are just one of the many actors orchestrating the complexity of the TME, which is populated by immune and non-immune cells (cancer-associated fibroblasts, cancer-associated adipocytes), as well as non-cellular components such as chemical inflammation mediators. In this review article we will overview the main features of the distinct cell compartments by discussing (i) the potential impact the TME may have on the prognostic stratification of breast cancers and (ii) the possible predictive value of some markers in the context of immunotherapy in light of the recent results of phase III studies in advanced and early triple-negative breast cancer patients.
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Affiliation(s)
- Laura Annaratone
- Unit of Pathology, Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Eliano Cascardi
- Unit of Pathology, Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Elena Vissio
- Unit of Pathology, Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Ivana Sarotto
- Unit of Pathology, Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy
| | - Ewa Chmielik
- Tumor Pathology Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Anna Sapino
- Unit of Pathology, Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Enrico Berrino
- Unit of Pathology, Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Caterina Marchiò
- Unit of Pathology, Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy,
- Department of Medical Sciences, University of Turin, Turin, Italy,
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13
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Li J, Liu L, Feng Z, Wang X, Huang Y, Dai H, Zhang L, Song F, Wang D, Zhang P, Ma B, Li H, Zheng H, Song F, Chen K. Tumor markers CA15-3, CA125, CEA and breast cancer survival by molecular subtype: a cohort study. Breast Cancer 2020; 27:621-630. [PMID: 32040723 DOI: 10.1007/s12282-020-01058-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 01/25/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND The burden of breast cancer has grown rapidly in China during recent decades. However, the association between tumor markers (CA15-3, CA125, and CEA) and breast cancer survival among certain molecular subtypes is unclear; we described this association in a large, population-based study. METHODS We conducted a cohort study including 10,836 women according to the Tianjin Breast Cancer Cases Cohort. Demographic and epidemiologic data were collected by a structured face-to-face questionnaire. Clinico-pathological parameters were abstracted from medical records, and follow-up information was obtained once a year by telephone. The primary endpoints were breast cancer-specific survival (BCSS) and disease-free survival (DFS). We utilized the Cox proportional hazard model to calculate hazard ratios (HRs) and 95% confidence intervals (CI). RESULTS Among all patients, elevated CA15-3 and CEA exhibited consistently and statistically significant reduced BCSS compared with normal ones (CA15-3: HR 1.54, 95% CI 1.01-2.34; CEA: HR 2.45, 95% CI 1.40-4.30). Similar patterns of association were observed for DFS (CA15-3: HR 2.09, 95% CI 1.44-3.02; CEA: HR 2.71, 95% CI 1.71-4.27). Moreover, in luminal A subtype, high CA15-3 and CEA levels were associated with decreased BCSS (CA15-3: HR 4.47, 95% CI 2.04-9.81; CEA: HR 3.79, 95% CI 1.68-8.55) and DFS (CA15-3: HR 4.06, 95% CI 2.29-7.18, CEA: HR 3.41, 95% CI 1.75-6.64). In basal-like subtype, elevated CEA conferred reduction for BCSS (HR 5.13, 95% CI 1.65-15.9). However, no association was observed between CA125 and breast cancer outcome. CONCLUSIONS Preoperative CA15-3 and CEA levels differ in breast cancer molecular subtypes and yield strong prognostic information in Chinese women with breast cancer. Measuring CA15-3 and CEA levels before surgery may have the potential in predicting breast cancer survival and offering patients' personalized treatment strategy among luminal A and basal-like subtypes.
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Affiliation(s)
- Junxian Li
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Luyang Liu
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Ziwei Feng
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Xin Wang
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Yubei Huang
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Hongji Dai
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Liwen Zhang
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Fangfang Song
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Dezheng Wang
- Tianjin Centers for Disease Control and Prevention, Tianjin, 300011, People's Republic of China
| | - Pengyu Zhang
- Department of Clinical Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, People's Republic of China
| | - Baoshan Ma
- College of Information Science and Technology, Liaoning Province, Dalian Maritime University, Dalian, 116026, People's Republic of China
| | - Haixin Li
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China.,Department of Cancer Biobank, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, People's Republic of China
| | - Hong Zheng
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China
| | - Fengju Song
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China.
| | - Kexin Chen
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, People's Republic of China.
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14
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Albalawi IA, Mir R, Abu Duhier FM. Genetic Effects of Vascular Endothelial Growth Factor A (VEGF-A) and Its Association with Disease Progression in Breast Cancer Population of Saudi Arabia. Asian Pac J Cancer Prev 2020; 21:139-145. [PMID: 31983176 PMCID: PMC7294010 DOI: 10.31557/apjcp.2020.21.1.139] [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: 09/03/2019] [Indexed: 12/12/2022] Open
Abstract
Aim: Previous studies have shown that vascular endothelial growth factor (VEGFA) gene variants were associated with breast cancer risk. The goal of the current study was to evaluate the genetic effects of the vascular endothelial growth factor (VEGF) on the risk of breast cancer and its association with disease progression. Methodology: This case control study was conducted on 110 Breast cancer cases and 110 gender matched healthy controls. Vascular endothelial growth factor A (VEGF-A) 1 (-460T>C) genotyping was performed using Amplification refractory mutation system PCR method. The vascular endothelial growth factor A (VEGF-A) (-460T>C) genotypes were collated with different clinicopathological features of breast cancer patients. Results: A significant difference was observed between the genotype distribution of VEGF-A (-460T>C) among breast cancer cases and gender matched healthy controls (p=0.006). The frequencies of all three genotypes CC,CT,TT reported in the breast cancer patients and sex matched healthy controls were 4.54%, 46.36% ,49.20% and 7.27%, 64.54%, 28.18% respectively. The increased susceptibility to breast cancer disease was found to be associated with VEGF (-460T>C) CC vs TT variant in codominant inheritance model OR 2.78 (0.83-9.26) RR 1.68(1.01 to 2.81) P=0.04. A significant association was reported with VEGF (-460T>C) (CC+CT vs. TT) variant in recessive inheritance model, (OR=2.45 (95% CI= (1.40-4.29), P=0.003. Our findings indicated that VEGF (-460T>C) TT genotype is associated with an increased susceptibility to breast cancer disease. Our result indicates a potential dominant effect of VEGF (-460T>C) TT genotype on susceptibility to the breast cancer disease. Conclusion: VEGF (-460T>C) TT genotype significantly increased the risk of breast cancer. VEGF-A (-460T>C) genetic ariability was significantly associated with distant metastasis of the disease. It may be a useful as predisposing genetic marker for breast cancer .Further studies with larger sample sizes are necessary to confirm our findings.
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Affiliation(s)
| | - Rashid Mir
- Prince Fahd Bin Sultan Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Kingdom of Saudi Arabia
| | - F M Abu Duhier
- Prince Fahd Bin Sultan Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Kingdom of Saudi Arabia
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15
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Woolf DK, Li SP, Detre S, Liu A, Gogbashian A, Simcock IC, Stirling J, Kosmin M, Cook GJ, Siddique M, Dowsett M, Makris A, Goh V. Assessment of the Spatial Heterogeneity of Breast Cancers: Associations Between Computed Tomography and Immunohistochemistry. BIOMARKERS IN CANCER 2019; 11:1179299X19851513. [PMID: 31210736 PMCID: PMC6552350 DOI: 10.1177/1179299x19851513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/23/2019] [Indexed: 11/17/2022]
Abstract
BACKGROUND Tumour heterogeneity is considered an important mechanism of treatment failure. Imaging-based assessment of tumour heterogeneity is showing promise but the relationship between these mathematically derived measures and accepted 'gold standards' of tumour biology such as immunohistochemical measures is not established. METHODS A total of 20 women with primary breast cancer underwent a research dynamic contrast-enhanced computed tomography prior to treatment with data being available for 15 of these. Texture analysis was performed of the primary tumours to extract 13 locoregional and global parameters. Immunohistochemical analysis associations were assessed by the Spearman rank correlation. RESULTS Hypoxia-inducible factor-1α was correlated with first-order kurtosis (r = -0.533, P = .041) and higher order neighbourhood grey-tone difference matrix coarseness (r = 0.54, P = .038). Vascular maturity-related smooth muscle actin was correlated with higher order grey-level run-length long-run emphasis (r = -0.52, P = .047), fractal dimension (r = 0.613, P = .015), and lacunarity (r = -0.634, P = .011). Micro-vessel density, reflecting angiogenesis, was also associated with lacunarity (r = 0.547, P = .035). CONCLUSIONS The associations suggest a biological basis for these image-based heterogeneity features and support the use of imaging, already part of standard care, for assessing intratumoural heterogeneity.
