Skip to main content
SpringerLink
Log in

A function-blocking CD47 antibody modulates extracellular vesicle-mediated intercellular signaling between breast carcinoma cells and endothelial cells

  • Research Article
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

Tumor cells release extracellular vesicles (EVs) into the tumor microenvironment that may facilitate malignant progression and metastasis. Breast carcinoma EVs express high levels of the thrombospondin-1 and signal regulatory protein-α receptor CD47, which is the target of several experimental therapeutics currently in clinical trials. We analyzed changes in gene expression and function in human umbilical vein endothelial cells (HUVEC) induced by treatment with EVs derived from breast carcinoma cells and the effects of the function-blocking CD47 antibody B6H12 on the resulting intercellular communication. CD47+ EVs exhibited greater uptake by HUVEC compared to CD47− EVs, but the CD47 antibody did not inhibit their uptake. Global and targeted analyses of transcripts demonstrated that treatment of HUVEC with EVs derived from MDA-MB-231 breast carcinomas cells altered pathways associated with tumor necrosis factor-α signaling, angiogenesis, lymphangiogenesis, endothelial-mesenchymal transition, and extracellular matrix. EVs from triple-negative MDA-MB-231 cells were more active than EVs from less metastatic breast carcinoma cell lines. Treatment with MDA-MB-231 EVs down-regulated VEGFR2 mRNA expression and tyrosine phosphorylation while enhancing phosphorylation of the tyrosine phosphatase SHP2. VEGFR2 expression and phosphorylation in HUVEC was further inhibited by the CD47 antibody. Consistent with the observed changes in endothelial-mesenchymal transition genes and SHP2, treatment with MDA-MB-231-derived EVs decreased Zeb1 protein levels in HUVEC, whereas the CD47 antibody increased Zeb1 levels. The induction of E-selectin and other known targets of tumor necrosis factor-α signaling by EVs was also enhanced by the CD47 antibody, and E-selectin was the most up-regulated transcript following CD47 antibody treatment alone. These studies reveal several mechanisms by which therapeutics targeting CD47 could modulate tumor growth by altering the cross talk between cancer-derived EVs and nonmalignant cells in the tumor stroma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

bCSC:

Breast cancer stem cells

ECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal transition

EnMT:

Endothelial-mesenchymal transition

EVs:

Extracellular vesicles

HUVEC:

Human umbilical vein endothelial cells

LYVE1:

Lymphatic vessel endothelial hyaluronan receptor 1

SHP2:

Tyrosine-protein phosphatase non-receptor type 11

SIRPα:

Signal regulatory protein-α

TNFα:

Tumor necrosis factor-α

TSP1/THBS1 :

Thrombospondin-1 protein/gene

TXNIP:

Thioredoxin-interacting protein

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor-2

References

  • Abdelsaid MA, Matragoon S, El-Remessy AB (2013) Thioredoxin-interacting protein expression is required for VEGF-mediated angiogenic signal in endothelial cells. Antioxid Redox Signal 19:2199–2212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abounit S, Zurzolo C (2012) Wiring through tunneling nanotubes--from electrical signals to organelle transfer. J Cell Sci 125:1089–1098

    Article  CAS  PubMed  Google Scholar 

  • Atala A (2012) Re: microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. J Urol 187:1506–1507

    Google Scholar 

  • Austefjord MW, Gerdes HH, Wang X (2014) Tunneling nanotubes: diversity in morphology and structure. Commun Integr Biol 7:e27934

    Article  PubMed  PubMed Central  Google Scholar 

  • Awad AE, Kandalam V, Chakrabarti S, Wang X, Penninger JM, Davidge ST, Oudit GY, Kassiri Z (2010) Tumor necrosis factor induces matrix metalloproteinases in cardiomyocytes and cardiofibroblasts differentially via superoxide production in a PI3Kgamma-dependent manner. Am J Physiol Cell Physiol 298:C679–C692

