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      Serum exosomal-annexin A2 is associated with African-American triple-negative breast cancer and promotes angiogenesis

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          Abstract

          Background

          Limited information is available on biomarker(s) for triple-negative breast cancer (TNBC) that can address the higher incidence and aggressiveness of TNBC in African-American (AA) women. Our previous studies have demonstrated annexin A2 (AnxA2) association with exosomes which promotes angiogenesis and metastasis. Therefore, our goal was to examine the expression and function of exosomal-annexin A2 (exo-AnxA2) derived from the serum samples of breast cancer patients.

          Methods

          The expression of serum exo-AnxA2 and its association with clinicopathological features of the breast cancer patients were determined. The role of serum exo-AnxA2 to promote angiogenesis was determined by an in vivo Matrigel plug assay.

          Results

          Our results show that the expression of serum exo-AnxA2 in breast cancer patients ( n = 169; 83.33 ± 2.040 ng/mL, P < 0.0001) is high compared to non-cancer females ( n = 68; 34.21 ± 2.238 ng/mL). High expression of exo-AnxA2 levels in breast cancer was significantly associated with tumor grade ( P < 0.0001), poor overall survival (hazard ratio (HR) 2.802; 95% confidence intervals (CI) = 1.030–7.620; P = 0.0353), and poor disease-free survival (HR 7.934; 95% CI = 1.778–35.398; P = 0.0301). The expression of serum exo-AnxA2 levels was significantly elevated in TNBC ( n = 68; 109.1 ± 2.905 ng/mL; P < 0.0001) in comparison to ER + ( n = 50; 57.35 ± 1.545 ng/mL), HER2 + ( n = 59; 78.25 ± 1.146 ng/mL), and non-cancer females ( n = 68; 34.21 ± 2.238 ng/mL). Exo-AnxA2 showed diagnostic values with a maximum AUC as 1.000 for TNBC, 0.8304 for ER +, and 0.9958 for HER2 + compared to non-cancer females. The expression of serum exo-AnxA2 was significantly elevated in AA women with TNBC ( n = 29; 118.9 ± 4.086 ng/mL, P < 0.0001) in comparison to Caucasian-American TNBC ( n = 27; 97.60 ± 3.298 ng/mL) patients. Our in vivo results suggest a role of serum exo-AnxA2 in angiogenesis and its association with aggressiveness of TNBC in AA women.

          Conclusions

          Our results demonstrated that the expression of serum exo-AnxA2 is high in AA women with TNBC and promotes angiogenesis. These findings suggest that exo-AnxA2 holds promise as a potential prognosticator of TNBC and may lead to an effective therapeutic option.

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          Most cited references30

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          Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules.

          Hypoxic conditions in prostate cancer (PCA) are associated with poor prognosis; however, precise mechanism/s through which hypoxia promotes malignant phenotype remains unclear. Here, we analyzed the role of exosomes from hypoxic PCA cells in enhancing the invasiveness and stemness of naïve PCA cells, as well as in promoting cancer-associated fibroblast (CAF) phenotype in prostate stromal cells (PrSC). Human PCA LNCaP and PC3 cells were exposed to hypoxic (1% O2 ) or normoxic (21% O2 ) conditions, and exosomes secreted under hypoxic (Exo(Hypoxic) ) and normoxic (Exo(Normoxic) ) conditions were isolated from conditioned media. Nanoparticle tracking analysis revealed that Exo(Hypoxic) have smaller average size as compared to Exo(Normoxic) . Immunoblotting results showed a higher level of tetraspanins (CD63 and CD81), heat shock proteins (HSP90 and HSP70), and Annexin II in Exo(Hypoxic) compared to Exo(Normoxic) . Co-culturing with Exo(Hypoxic) increased the invasiveness and motility of naïve LNCaP and PC3 cells, respectively. Exo(Hypoxic) also promoted prostasphere formation by both LNCaP and PC3 cells, and enhanced α-SMA (a CAF biomarker) expression in PrSC. Compared to Exo(Normoxic) , Exo(Hypoxic) showed higher metalloproteinases activity and increased level of diverse signaling molecules (TGF-β2, TNF1α, IL6, TSG101, Akt, ILK1, and β-catenin). Furthermore, proteome analysis revealed a higher number of proteins in Exo(Hypoxic) (160 proteins) compared to Exo(Normoxic) (62 proteins), primarily associated with the remodeling of epithelial adherens junction pathway. Importantly, Exo(Hypoxic) targeted the expression of adherens junction proteins in naïve PC3 cells. These findings suggest that Exo(Hypoxic) are loaded with unique proteins that could enhance invasiveness, stemness, and induce microenvironment changes; thereby, promoting PCA aggressiveness. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.
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            Microvesicles as mediators of intercellular communication in cancer--the emerging science of cellular 'debris'.