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Affiliation(s)
- David K Woolf
- Breast Cancer Research Unit, Mount Vernon Cancer Centre, Northwood, UK
- Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Sonia P Li
- Breast Cancer Research Unit, Mount Vernon Cancer Centre, Northwood, UK
| | - Simone Detre
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK
| | - Alison Liu
- Division of Imaging Sciences, King’s College London, St Thomas’ Hospital, London, UK
| | - Andrew Gogbashian
- Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, UK
| | - Ian C Simcock
- Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, UK
| | - James Stirling
- Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, UK
| | - Michael Kosmin
- Breast Cancer Research Unit, Mount Vernon Cancer Centre, Northwood, UK
| | - Gary J Cook
- Division of Imaging Sciences, King’s College London, St Thomas’ Hospital, London, UK
| | - Muhammad Siddique
- Division of Imaging Sciences, King’s College London, St Thomas’ Hospital, London, UK
| | - Mitch Dowsett
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK
| | - Andreas Makris
- Breast Cancer Research Unit, Mount Vernon Cancer Centre, Northwood, UK
| | - Vicky Goh
- Division of Imaging Sciences, King’s College London, St Thomas’ Hospital, London, UK
- Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, UK
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16
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Kiso M, Tanaka S, Saji S, Toi M, Sato F. Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network. Int J Cancer 2018; 143:2905-2918. [PMID: 29971782 PMCID: PMC6282968 DOI: 10.1002/ijc.31645] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 05/15/2018] [Accepted: 05/24/2018] [Indexed: 01/04/2023]
Abstract
VEGF stimulates endothelial cells as a key molecule in angiogenesis. VEGF also works as a multifunction molecule, which targets a variety of cell members in the tumor microenvironment. We aimed to reveal VEGF-related molecular mechanisms on breast cancer cells. VEGF-knocked-out MDA-MB-231 cells (231 VEGFKOex3 ) showed rounded morphology and shorter perimeter (1.6-fold, p < 0.0001). The 231 VEGFKOex3 cells also showed impaired cell migration (2.6-fold, p = 0.002). Bevacizumab treatment did not induce any change in morphology and mobility. Soluble neuropilin-1 overexpressing MDA-MB-231 cells (231 sNRP1 ) exhibited rounded morphology and shorter perimeter (1.3-fold, p < 0.0001). The 231 sNRP1 cells also showed impaired cell migration (1.7-fold, p = 0.003). These changes were similar to that of 231 VEGFKOex3 cells. As MDA-MB-231 cells express almost no VEGFR, these results indicate that the interaction between NRP1 and long isoform of VEGF containing a NRP-binding domain regulates the morphology and migration ability of MDA-MB-231 cells. Genome-wide gene expression profiling identified ARHGAP17 as one of the target genes in the downstream of the VEGF/NRP1 signal. We also show that VEGF/NRP1 signal controls filopodia formation of the cells by modulating Cdc42 activity via ARHGAP17. Among 1,980 breast cancer cases from a public database, the ratio of VEGF and SEMA3A in primary tumors (n = 450) of hormone-receptor-negative breast cancer is associated with ARHGAP17 expression inversely, and with disease free survival. Altogether, the bevacizumab-independent VEGF/NRP1/ARHGAP17/Cdc42 regulatory network plays important roles in malignant behavior of breast cancer.
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Affiliation(s)
- Marina Kiso
- Department of Breast SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
| | - Sunao Tanaka
- Department of Breast SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
| | - Shigehira Saji
- Department of Medical OncologyFukushima Medical UniversityFukushimaJapan
| | - Masakazu Toi
- Department of Breast SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
| | - Fumiaki Sato
- Department of Breast SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
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Yamazaki H, Yokose T, Hayashi H, Iwasaki H, Osanai S, Suganuma N, Nakayama H, Masudo K, Rino Y, Masuda M. Expression of vascular endothelial growth factor receptor 2 and clinical response to lenvatinib in patients with anaplastic thyroid cancer. Cancer Chemother Pharmacol 2018; 82:649-654. [PMID: 30051190 DOI: 10.1007/s00280-018-3657-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 07/23/2018] [Indexed: 01/02/2023]
Abstract
PURPOSE Angiogenesis plays a crucial role in the development, growth, and metastasis of carcinomas, and studies have reported conflicting evidence regarding the VEGFR expression in anaplastic thyroid cancer. We investigated the expression of VEGFR2 in patients with anaplastic thyroid cancer (ATC) and analyzed the clinical response to the VEGFR inhibitor lenvatinib. METHODS This cross-sectional study included primary tumor samples obtained from 12 patients with ATC, including 5 males and 7 females (age range 63-89 years) who underwent surgery or core needle biopsy for a thyroid tumor in the Department of Breast and Endocrine Surgery at Kanagawa Cancer Center in Kanagawa, Japan. VEGFR2 protein expression in the ATC samples was analyzed by immunohistochemistry in all patients, and the therapeutic effect of lenvatinib was evaluated in seven patients who underwent tissue biopsy and lesion evaluation. RESULTS VEGFR expression was not detected in any of the samples from the 12 patients. Four of the 12 patients treated with lenvatinib had partial response, the three patients achieved stable disease, and the five patients were not examined. CONCLUSIONS There was no correlation between the expression of VEGFR2 in tumor tissue and the clinical response to lenvatinib among patients with ATC. Further studies are necessary to elucidate the mechanism underlying the response to lenvatinib.
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Affiliation(s)
- Haruhiko Yamazaki
- Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahiku, Yokohama City, Kanagawa, Japan.
| | - Tomoyuki Yokose
- Department of Pathology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahiku, Yokohama City, Kanagawa, Japan
| | - Hiroyuki Hayashi
- Department of Pathology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahiku, Yokohama City, Kanagawa, Japan
| | - Hiroyuki Iwasaki
- Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahiku, Yokohama City, Kanagawa, Japan
| | - Sachie Osanai
- Department of Pathology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahiku, Yokohama City, Kanagawa, Japan
| | - Nobuyasu Suganuma
- Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahiku, Yokohama City, Kanagawa, Japan
| | - Hirotaka Nakayama
- Department of Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama City, Kanagawa, Japan
| | - Katsuhiko Masudo
- Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, 4-57 Urafunecho, Minamiku, Yokohama City, Kanagawa, Japan
| | - Yasushi Rino
- Department of Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama City, Kanagawa, Japan
| | - Munetaka Masuda
- Department of Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama City, Kanagawa, Japan
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Saahene RO, Wang J, Wang ML, Agbo E, Pang D. The Antitumor Mechanism of Paeonol on CXCL4/CXCR3-B Signals in Breast Cancer Through Induction of Tumor Cell Apoptosis. Cancer Biother Radiopharm 2018; 33:233-240. [PMID: 29847158 DOI: 10.1089/cbr.2018.2450] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Paeonol, a phenolic component from the root bark of Paeonia moutan, has been identified to possess antitumor effects. However, the effect of paeonol and the mechanism of CXCL4/CXCR3-B signals in paeonol-induced breast cancer cell remain unknown. MATERIALS AND METHODS After MDA-MB-231 cells were pretreated with paeonol or DMSO, the proliferation activity was detected by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), Hoechst, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and Annexin-V/propidium iodide staining flow cytometry. Western blot and immunohistochemistry of human breast cancer and noncancerous tissues were performed to determine the molecular alteration of CXCL4/CXCR3-B signals. RESULTS Compared with the control, paeonol-treated breast cancer cells had low proliferation activity and high apoptotic index, indicating that paeonol induces breast cancer cell apoptosis. Western blot and immunohistochemistry showed that paeonol increased CXCR3-B signal, downregulated CXCL4, heme oxygenase (HO-1) with a corresponding increased BACH1, and decreased nuclear factor E2-related factor 2 (Nrf2). CONCLUSIONS Thus, CXCL4/CXCR3-B may be involved in the mechanism of apoptosis induced by paeonol in breast cancer cells by regulating the expression of BACH1 and Nrf2 to downregulating HO-1 and promote apoptosis. Therefore, the authors suggest paeonol has a significant growth inhibitory effect on breast cancer cells, which may be related to the induction of apoptosis.
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Affiliation(s)
- Roland O Saahene
- 1 Department of Immunology, College of Basic Medicine, Jiamusi University , People's Republic of China
| | - Jianjie Wang
- 1 Department of Immunology, College of Basic Medicine, Jiamusi University , People's Republic of China
| | - Mo-Lin Wang
- 1 Department of Immunology, College of Basic Medicine, Jiamusi University , People's Republic of China
| | - Elvis Agbo
- 2 Department of Anatomy, Jiamusi University , People's Republic of China
| | - Dezhi Pang
- 1 Department of Immunology, College of Basic Medicine, Jiamusi University , People's Republic of China
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Malone C, Kerin MJ. Angiogenesis-Related Markers and their Potential Clinical Significance. Int J Biol Markers 2018; 14:3-7. [PMID: 10367243 DOI: 10.1177/172460089901400102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- C Malone
- Academic Surgical Unit, Castle Hill Hospital, University of Hull, U.K
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Abstract
Background Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on endothelial cells as a result of vascular endothelial growth factor (VEGF) stimulation. Purpose To determine if measurement in serum of VEGF or VCAM-1 provides an accurate measure of tumor angiogenesis. Methods VCAM-1 and VEGF were measured in the serum of women with early and advanced breast cancer by ELISA. Levels were compared to levels of VCAM-1 and VEGF in women with normal breasts and levels of the endothelial glycoprotein von Willebrand factor. Levels of VEGF and VCAM-1 in women with early breast cancer were correlated with established clinicopathological prognostic markers and intratumoral microvessel density (IMD). Results In early breast cancer serum VCAM-1 correlated closely with the microvessel density in tumors (r=0.61, p<0.001). Women with lymph node-positive and high-grade tumors had higher levels of serum VCAM-1 than women with lymph node-negative and low-grade tumors. Serum VEGF demonstrated no correlation with established prognostic features or IMD. Levels of VCAM-1 and VEGF were raised in women with advanced breast cancer. Conclusion Serum VCAM-1 is a surrogate marker of angiogenesis in breast cancer and its measurement may help in the assessment of antiangiogenic drugs currently in phase II trials.