    Article  CAS  PubMed  Google Scholar 

  • Barazi HO, Li Z, Cashel JA, Krutzsch HC, Annis DS, Mosher DF, Roberts DD, (2002) Regulation of Integrin Function by CD47 Ligands. J Biol Chem 277 45:42859-42866. https://doi.org/10.1074/jbc.M206849200

  • Baluk, P, Mcdonald, DM. (2008). Markers for microscopic imaging of lymphangiogenesis and angiogenesis. Ann N Y Acad Sci, 1131, 1–12

  • Borsig L, Wong R, Hynes RO, Varki NM, Varki A (2002) Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci U S A 99:2193–2198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burger P, Hilarius-Stokman P, De Korte D, Van Den Berg TK, Van Bruggen R (2012) CD47 functions as a molecular switch for erythrocyte phagocytosis. Blood 119:5512–5521

    Article  CAS  PubMed  Google Scholar 

  • Calzada MJ, Zhou L, Sipes JM, Zhang J, Krutzsch HC, Iruela-Arispe ML, Annis DS, Mosher DF, Roberts DD (2004) Alpha4beta1 integrin mediates selective endothelial cell responses to thrombospondins 1 and 2 in vitro and modulates angiogenesis in vivo. Circ Res 94:462–470

    Article  CAS  PubMed  Google Scholar 

  • Chauhan S, Danielson S, Clements V, Edwards N, Ostrand-Rosenberg S, Fenselau C (2017) Surface glycoproteins of exosomes shed by myeloid-derived suppressor cells contribute to function. J Proteome Res 16:238–246

    Article  CAS  PubMed  Google Scholar 

  • Cherubini E, Mariotta S, Scozzi D, Mancini R, Osman G, D'ascanio M, Bruno P, Cardillo G, Ricci A (2017) BDNF/TrkB axis activation promotes epithelial-mesenchymal transition in idiopathic pulmonary fibrosis. J Transl Med 15:196

    Article  PubMed  PubMed Central  Google Scholar 

  • Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T (1995) Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 9:899–909

    Article  CAS  PubMed  Google Scholar 

  • DiMaio TA, Gutierrez KD, Lagunoff M, (2014) Kaposi's Sarcoma-Associated Herpesvirus Downregulates Transforming Growth Factor  2 To Promote Enhanced Stability of Capillary-Like Tube Formation. J Virol 88 24:14301-14309

  • Di Vizio D, Morello M, Dudley AC, Schow PW, Adam RM, Morley S, Mulholland D, Rotinen M, Hager MH, Insabato L, Moses MA, Demichelis F, Lisanti MP, Wu H, Klagsbrun M, Bhowmick NA, Rubin MA, D'souza-Schorey C, Freeman MR (2012) Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. Am J Pathol 181:1573–1584

    Article  PubMed  PubMed Central  Google Scholar 

  • Du Y, Liu H, He Y, Liu Y, Yang C, Zhou M, Wang W, Cui L, Hu J, Gao F (2013) The interaction between LYVE-1 with hyaluronan on the cell surface may play a role in the diversity of adhesion to cancer cells. PLoS One 8:e63463

    Article  PubMed  PubMed Central  Google Scholar 

  • Fairaq A, Goc A, Artham S, Sabbineni H, Somanath PR (2015) TNFalpha induces inflammatory stress response in microvascular endothelial cells via Akt- and P38 MAP kinase-mediated thrombospondin-1 expression. Mol Cell Biochem 406:227–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fenouille N, Tichet M, Dufies M, Pottier A, Mogha A, Soo JK, Rocchi S, Mallavialle A, Galibert MD, Khammari A, Lacour JP, Ballotti R, Deckert M, Tartare-Deckert S (2012) The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PLoS One 7:e40378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forsyth KD, Talbot V, Beckman I (1994) Endothelial serpins--protectors of the vasculature? Clin Exp Immunol 95:277–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujioka Y, Matozaki T, Noguchi T, Iwamatsu A, Yamao T, Takahashi N, Tsuda M, Takada T, Kasuga M (1996) A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Mol Cell Biol 16:6887–6899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, Tetta C, Bussolati B, Camussi G (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71:5346–5356