            Cancer cells emit a heterogeneous mixture of vesicular, organelle-like structures (microvesicles, MVs) into their surroundings including blood and body fluids. MVs are generated via diverse biological mechanisms triggered by pathways involved in oncogenic transformation, microenvironmental stimulation, cellular activation, stress, or death. Vesiculation events occur either at the plasma membrane (ectosomes, shed vesicles) or within endosomal structures (exosomes). MVs are increasingly recognized as mediators of intercellular communication due to their capacity to merge with and transfer a repertoire of bioactive molecular content (cargo) to recipient cells. Such processes may occur both locally and systemically, contributing to the formation of microenvironmental fields and niches. The bioactive cargo of MVs may include growth factors and their receptors, proteases, adhesion molecules, signalling molecules, as well as DNA, mRNA, and microRNA (miRs) sequences. Tumour cells emit large quantities of MVs containing procoagulant, growth regulatory and oncogenic cargo (oncosomes), which can be transferred throughout the cancer cell population and to non-transformed stromal cells, endothelial cells and possibly to the inflammatory infiltrates (oncogenic field effect). These events likely impact tumour invasion, angiogenesis, metastasis, drug resistance, and cancer stem cell hierarchy. Ongoing studies explore the molecular mechanisms and mediators of MV-based intercellular communication (cancer vesiculome) with the hope of using this information as a possible source of therapeutic targets and disease biomarkers in cancer.
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              Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models.

              Exosomes play an important role in cell-to-cell communication to promote tumor metastasis. In order to image the fate of cancer-cell-derived exosomes in orthotopic nude mouse models of breast cancer, we used green fluorescent protein (GFP)-tagged CD63, which is a general marker of exosomes. Breast cancer cells transferred their own exosomes to other cancer cells and normal lung tissue cells in culture. In orthotopic nude-mouse models, breast cancer cells secreted exosomes into the tumor microenvironment. Tumor-derived exosomes were incorporated into tumor-associated cells as well as circulating in the blood of mice with breast cancer metastases. These results suggest that tumor-derived exosomes may contribute to forming a niche to promote tumor growth and metastasis. Our results demonstrate the usefulness of GFP imaging to investigate the role of exosomes in cancer metastasis. Copyright © 2012 Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                Pankaj.Chaudhary@unthsc.edu
                Jamboor.Vishwanatha@unthsc.edu
                Journal
                Breast Cancer Res
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central (London )
                1465-5411
                1465-542X
                28 January 2020
                28 January 2020
                2020
                : 22
                : 11
                Affiliations
                [1 ]ISNI 0000 0000 9765 6057, GRID grid.266871.c, Department of Microbiology, Immunology and Genetics, Graduate School of Biomedical Sciences, , University of North Texas Health Science Center, ; 3500 Camp Bowie Blvd., Fort Worth, TX 76107 USA
                [2 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Simmons Comprehensive Cancer Center, , University of Texas Southwestern Medical Center, ; Dallas, TX 75390 USA
                [3 ]ISNI 0000 0000 9765 6057, GRID grid.266871.c, Department of Biostatistics and Epidemiology, School of Public Health, , University of North Texas Health Science Center, ; Fort Worth, TX 76107 USA
                [4 ]ISNI 0000 0000 9765 6057, GRID grid.266871.c, Texas Center for Health Disparities, , University of North Texas Health Science Center, ; Fort Worth, TX 76107 USA
                Author information
                http://orcid.org/0000-0003-0518-4120
                Article
                1251
                10.1186/s13058-020-1251-8
                6986157
                31992335
                350e1027-51a2-43ef-8fc2-26fb27d4b544
                © The Author(s). 2020

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 October 2019
                : 21 January 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: CA220273, CA233355, and CA142543
                Funded by: FundRef http://dx.doi.org/10.13039/100006545, National Institute on Minority Health and Health Disparities;
                Award ID: MD006882
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                annexin a2,exosomes,breast cancer,angiogenesis,and racial disparity
                Oncology & Radiotherapy
                annexin a2, exosomes, breast cancer, angiogenesis, and racial disparity

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