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Affiliation(s)
- G J Byrne
- Department of Surgery, University Hospital of South Manchester, UK
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21
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Nicolini A, Campani D, Miccoli P, Spinelli C, Carpi A, Menicagli M, Ferrari P, Gadducci G, Rossi G, Fini M, Giavaresi G, Bonazzi V, Giardino R. Vascular Endothelial Growth Factor (Vegf) and Other Common Tissue Prognostic Indicators in Breast Cancer: A Case-Control Study. Int J Biol Markers 2018; 19:275-81. [PMID: 15646833 DOI: 10.1177/172460080401900404] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
VEGF is a specific mitogen and survival factor for endothelial cells and a key promoter of angiogenesis in physiological and pathological conditions. Nevertheless, VEGF tissue evaluation in cancer patients as a prognostic factor compared to the conventional histological and biological parameters is still controversial. In this case-control study, tissue VEGF was retrospectively determined by immunohistochemistry and related to T, N, ER, PgR, c-erbB-2, p53, MIB-1 and cyclin D1 in 129 breast cancer patients. Seventy-four of these patients had developed distant metastases postoperatively. The remaining 55 patients had remained disease-free >10 years after surgery. In 17 (13%) of the 129 patients (six with distant metastases and eleven disease-free) tissue and plasma VEGF were concomitantly evaluated. In univariate analysis no significant differences in VEGF and tumor size were found between metastatic and disease-free patients, whereas there were significant differences in N, ER, PgR, c-erbB-2, p53, MIB-1 and cyclin D1 (p ranging from 0.001 to 0.0001). In multivariate analysis VEGF showed less significance than N, ER, c-erbB-2, MIB-1 and cyclin D1 (p=0.012, p=0.007, p=0.005, p=0.005, p=0.002 and p=0.001, respectively). VEGF was a significant unfavorable prognostic indicator only in the N+ subset (p=0.015), while ER (p=0.05 and p=0.021) and MIB-1 (p=0.031 and p=0.022) were significant in both the N+ and N– subgroups. In multivariate analysis in the 74 metastatic cases VEGF did not show any significance in relation to disease-free interval and overall survival from the time of mastectomy and from the time of relapse, whereas N and PgR did (p ranging from 0.018 to 0.001). In conclusion, tissue VEGF does not seem a suitable candidate to replace conventional histological and other common biological prognostic factors in breast cancer.
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Affiliation(s)
- A Nicolini
- Department of Internal Medicine, University of Pisa, Italy.
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22
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Meo S, Dittadi R, Peloso L, Gion M. The Prognostic Value of Vascular Endothelial Growth Factor, Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Node-Negative Breast Cancer. Int J Biol Markers 2018; 19:282-8. [PMID: 15646834 DOI: 10.1177/172460080401900405] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The vascular endothelial growth factor (VEGF) and the plasminogen activator system play an essential role in solid tumor angiogenesis and in tumor invasion and metastasis. In the present study we investigated the relationship between patient outcome and levels of VEGF, urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor cytosols of 196 node-negative primary invasive breast cancer patients who did not receive any adjuvant therapy. The median follow-up was 65 months. VEGF, uPA and PAI-1 were measured by commercially available enzyme-linked immunosorbent assays. Cox's univariate analysis showed that pT (p=0.0007), uPA (p=0.0156) and PAI-1 (p=0.0015) had a significant impact on relapse-free survival, whereas VEGF did not have any prognostic value (p=0.18). Bivariate analysis showed significant interactions between uPA and PAI-1 (p=0.0035) and between VEGF and PAI-1 (p=0.006). Our study confirms that uPA and PAI-1 cytosol levels can be considered as prognostic factors for relapse-free survival in node-negative breast cancer. Moreover, the interaction between VEGF and PAI-1 warrants further investigation into the relationship between the biomarkers of angiogenesis and those of the protease cascade.
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Affiliation(s)
- S Meo
- ABO Association, c/o Regional Center for the Study of Biological Markers of Malignancy, General Regional Hospital, ULSS 12, Venice, Italy
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23
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Hoar FJ, Lip GYH, Belgore F, Stonelake PS. Circulating Levels of Vegf-A, VEGF-D and soluble VEGF-A Receptor (sFlt-1) in Human Breast Cancer. Int J Biol Markers 2018; 19:229-35. [PMID: 15503825 DOI: 10.1177/172460080401900308] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
As circulating levels of vascular endothelial growth factor (VEGF-A) are raised in malignancy, the aim of this study was to investigate whether similar changes occur in two related factors, VEGF-D and the soluble VEGF-A receptor Flt-1 (sFlt-1). Circulating levels of VEGF-A, VEGF-D and sFlt-1 were determined by ELISA in 51 patients with primary breast cancer and matched healthy controls. Results were correlated with clinicopathological data. Whilst there was a difference in VEGF-A levels between patient and control groups (p=0.03), no such difference was observed for sFlt-1 or VEGF-D levels and there was no association between individual factors and the clinicopathological variables examined. However, there was a positive correlation between VEGF-A and sFlt-1 levels in both patient and control groups (p<0.0001). In addition, the ratio of sFlt-1 to VEGF-A was significantly different between patients and controls (p<0.0001) and was also associated with tumour size (p=0.01) within the patient group. During tumour progression there is a change in the relative amounts of sFlt-1 and VEGF-A in the circulation. Measuring the sFlt-1:VEGF-A ratio may have more significance than VEGF-A alone and further studies are needed to determine whether the ratio is of use as a prognostic marker or as a means of monitoring response to anti-angiogenic therapy in cancer.
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Affiliation(s)
- F J Hoar
- Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham--U.K
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24
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Chen D, Zhang Y, Shi F, Zhu H, Li M, Luo J, Chen K, Kong L, Yu J. Intrapericardial bevacizumab safely and effectively treats malignant pericardial effusion in advanced cancer patients. Oncotarget 2018; 7:52436-52441. [PMID: 27203219 PMCID: PMC5239564 DOI: 10.18632/oncotarget.9420] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 05/09/2016] [Indexed: 12/19/2022] Open
Abstract
We evaluated the safety and efficacy of intrapericardial bevacizumab (BEV) for treating symptomatic malignant pericardiac effusion (MPCE) in seven advanced cancer patients. All patients had previously undergone multiple lines of systemic therapy. Each patient received paracentesis and intrapericardial infusions of 100 or 200 mg of BEV every two weeks. Systemic treatments for primary tumors continued for all patients during BEV treatment. Of the seven patients, three achieved a complete response, two achieved a partial response, and two showed no response with regard to MPCE after BEV infusion. The median overall survival time was 168 days (range, 22-224 days). In six of the seven patients, effusion did not recur before death. Toxicity associated with BEV treatment was mild and manageable in all patients. This study provides preliminary evidence that intrapericardial BEV may be an effective and safe treatment for MPCE in patients with advanced cancers.
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Affiliation(s)
- Dawei Chen
- Weifang Medical University, Weifang, China.,Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
| | - Yan Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.,Shandong Academy of Medical Sciences, Jinan, China
| | - Fang Shi
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.,Shandong Academy of Medical Sciences, Jinan, China
| | - Hui Zhu
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.,Shandong Academy of Medical Sciences, Jinan, China
| | - Minghuan Li
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.,Shandong Academy of Medical Sciences, Jinan, China
| | - Judong Luo
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.,Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, China
| | - Kaijun Chen
- Department of Clinical Laboratory, Mengyin People's Hospital, Linyi, China
| | - Li Kong
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.,Shandong Academy of Medical Sciences, Jinan, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.,Shandong Academy of Medical Sciences, Jinan, China
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Sohn EJ, Jung DB, Lee H, Han I, Lee J, Lee H, Kim SH. CNOT2 promotes proliferation and angiogenesis via VEGF signaling in MDA-MB-231 breast cancer cells. Cancer Lett 2017; 412:88-98. [PMID: 29024811 DOI: 10.1016/j.canlet.2017.09.052] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 09/27/2017] [Accepted: 09/28/2017] [Indexed: 11/24/2022]
Abstract
Here the underlying role of CNOT2, a subunit of CCR4-NOT complex, was elucidated in cancer progression. CNOT2 was overexpressed in HIT-T15, ASPC-1, BXPC-3, PC-3, LNCaP, MCF-7 and MDA-MB-231 cell lines, which was confirmed by Tissue array in various human tumor tissues. Also, CNOT2 depletion suppressed proliferation and colony formation of MDA-MB-231 cells. Of note, microarray revealed decreased expression of CNOT2, VEGF-A, HIF2 alpha (<0.5 fold) and increased expression of UMOD1, LOC727847, MMP4, hCG and other genes (>2.0 fold) in CNOT2 depleted MDA-MB-231 cells compared to untreated control. Consistently, downregulation of VEGF, CNOT2 and HIF2 alpha was verified in CNOT2 depleted MDA-MB-231 cells by RT-qPCR. Additionally, CNOT2 depletion inhibited VEGF induced tube formation in HUVECs and reduced neovascularization in CAM assay. Furthermore, the growth of CNOT2 depleted MDA-MB-231 cells was significantly reduced in Balb/c nude mice along with decreased expression of VEGF and PCNA by immunohistochemistry compared to untreated control group. Overall, our findings provide evidences that CNOT2 promotes proliferation and angiogenesis via VEGF signaling in MDA-MB-231 breast cancer cells as a potent molecular target for breast cancer treatment.
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Affiliation(s)
- Eun Jung Sohn
- Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Deok-Beom Jung
- Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - HyoJung Lee
- Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Ihn Han
- Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Jihyun Lee
- Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Hyemin Lee
- Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Sung-Hoon Kim
- Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
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26
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Vieira-Monteiro HDA, Freitas-Alves DR, Sobral-Leite M, Delou JMDA, Goulart-Citrangulo SMT, do Nascimento CT, E Castro TN, Koifman S, Perini JA, Vianna-Jorge R. Prognostic evaluation of VEGFA genotypes and haplotypes in a cohort of Brazilian women with non metastatic breast cancer. Cancer Biol Ther 2017; 17:674-83. [PMID: 27195611 DOI: 10.1080/15384047.2016.1190486] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Vascular Endothelial Growth Factor (VEGF) mediates angiogenesis, which is crucial for tumor development and progression. The present study aimed to evaluate the impact of VEGFA gene polymorphisms rs699947, rs833061, rs1570360, rs2010963 and rs3025039 on breast cancer features and prognosis. A cohort of Brazilian women (N = 1038) with unilateral non-metastatic breast cancer was evaluated. The association between VEGFA polymorphisms and histopathological features or pathological complete response (pCR) to neoadjuvant chemotherapy was evaluated by the Chi-square test, with calculation of the respective odds ratio (OR) and 95% confidence intervals (95% CI). The impact of individual categories on disease-free survival was evaluated using Kaplan-Meier curves and multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HRadjusted). Variant genotypes of rs699947 (CA + AA) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.82; 95% CI = 1.15 - 2.89), and with shorter disease-free survival among patients treated with neoadjuvant chemotherapy followed by mastectomy (HRadjusted = 1.82; 95% CI = 1.16 - 2.86). Variant genotypes of rs833061 (TC + CC) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.79; 95% CI = 1.12 - 2.84) and with positive lymph node status (OR = 1.34; 95% CI = 1.01 - 1.77), but showed no independent effect on disease-free survival. Variant haplotypes (*2 to *5) appear to favor pCR (OR = 7.1; 95% CI = 1.7 - 30.1). VEGFA genotyping may add to prognostic evaluation of breast cancer, with rs699947 being the most likely to contribute.
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Affiliation(s)
- Hayra de Andrade Vieira-Monteiro
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil
| | - Daniely Regina Freitas-Alves
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil
| | - Marcelo Sobral-Leite
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,c Division of Molecular Pathology, Netherlands Cancer Institute , Amsterdam , The Netherlands
| | - João Marcos de Azevedo Delou
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,d Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro , Rio de Janeiro , RJ , Brasil
| | | | | | - Thales Nascimento E Castro
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil
| | - Sérgio Koifman
- b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil
| | - Jamila Alessandra Perini
- b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil.,e Laboratório de Pesquisa de Ciências Farmacêuticas, Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste , Rio de Janeiro , RJ , Brasil
| | - Rosane Vianna-Jorge
- a Coordenação de Pesquisa, Instituto Nacional do Câncer , Rio de Janeiro , RJ , Brasil.,b Programa de Saúde Pública e Meio Ambiente - Escola Nacional de Saúde Pública - FIOCRUZ , Rio de Janeiro , RJ , Brasil.,d Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro , Rio de Janeiro , RJ , Brasil
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27
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Johnson KE, Forward JA, Tippy MD, Ceglowski JR, El-Husayni S, Kulenthirarajan R, Machlus KR, Mayer EL, Italiano JE, Battinelli EM. Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis. Arterioscler Thromb Vasc Biol 2017; 37:664-674. [PMID: 28153880 DOI: 10.1161/atvbaha.116.308791] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 01/19/2017] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Platelets, which are mainly known for their role in hemostasis, are now known to play a crucial role in metastasis. Tamoxifen is a selective estrogen receptor modulator that is widely used for the treatment of breast cancer. Tamoxifen and its metabolites have been shown to directly impact platelet function, suggesting that this drug has additional mechanisms of action. The purpose of this study was to determine whether tamoxifen exerts antitumor effects through direct platelet inhibition. APPROACH AND RESULTS This study found that pretreatment with tamoxifen leads to a significant inhibition of platelet activation. Platelets exposed to tamoxifen released significantly lower amounts of proangiogenic regulator vascular endothelial growth factor. In vitro angiogenesis assays confirmed that tamoxifen pretreatment led to diminished capillary tube formation and decreased endothelial migration. Tamoxifen and its metabolite, 4-hydroxytamoxifen, also significantly inhibited the ability of platelets to promote metastasis in vitro. Using a membrane-based array, we identified several proteins associated with angiogenesis metastasis that were lower in activated releasate from tamoxifen-treated platelets, including angiogenin, chemokine (C-X-C motif) ligand 1, chemokine (C-C motif) ligand 5, epidermal growth factor, chemokine (C-X-C motif) ligand 5, platelet-derived growth factor dimeric isoform BB, whereas antiangiogenic angiopoietin-1 was elevated. Platelets isolated from patients on tamoxifen maintenance therapy were also found to have decreased activation responses, diminished vascular endothelial growth factor release, and lower angiogenic and metastatic potential. CONCLUSIONS We demonstrate that tamoxifen and its metabolite 4-hydroxytamoxifen directly alter platelet function leading to decreased angiogenic and metastatic potential. Furthermore, this study supports the idea of utilizing targeted platelet therapies to inhibit the platelet's role in angiogenesis and malignancy.
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Affiliation(s)
- Kelly E Johnson
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Jodi A Forward
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Mason D Tippy
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Julia R Ceglowski
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Saleh El-Husayni
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Rajesh Kulenthirarajan
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Kellie R Machlus
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Erica L Mayer
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Joseph E Italiano
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.)
| | - Elisabeth M Battinelli
- From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.E.J., J.A.F., M.D.T., J.R.C., S.E.-H., R.K., K.R.M., J.E.I., E.M.B.); Department of Medicine, Harvard Medical School, Boston, MA (K.E.J., K.R.M., E.L.M., J.E.I., E.M.B.); Vascular Biology Program, Department of Surgery, Children's Hospital Boston, MA (J.E.I.); and Division of Hematology, Dana-Farber Cancer Institute, Boston, MA (E.L.M.).
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28
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Cirincione R, Di Maggio FM, Forte GI, Minafra L, Bravatà V, Castiglia L, Cavalieri V, Borasi G, Russo G, Lio D, Messa C, Gilardi MC, Cammarata FP. High-Intensity Focused Ultrasound- and Radiation Therapy-Induced Immuno-Modulation: Comparison and Potential Opportunities. ULTRASOUND IN MEDICINE & BIOLOGY 2017; 43:398-411. [PMID: 27780661 DOI: 10.1016/j.ultrasmedbio.2016.09.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 09/20/2016] [Accepted: 09/21/2016] [Indexed: 05/12/2023]
Abstract
In recent years, high-intensity focused ultrasound (HIFU) has emerged as a new and promising non-invasive and non-ionizing ablative technique for the treatment of localized solid tumors. Extensive pre-clinical and clinical studies have evidenced that, in addition to direct destruction of the primary tumor, HIFU-thermoablation may elicit long-term systemic host anti-tumor immunity. In particular, an important consequence of HIFU treatment includes the release of tumor-associated antigens (TAAs), the secretion of immuno-suppressing factors by cancer cells and the induction of cytotoxic T lymphocyte (CTL) activity. Radiation therapy (RT) is the main treatment modality used for many types of tumors and about 50% of all cancer patients receive RT, often used in combination with surgery and chemotherapy. It is well known that RT can modulate anti-tumor immune responses, modifying micro-environment and stimulating inflammatory factors that can greatly affect cell invasion, bystander effects, radiation tissue complications (such as fibrosis), genomic instability and thus, intrinsic cellular radio-sensitivity. To date, various combined therapeutic strategies (such as immuno-therapy) have been performed in order to enhance RT success in treating locally advanced and recurrent tumors. Recent works suggested the combined use of HIFU and RT treatments to increase the tumor cell radio-sensitivity, in order to synergize the effects reaching the maximum results with minimal doses of ionizing radiation (IR). Here, we highlight the opposite immuno-modulation roles of RT and HIFU, providing scientific reasons to test, by experimental approaches, the use of HIFU immune-stimulatory capacity to improve tumor radio-sensitivity, to reduce the RT induced inflammatory response and to decrease the dose-correlated side effects in normal tissues.
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Affiliation(s)
| | - Federica Maria Di Maggio
- IBFM CNR, Cefalù, Palermo, Italy; Department of Pathobiology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | | | | | - Valentina Bravatà
- IBFM CNR, Cefalù, Palermo, Italy; Department of Pathobiology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | | | - Vincenzo Cavalieri
- Laboratory of Molecular Biology and Functional Genomics, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy
| | | | | | - Domenico Lio
- Department of Pathobiology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | - Cristina Messa
- IBFM CNR, Cefalù, Palermo, Italy; Department of Health Sciences, Tecnomed Foundation, University of Milano-Bicocca, Milan, Italy; Nuclear Medicine Center, San Gerardo Hospital, Monza, Italy
| | - Maria Carla Gilardi
- IBFM CNR, Cefalù, Palermo, Italy; Department of Health Sciences, Tecnomed Foundation, University of Milano-Bicocca, Milan, Italy; Nuclear Medicine, San Raffaele Scientific Institute, Milan, Italy
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29
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Hrgovic I, Doll M, Pinter A, Kaufmann R, Kippenberger S, Meissner M. Histone deacetylase inhibitors interfere with angiogenesis by decreasing endothelial VEGFR-2 protein half-life in part via a VE-cadherin-dependent mechanism. Exp Dermatol 2017; 26:194-201. [DOI: 10.1111/exd.13159] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2016] [Indexed: 12/30/2022]
Affiliation(s)
- Igor Hrgovic
- Department of Dermatology, Venereology and Allergology; Johann Wolfgang Goethe-University; Frankfurt/Main Germany
| | - Monika Doll
- Department of Dermatology, Venereology and Allergology; Johann Wolfgang Goethe-University; Frankfurt/Main Germany
| | - Andreas Pinter
- Department of Dermatology, Venereology and Allergology; Johann Wolfgang Goethe-University; Frankfurt/Main Germany
| | - Roland Kaufmann
- Department of Dermatology, Venereology and Allergology; Johann Wolfgang Goethe-University; Frankfurt/Main Germany
| | - Stefan Kippenberger
- Department of Dermatology, Venereology and Allergology; Johann Wolfgang Goethe-University; Frankfurt/Main Germany
| | - Markus Meissner
- Department of Dermatology, Venereology and Allergology; Johann Wolfgang Goethe-University; Frankfurt/Main Germany
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30
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Zhang Y, Liu J, Lin J, Zhou L, Song Y, Wei B, Luo X, Chen Z, Chen Y, Xiong J, Xu X, Ding L, Ye Q. The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer. Oncotarget 2016; 7:9859-75. [PMID: 26848522 PMCID: PMC4891089 DOI: 10.18632/oncotarget.7126] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 01/18/2016] [Indexed: 01/26/2023] Open
Abstract
Angiogenesis is essential for tumor growth. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis. However, how transcription factors interact with histone-modifying enzymes to regulate VEGF transcription and tumor angiogenesis remains unclear. Here, we show that transcription factor GATA1 associates with the histone methyltransferase SET7 to promote VEGF transcription and breast tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that GATA1 was required for recruitment of SET7, RNA polymerase II and transcription factor II B to VEGF core promoter. GATA1 enhanced breast cancer cell (MCF7, ZR75-1 and MDA-MB-231)-secreted VEGF via SET7, which promoted vascular endothelial cell (HUVEC) proliferation, migration and tube formation. SET7 was required for GATA1-induced breast tumor angiogenesis and growth in nude mice. Immunohistochemical staining showed that expression of GATA1 and SET7 was upregulated and positively correlated with VEGF expression and microvessel number in 80 breast cancer patients. GATA1 and SET7 are independent poor prognostic factors in breast cancer. Our data provide novel insights into VEGF transcriptional regulation and suggest GATA1/SET7 as cancer therapeutic targets.
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Affiliation(s)
- Yanan Zhang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, People's Republic of China
| | - Jie Liu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China
| | - Jing Lin
- First Affiliated Hospital, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Lei Zhou
- Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yuhua Song
- The Affiliated Hospital of Qing Dao University, Qingdao, People's Republic of China
| | - Bo Wei
- Department of General Surgery, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Xiaoli Luo
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China
| | - Zhida Chen
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,Department of General Surgery, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Yingjie Chen
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,The Affiliated Hospital of Qing Dao University, Qingdao, People's Republic of China
| | - Jiaxiu Xiong
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,Department of General Surgery, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Xiaojie Xu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China
| | - Lihua Ding
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, People's Republic of China
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31
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Lee JH, Shin HJ, Yoon JH, Kim EK, Moon HJ, Lee HS, Kwon HJ, Kwak JY. Predicting lymph node metastasis in patients with papillary thyroid carcinoma by vascular index on power Doppler ultrasound. Head Neck 2016; 39:334-340. [PMID: 27704649 DOI: 10.1002/hed.24592] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND For patients with papillary thyroid carcinoma (PTC), lymph node metastasis is associated with an increased recurrence rate. The purpose of this study was to investigate whether the vascular endothelial growth factor (VEGF), microvessel density (MVD), and vascular index (VI) can predict lymph node metastasis in patients with PTC. METHODS From January 2011 to October 2011, 202 patients with PTCs underwent preoperative staging ultrasound evaluation. To evaluate vascularity, we measured the VI, VEGF expression, and MVD. RESULTS The VI was significantly correlated with MVD (p = .009). On multivariate analysis, young age showed a significant correlation with lymph node metastasis (p < .001; p < .001; p < .001). However, the other clinicopathologic features, VEGF, MVD, and VI failed to show any significant correlations with lymph node metastasis. CONCLUSION Although the VI showed significant correlation with MVD, it was not significantly correlated to lymph node metastasis. © 2016 Wiley Periodicals, Inc. Head Neck 39: 334-340, 2017.
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Affiliation(s)
- Ji Hye Lee
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Hyun Joo Shin
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Jung Hyun Yoon
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Eun-Kyung Kim
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Hee Jung Moon
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Hye Sun Lee
- Biostastistics Collaboration Unit, Medical Research Center, Yonsei University, College of Medicine, Seoul, Korea
| | - Hyeong Ju Kwon
- Department of Pathology, Yonsei University, College of Medicine, Seoul, Korea.,Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Korea
| | - Jin Young Kwak
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
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Ribatti D, Nico B, Ruggieri S, Tamma R, Simone G, Mangia A. Angiogenesis and Antiangiogenesis in Triple-Negative Breast cancer. Transl Oncol 2016; 9:453-457. [PMID: 27751350 PMCID: PMC5067931 DOI: 10.1016/j.tranon.2016.07.002] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 07/07/2016] [Accepted: 07/11/2016] [Indexed: 01/20/2023] Open
Abstract
Several data support a central role for angiogenesis in breast cancer growth and metastasis. Observational studies have demonstrated that microvascular density (MVD) is a prognostic factor in invasive breast cancer, whereas others reached the opposite conclusion. Vascular endothelial growth factor is the most important angiogenic factor with proven significance in breast cancer, as it has been assessed in both experimental and clinical studies. Triple-negative breast cancer (TNBC) is a type of breast cancer which lacks estrogen, progesterone, and HER-2/neu receptors. MVD in both basal-like and TNBC is significantly higher than in non–basal-like and non-TNBC. In breast cancer and other malignancies, the development of agents that inhibit tumor angiogenesis has been an active area of investigation. In TNBC, clinical trials combining targeted agents and chemotherapy have failed to show substantial survival improvement. There is evidence that patients with TNBC may have a greater probability of obtaining some kind of clinical efficacy benefit from bevacizumab-based therapy.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy; IRCCS Istituto Tumori "Giovanni Paolo II," Bari, Italy.
| | - Beatrice Nico
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Simona Ruggieri
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Giovanni Simone
- Pathology Department, IRCCS Istituto Tumori "Giovanni Paolo II," Bari, Italy
| | - Anita Mangia
- Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II," Bari, Italy
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33
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Su JC, Mar AC, Wu SH, Tai WT, Chu PY, Wu CY, Tseng LM, Lee TC, Chen KF, Liu CY, Chiu HC, Shiau CW. Disrupting VEGF-A paracrine and autocrine loops by targeting SHP-1 suppresses triple negative breast cancer metastasis. Sci Rep 2016; 6:28888. [PMID: 27364975 PMCID: PMC4929457 DOI: 10.1038/srep28888] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 06/09/2016] [Indexed: 12/31/2022] Open
Abstract
Patients with triple-negative breast cancer (TNBC) had an increased likelihood of distant recurrence and death, as compared with those with non-TNBC subtype. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting oncogenesis and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recent studies suggest regorafenib acts as a SHP-1 phosphatase agonist. Here, we investigated the potential of regorafenib to suppress metastasis of TNBC cells through targeting SHP-1/p-STAT3/VEGF-A axis. We found a significant correlation between cancer cell migration and SHP-1/p-STAT3/VEGF-A expression in human TNBC cells. Clinically, high VEGF-A expression is associated with worse disease-free and distant metastasis-free survival. Regorafenib induced significant anti-migratory effects, in association with downregulation of p-STAT3 and VEGF-A. To exclude the role of RTK inhibition in regorafenib-induced anti-metastasis, we synthesized a regorafenib derivative, SC-78, that had minimal effect on VEGFR2 and PDGFR kinase inhibition, while having more potent effects on SHP-1 activation. SC-78 demonstrated superior in vitro and in vivo anti-migration to regorafenib. Furthermore, VEGF-A dependent autocrine/paracrine loops were disrupted by regorafenib and SC-78. This study implies that SHP-1/p-STAT3/VEGF-A axis is a potential therapeutic target for metastatic TNBC, and the more potent SC-78 may be a promising lead for suppressing metastasis of TNBC.
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Affiliation(s)
- Jung-Chen Su
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.,Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Ai-Chung Mar
- Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11529, Taiwan
| | - Szu-Hsien Wu
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Tien Tai
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.,National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Yi Chu
- School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.,Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan
| | - Chia-Yun Wu
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ling-Ming Tseng
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Te-Chang Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
| | - Kuen-Feng Chen
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.,National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Yu Liu
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hao-Chieh Chiu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Chung-Wai Shiau
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
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Abstract
Tumor neovascularization acquires their vessels through a number of processes including angiogenesis, vasculogenesis, vascular remodeling, intussusception, and possibly vascular mimicry in certain tumors. The end result of the tumor vasculature has been quantified by counting the number of immunohistochemically identified microvessels in areas of maximal vascularity, so-called hot spot. Other techniques have been developed such as Chalkley counting and the use of image analysis systems that are robust and reproducible as well as being more objective. Many of the molecular pathways that govern tumor neovascularization have been identified and many reagents are now available to study these tissue sections. These include angiogenic growth factors and their receptors and cell adhesion molecules, proteases, and markers of activated, proliferating, cytokine-stimulated, or angiogenic vessels, such as CD105. It is also possible to differentiate quiescent from active vessels. Other reagents that can identify proteins involved in microenvironmental influences such as hypoxia have also been generated. Although the histological assessment of tumor vascularity is used mostly in the research context, it may also have clinical applications if appropriate methodology and trained observers perform the studies.
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Affiliation(s)
- Jia-Min Pang
- Department of Pathology, Peter MacCallum Cancer Centre, 2 St Andrews Place, Melbourne, 3002, Australia
| | - Nicholas Jene
- Department of Pathology, Peter MacCallum Cancer Centre, 2 St Andrews Place, Melbourne, 3002, Australia
| | - Stephen B Fox
- Department of Pathology, Peter MacCallum Cancer Centre, 2 St Andrews Place, Melbourne, 3002, Australia.
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Agostino NM, Saraceni C, Kincaid H, Shi W, Nevala WK, Markovic S, Nair SG. A prospective evaluation of the role of Vascular Endothelial Growth Factor (VEGF) and the immune system in stage III/IV melanoma. SPRINGERPLUS 2015; 4:186. [PMID: 25932372 PMCID: PMC4411400 DOI: 10.1186/s40064-015-0951-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 03/27/2015] [Indexed: 11/12/2022]
Abstract
Background The immune system and vascular endothelial growth factor (VEGF) may be influential in melanoma behavior. We performed a prospective, exploratory analysis in 10 stage III and 22 stage IV melanoma patients to observe factors influencing outcomes. Patients and methods Patients accrued during 2010 and 2011 were treated according to standard protocols for disease stage. We analyzed selected biomarkers for predictive patterns of clinical response. Survival outcomes were calculated using Kaplan-Meier curves. Results Baseline LDH was negatively correlated with length of survival and positively correlated to baseline VEGF in stage IV melanoma patients. We found a positive correlation between peripheral blood Treg concentrations and baseline VEGF in stage IV patients. No stage III patients died during the study period; median survival for stage IV patients was 48 months using a Kaplan-Meier survival curve, which illustrates the enrichment for exceptional stage IV survivors. Six stage IV patients remain disease free, including 4 of the 10 patients who received IL-2 +/− metastatectomy. Conclusions Recent advances in immunotherapy have demonstrated durable therapeutic responses which may favorably impact survival. Examining T-cell characteristics of metastatic melanoma patients may gain further insight into underlying immunomodulation mechanisms to guide improved therapies.
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Affiliation(s)
- Nicole Marie Agostino
- Lehigh Valley Health Network, Department of Hematology Oncology, John and Dorothy Morgan Cancer Center, 1240 S. Cedar Crest Blvd, Suite 401, Allentown, PA 18103 USA
| | - Christine Saraceni
- Lehigh Valley Health Network, Department of Hematology Oncology, John and Dorothy Morgan Cancer Center, 1240 S. Cedar Crest Blvd, Suite 401, Allentown, PA 18103 USA
| | - Hope Kincaid
- Lehigh Valley Health Network, Department of Hematology Oncology, John and Dorothy Morgan Cancer Center, 1240 S. Cedar Crest Blvd, Suite 401, Allentown, PA 18103 USA
| | - Wenjing Shi
- Lehigh Valley Health Network, Department of Hematology Oncology, John and Dorothy Morgan Cancer Center, 1240 S. Cedar Crest Blvd, Suite 401, Allentown, PA 18103 USA
| | | | | | - Suresh G Nair
- Lehigh Valley Health Network, Department of Hematology Oncology, John and Dorothy Morgan Cancer Center, 1240 S. Cedar Crest Blvd, Suite 401, Allentown, PA 18103 USA
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Mazumdar S, Arendt LM, Phillips S, Sedic M, Kuperwasser C, Gill G. CoREST1 promotes tumor formation and tumor stroma interactions in a mouse model of breast cancer. PLoS One 2015; 10:e0121281. [PMID: 25793264 PMCID: PMC4368644 DOI: 10.1371/journal.pone.0121281] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 01/29/2015] [Indexed: 01/14/2023] Open
Abstract
Regulators of chromatin structure and gene expression contribute to tumor formation and progression. The co-repressor CoREST1 regulates the localization and activity of associated histone modifying enzymes including lysine specific demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1). Although several CoREST1 associated proteins have been reported to enhance breast cancer progression, the role of CoREST1 in breast cancer is currently unclear. Here we report that knockdown of CoREST1 in the basal-type breast cancer cell line, MDA-MB-231, led to significantly reduced incidence and diminished size of tumors compared to controls in mouse xenograft studies. Notably, CoREST1-depleted cells gave rise to tumors with a marked decrease in angiogenesis. CoREST1 knockdown led to a decrease in secreted angiogenic and inflammatory factors, and mRNA analysis suggests that CoREST1 promotes expression of genes related to angiogenesis and inflammation including VEGF-A and CCL2. CoREST1 knockdown decreased the ability of MDA-MB-231 conditioned media to promote endothelial cell tube formation and migration. Further, tumors derived from CoREST1-depleted cells had reduced macrophage infiltration and the secretome of CoREST1 knockdown cells was deficient in promoting macrophage migration and macrophage-mediated angiogenesis. Taken together, these findings reveal that the epigenetic regulator CoREST1 promotes tumorigenesis in a breast cancer model at least in part through regulation of gene expression patterns in tumor cells that have profound non-cell autonomous effects on endothelial and inflammatory cells in the tumor microenvironment.
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Affiliation(s)
- Sohini Mazumdar
- Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- Genetics Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Lisa M. Arendt
- Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Sarah Phillips
- Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- Genetics Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Maja Sedic
- Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- Cellular, Molecular and Developmental Biology Program, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Charlotte Kuperwasser
- Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Grace Gill
- Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- * E-mail:
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Combined neoadjuvant chemotherapy with bevacizumab improves pathologic complete response in patients with hormone receptor negative operable or locally advanced breast cancer. Am J Clin Oncol 2015; 38:74-9. [PMID: 23563210 DOI: 10.1097/coc.0b013e31828940c3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES To evaluate the pathologic complete response (pCR) and safety of bevacizumab (B) with chemotherapy in the neoadjuvant setting of breast cancer (BC). METHODS A prospective single-arm, single-institution phase II trial for women with stage IIA-B/IIIA-B-C BC. Patients received neoadjuvant docetaxel, cyclophosphamide, B every 3 weeks for 4 cycles followed by doxorubicin every 3 weeks for 4 cycles followed by surgery. After healing, B was given every 3 weeks for 9 cycles. Radiation therapy, trastuzumab and endocrine therapy were given as indicated. RESULTS Thirty-nine of 40 patients were evaluable. Median age of participants was 45 years (range, 26 to 72 y). The most serious grade ≥3 adverse events were infection (4), congestive heart failure (2), and pulmonary embolism (1). Thirty-eight of 39 patients underwent surgery. The pCR rate was 41% (16/39), significantly higher than the null-hypothesis rate of 25% (P=0.0204). Rates of pCR were 52% (15/29) in ductal carcinoma compared with 10% (1/10) in nonductal disease (P=0.021), and 59% (10/17) in estrogen receptor-/progesteron receptor- patients compared with 27% (6/22) among patient with at least one positive hormone receptor (P=0.047). African Americans (AA) had 75% pCR (9/12), whereas Whites had only 28% pCR (7/25; P=0.0069), possibly in part because 100% of AA (12/12) had ductal carcinoma compared with only 64% (16/25) of Whites (P=0.017). CONCLUSIONS Chemotherapy with B improved pCR in BC patients, but was associated with significant toxicity and rare but very serious complications. The improvement was more pronounced in AA patients, those with ductal carcinoma, and those with estrogen receptor-/progesteron receptor - BC.ClinicalTrials.gov Identifier: NCT00203502.
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Rapoport BL. Sorafenib: a brief review with emphasis on its possible role in breast cancer. BREAST CANCER MANAGEMENT 2015. [DOI: 10.2217/bmt.15.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY The treatment of metastatic breast cancer is palliative and usually requires hormone treatment, and/or chemotherapy and trastuzumab for HER2-positive disease. Randomized studies only demonstrate marginal survival benefit with combination chemotherapy, as opposed to sequential single agents or nontaxane versus taxane-containing regimens. Metastatic breast cancer remains an unmet medical need. Sorafenib is an oral multikinase inhibitor that exhibits antiangiogenic activity by targeting numerous proangiogenic pathways. Sorafenib has marketing authorization for the treatment of patients with advanced renal cell, hepatocellular and thyroid carcinomas. Recent studies have explored the usage of sorafenib as a single agent and in combination with chemotherapy. An overview of sorafenib is presented in this article with the current data and potential future usage in patients with metastatic breast cancer.
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Kapahi R, Guleria K, Sambyal V, Manjari M, Sudan M, Uppal MS, Singh NR. Association of VEGF and VEGFR1 polymorphisms with breast cancer risk in North Indians. Tumour Biol 2015; 36:4223-34. [PMID: 25604142 DOI: 10.1007/s13277-015-3059-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 01/05/2015] [Indexed: 02/07/2023] Open
Abstract
The aim of present study was to evaluate the relationship between vascular endothelial growth factor (VEGF) -2578C/A, -2549I/D, -460T/C and -7C/T and VEGFR1 -710C/T polymorphisms with risk to breast cancer in North Indians. A total of 204 sporadic breast cancer patients and 204 controls were recruited for this case-control study. Significantly increased frequency of II genotype of -2549I/D polymorphism was observed in patients as compared to control individuals (odds ratio (OR) = 2.76, 95 % confidence interval (CI), 1.55-4.92; p = 0.0005). VEGF -2578AA genotype (OR = 2.87; 95 % CI, 1.61-5.10; p = 0.0003) and A allele (OR = 1.65, 95 % CI, 1.25-2.18; p = 0.0004) were found to be associated with increased risk for breast cancer. Individuals carrying CC genotype (OR = 2.23, 95 % CI, 1.25-3.97) and C allele (OR = 1.42, 95 % CI, 1.07-1.87) of VEGF -460T/C polymorphism were at higher risk of breast cancer. There was no significant difference in genotype and allele distribution of VEGF -7C/T and VEGFR1 -710C/T polymorphisms between cases and control individuals (p > 0.05). Linkage disequilibrium analysis showed a strong linkage between VEGF -2549I/D and -2578C/A polymorphisms (Lewontin's [Formula: see text] = 0.99; r (2) = 0.97), -2549I/D and -460T/C ([Formula: see text] = 0.94; r (2) = 0.84), and -2578C/A and -460T/C polymorphisms ([Formula: see text] = 0.93; r (2) = 0.83). In the present study, we concluded that VEGF -2549I/D, -2578C/A and -460T/C polymorphisms are associated with risk to breast cancer in Punjab, North India.
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Affiliation(s)
- Ruhi Kapahi
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, 143005, Punjab, India
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Angiogenesis and tumor microenvironment: bevacizumab in the breast cancer model. Target Oncol 2014; 10:189-98. [PMID: 25185646 DOI: 10.1007/s11523-014-0334-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 08/29/2014] [Indexed: 01/05/2023]
Abstract
Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. Antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. According to Jain et al., an alternative hypothesis could be that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. With emphasize on the research works of Jain et al., the aim of this review is to describe the impact of antivascular endothelial growth factor (VEGF) therapy on "pseudo-normalization" of tumor vasculature and tumor microenvironment, its role in early and metastatic breast cancer, and the clinical evidence supporting this original concept. The phase III clinical trials showed that extended tumors, metastatic or locally advanced, are likely to benefit from bevacizumab therapy in combination with chemotherapy, assuming that a high level of tumor neoangiogenesis as in triple-negative tumors is the best target. In adjuvant setting, the lower level of tumor vasculature could mask a potential benefit of anti-VEGF therapy. All these findings highlight the need to identify biomarkers to help in the selection of patients most likely to respond to anti-VEGF therapy, to better understand the mechanism of angiogenesis and of resistance to anti-VEGF therapy according to molecular subtypes.
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Macarulla T, Sauri T, Tabernero J. Evaluation of aflibercept in the treatment of metastatic colorectal cancer. Expert Opin Biol Ther 2014; 14:1493-505. [DOI: 10.1517/14712598.2014.947956] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Gökmen-Polar Y, Goswami CP, Toroni RA, Sanders KL, Mehta R, Sirimalle U, Tanasa B, Shen C, Li L, Ivan M, Badve S, Sledge GW. Gene Expression Analysis Reveals Distinct Pathways of Resistance to Bevacizumab in Xenograft Models of Human ER-Positive Breast Cancer. J Cancer 2014; 5:633-45. [PMID: 25157274 PMCID: PMC4142325 DOI: 10.7150/jca.8466] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 06/20/2014] [Indexed: 12/29/2022] Open
Abstract
Bevacizumab, the recombinant antibody targeting vascular endothelial growth factor (VEGF), improves progression-free but not overall survival in metastatic breast cancer. To seek further insights in resistance mechanisms to bevacizumab at the molecular level, we developed VEGF and non-VEGF-driven ER-positive MCF7-derived xenograft models allowing comparison of tumor response at different timepoints. VEGF gene (MV165) overexpressing xenografts were initially sensitive to bevacizumab, but eventually acquired resistance. In contrast, parental MCF7 cells derived tumors were de novo insensitive to bevacizumab. Microarray analysis with qRT-PCR validation revealed that Follistatin (FST) and NOTCH were the top signaling pathways associated with resistance in VEGF-driven tumors (P<0.05). Based on the presence of VEGF, treatment with bevacizumab resulted in altered patterns of metagenes and PAM50 gene expression. In VEGF-driven model after short and long-term bevacizumab treatments, a change in the intrinsic subtype (luminal to myoepithelial/basal-like) was observed in association with increased expression of genes implicated with cancer stem cell phenotype (P<0.05). Our results show that the presence or absence of VEGF expression affects the response to bevacizumab therapy and gene pathways. In particular, long-term bevacizumab treatment shifts the cancer cells to a more aggressive myoepithelial/basal subtype in VEGF-expressing model, but not in non-VEGF model. These findings could shed light on variable results to anti-VEGF therapy in patients and emphasize the importance of patient stratification based on the VEGF expression. Our data strongly suggest consideration of patient subgroups for treatment and designing novel combinatory therapies in the clinical setting.
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Affiliation(s)
- Yesim Gökmen-Polar
- 1. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Chirayu P Goswami
- 2. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN
| | - Rachel A Toroni
- 3. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Kerry L Sanders
- 3. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Rutika Mehta
- 1. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Usha Sirimalle
- 1. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Bogdan Tanasa
- 4. Scripps Research Institute, University of Medicine and Pharmac, La Jolla, CA
| | - Changyu Shen
- 2. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN
| | - Lang Li
- 2. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN
| | - Mircea Ivan
- 3. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Sunil Badve
- 1. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN; ; 3. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - George W Sledge
- 1. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN; ; 3. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
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Liu Y, Liu Y, Zhang H, Sun C, Zhao Q, Di C, Li H, Gan L, Wang Y. Effects of carbon-ion beam irradiation on the angiogenic response in lung adenocarcinoma A549 cells. Cell Biol Int 2014; 38:1304-10. [PMID: 24942319 DOI: 10.1002/cbin.10327] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 05/17/2014] [Indexed: 11/06/2022]
Abstract
Radiotherapy has been focused mainly on killing cancer cells, and little attention has been paid to the process supporting tumor growth and metastasis, including the process of angiogenesis. To investigate the effects of carbon-ion irradiation on angiogenesis in lung cancer cells, we examined the expression of vascular endothelial growth factor and basic fibroblast growth factor in the tumor conditioned medium (TCM) of A549 cells exposed to carbon-ion or X-ray irradiation, as well as endothelial cell growth, invasion, and tube formation induced by TCM. No changes in vascular endothelial growth factor secretion were detected in the TCM of A549 cells exposed to carbon-ion irradiation at 2 or 4 Gy, whereas 1 Gy of irradiation significantly decreased vascular endothelial growth factor and basic fibroblast growth factor levels. Carbon-ion irradiation at 1 Gy inhibited endothelial cell invasion and tube formation. The TCM from A549 cells irradiated with X-ray promoted angiogenesis, whereas the TCM of A549 cells exposed to carbon-ion irradiation at 2 or 4 Gy had no effect. These findings suggest that carbon-ion irradiation at 1 Gy significantly suppressed the process of angiogenesis in vitro by inhibiting endothelial cell invasion and tube formation, which are related to vascular endothelial growth factor and basic fibroblast growth factor production.
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Affiliation(s)
- Yuanyuan Liu
- Department of Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou, 730000, China
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Vascular endothelial growth factor gene polymorphism (-634G/C) and breast cancer risk. Tumour Biol 2014; 35:7793-8. [PMID: 24816918 DOI: 10.1007/s13277-014-1997-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 04/22/2014] [Indexed: 10/25/2022] Open
Abstract
The aim of this meta-analysis was to assess if the -634G/C polymorphism represents a predisposition factor for the risk of breast cancer. We included eight published case-control studies, in which a total of 6,175 cancer cases and 6,421 cancer-free controls were included. Pooled ORs and 95 % CIs were calculated by the fixed effects model to evaluate the association of the -634G/C polymorphism and breast cancer risk. When all studies were pooled, we did not find statistical evidence of any significant association with overall breast cancer risk (ORBB vs. bb = 1.00, 95 % CI = 0.93-1.07, P = 0.999; ORBB + Bb vs. bb = 1.00, 95 % CI = 0.95-1.05, P = 0.999; ORBB vs. Bb + bb = 1.03, 95 % CI = 0.96-1.09, P = 0.984; ORallele B vs. allele b = 1.01, 95 % CI = 0.97-1.05, P = 0.998; ORBb vs. bb = 0.99, 95 % CI = 0.92-1.06, P = 0.992). In further stratified analyses by ethnicity and control source, no significant association was revealed. This study suggests that the -634G/C polymorphism does not appear to represent a risk factor for breast cancer.
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Sunitinib monotherapy in a patient with primary breast cancer. Int Cancer Conf J 2014. [DOI: 10.1007/s13691-013-0122-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Role of VEGF-A and its receptors in sporadic and MEN2-associated pheochromocytoma. Int J Mol Sci 2014; 15:5323-36. [PMID: 24675699 PMCID: PMC4013566 DOI: 10.3390/ijms15045323] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 03/18/2014] [Accepted: 03/18/2014] [Indexed: 01/28/2023] Open
Abstract
Pheochromocytoma (PHEO), a rare catecholamine producing tumor arising from the chromaffin cells, may occurs sporadically (76%–80%) or as part of inherited syndromes (20%–24%). Angiogenesis is a fundamental step in tumor proliferation and vascular endothelial growth factor (VEGF-A) is the most well-characterized angiogenic factor. The role of angiogenic markers in PHEO is not fully understood; investigations were therefore made to evaluate the expression of VEGF-A and its receptors in PHEO and correlate to clinical parameters. Twenty-nine samples of PHEO were evaluated for VEGF-A, VEGF receptor-1 (VEGFR-1) VEGFR-2 expression and microvessel density (MVD) by immunohistochemistry. Clinical data were reviewed in medical records. The mean age of patients was 38 ± 14 years, and 69% were woman. VEGF-A, VEGFR-1 and VEGFR-2 staining were detected in nearly all PHEO samples. No significant correlation was observed between VEGF-A, VEGFR-1, VEGFR-2 expression or MVD and age at diagnosis, tumor size or sporadic and hereditary PHEO. However, the levels of expression of these molecules were significantly higher in malignant PHEO samples (p = 0.027, p = 0.003 and p = 0.026, respectively).VEGF-A and its receptors were shown to be up-regulated in malignant PHEO, suggesting that these molecules might be considered as therapeutic targets for unresectable or metastatic tumors.
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Maschio LB, Madallozo BB, Capellasso BAM, Jardim BV, Moschetta MG, Jampietro J, Soares FA, Zuccari DAPDC. Immunohistochemical investigation of the angiogenic proteins VEGF, HIF-1α and CD34 in invasive ductal carcinoma of the breast. Acta Histochem 2014; 116:148-57. [PMID: 23899963 DOI: 10.1016/j.acthis.2013.06.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 06/25/2013] [Accepted: 06/27/2013] [Indexed: 01/02/2023]
Abstract
The expression of prognostic markers in cancer has become important in diagnostic routine and research. A high mitotic rate compromises the individual cell access to oxygen and nutrients, due to reduced blood supply. Cells undertake adaptive measures such as vascular endothelial growth factor (VEGF), expressed under the control of hypoxia-inducible factor-1α (HIF-1α). CD34 is an endothelial marker which can show the presence and distribution of blood vessels. This study evaluated the presence and relative expression of VEGF, HIF-1α and CD34 using immunohistochemistry of 60 breast tumors and double staining, correlating the findings with clinical and pathological variables. High VEGF expression was correlated with low cell proliferation, lymph node-negative, smaller tumor size and patients not receiving hormone therapy. High HIF-1α expression predominated in younger (<50-year) patients, subjected to neo-adjuvant therapy and in p53-negative tumors. Absence of metastasis, radiotherapy or hormone treatment, and estrogen receptor (ER)-positive tumors showed high CD34 immunoreactivity. We suggest that the angiogenic factors VEGF, HIF-1α and CD34 are important in breast cancer progression and their abundance in breast tumors has prognostic and predictive value.
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Xynos ID, Tanna N, Patten DK, Palmieri C. Prior exposure to chemotherapy: a marker of sensitivity and selection for antiangiogenic therapy in breast cancer? Expert Rev Anticancer Ther 2013; 14:163-72. [PMID: 24308686 DOI: 10.1586/14737140.2014.846220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The identification of patients who are more likely to derive benefit from antiangiogenic therapy is a key to refine patient selection and so maximize clinical benefit, and reduce unnecessary treatment costs. Improved patient selection will equally be effective in minimizing the exposure of non-eligible patients to ineffectual treatment which could be associated with adverse effects as well as delaying effective treatment. Herein, we review the literature from clinical trials suggesting that the addition of antiangiogenic agents to chemotherapy for the treatment of HER-2 negative metastatic breast cancer in patients previously exposed to chemotherapy may deliver differential therapeutic benefit and may serve as a selection criteria in the current absence of a robust biomarker.
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Affiliation(s)
- Ioannis D Xynos
- Department of Medical Oncology, Imperial College Healthcare NHS Trust, London, UK
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Fujita H, Miyadera K, Kato M, Fujioka Y, Ochiiwa H, Huang J, Ito K, Aoyagi Y, Takenaka T, Suzuki T, Ito S, Hashimoto A, Suefuji T, Egami K, Kazuno H, Suda Y, Nishio K, Yonekura K. The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profile. Mol Cancer Ther 2013; 12:2685-96. [PMID: 24140932 DOI: 10.1158/1535-7163.mct-13-0459] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signal-targeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI50 > 10 μmol/L) in VEGFR signal- or MET signal-independent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity.
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Affiliation(s)
- Hidenori Fujita
- Corresponding Author: Hidenori Fujita, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.
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Ahluwalia A, Jones MK, Szabo S, Tarnawski AS. Aberrant, ectopic expression of VEGF and VEGF receptors 1 and 2 in malignant colonic epithelial cells. Implications for these cells growth via an autocrine mechanism. Biochem Biophys Res Commun 2013; 437:515-520. [PMID: 23831629 DOI: 10.1016/j.bbrc.2013.06.096] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 06/25/2013] [Indexed: 02/06/2023]
Abstract
UNLABELLED Vascular endothelial growth factor A (referred to as VEGF) is implicated in colon cancer growth. Currently, the main accepted mechanism by which VEGF promotes colon cancer growth is via the stimulation of angiogenesis, which was originally postulated by late Judah Folkman. However, the cellular source of VEGF in colon cancer tissue; and, the expression of VEGF and its receptors VEGF-R1 and VEGF-R2 in colon cancer cells are not fully known and are subjects of controversy. MATERIAL AND METHODS We examined and quantified expression of VEGF, VEGF-R1 and VEGF-R2 in three different human colonic tissue arrays containing sections of adenocarcinoma (n=43) and normal mucosa (n = 41). In human colon cancer cell lines HCT116 and HT29 and normal colon cell lines NCM356 and NCM460, we examined expression of VEGF, VEGF-R1 and VEGF-R2 mRNA and protein, VEGF production and secretion into the culture medium; and, the effect of a potent, selective inhibitor of VEGF receptors, AL-993, on cell proliferation. RESULTS Human colorectal cancer specimens had strong expression of VEGF in cancer cells and also expressed VEGF-R1 and VEGF-R2.In vitro studies showed that human colon cancer cell lines, HCT116 and HT29, but not normal colonic cell lines, express VEGF, VEGF-R1 and VEGF-R2 and secrete VEGF into the medium up to a concentration 2000 pg/ml within 48 h. Furthermore, we showed that inhibition of VEGF receptors using a specific VEGF-R inhibitor significantly reduced proliferation (by >50%) of cultured colon cancer cell lines. CONCLUSIONS Our findings support the contention that VEGF generated by colon cancer cells stimulates their growth directly through an autocrine mechanism that is independent of its primary function in the induction of angiogenesis.
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