    Article  CAS  PubMed  Google Scholar 

  • Grimmelikhuijzen CJ, Hauser F (2012) Mini-review: the evolution of neuropeptide signaling. Regul Pept 177(Suppl):S6–S9

    Article  PubMed  Google Scholar 

  • Hirakawa S (2011) Regulation of pathological lymphangiogenesis requires factors distinct from those governing physiological lymphangiogenesis. J Dermatol Sci 61:85–93

    Article  CAS  PubMed  Google Scholar 

  • Holzel M, Bovier A, Tuting T (2013) Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer 13:365–376

    Article  PubMed  Google Scholar 

  • Horiguchi A, Chen DY, Goodman OB Jr, Zheng R, Shen R, Guan H, Hersh LB, Nanus DM (2008) Neutral endopeptidase inhibits prostate cancer tumorigenesis by reducing FGF-2-mediated angiogenesis. Prostate Cancer Prostatic Dis 11:79–87

    Article  CAS  PubMed  Google Scholar 

  • Hosseini-Beheshti E, Pham S, Adomat H, Li N, Tomlinson Guns ES (2012) Exosomes as biomarker enriched microvesicles: characterization of exosomal proteins derived from a panel of prostate cell lines with distinct AR phenotypes. Mol Cell Proteomics 11:863–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang H, Langenkamp E, Georganaki M, Loskog A, Fuchs PF, Dieterich LC, Kreuger J, Dimberg A (2015) VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-kappaB-induced endothelial activation. FASEB J 29:227–238

    Article  CAS  PubMed  Google Scholar 

  • Isenberg JS, Frazier WA, Roberts DD (2008) Thrombospondin-1: a physiological regulator of nitric oxide signaling. Cell Mol Life Sci 65:728–742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Isenberg JS, Annis DS, Pendrak ML, Ptaszynska M, Frazier WA, Mosher DF, Roberts DD (2009) Differential interactions of thrombospondin-1, −2, and −4 with CD47 and effects on cGMP signaling and ischemic injury responses. J Biol Chem 284:1116–1125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang P, Lagenaur CF, Narayanan V (1999) Integrin-associated protein is a ligand for the P84 neural adhesion molecule. J Biol Chem 274:559–562

    Article  CAS  PubMed  Google Scholar 

  • Johnson LA, Prevo R, Clasper S, Jackson DG (2007) Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem 282:33671–33680

    Article  CAS  PubMed  Google Scholar 

  • Kajiyama H, Shibata K, Terauchi M, Morita T, Ino K, Mizutani S, Kikkawa F (2005) Neutral endopeptidase 24.11/CD10 suppresses progressive potential in ovarian carcinoma in vitro and in vivo. Clin Cancer Res 11:1798–1808

    Article  CAS  PubMed  Google Scholar 

  • Kamerkar S, Lebleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, Lee JJ, Kalluri R (2017) Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546:498–503

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kaur S, Martin-Manso G, Pendrak ML, Garfield SH, Isenberg JS, Roberts DD (2010) Thrombospondin-1 inhibits VEGF receptor-2 signaling by disrupting its association with CD47. J Biol Chem 285:38923–38932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak ML, Nicolae A, Singh SP, Nie Z, Levens D, Isenberg JS, Roberts DD (2013) Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors. Sci Rep 3:1673

    Article  PubMed  PubMed Central  Google Scholar 

  • Kaur S, Chang T, Singh SP, Lim L, Mannan P, Garfield SH, Pendrak ML, Soto-Pantoja DR, Rosenberg AZ, Jin S, Roberts DD (2014a) CD47 signaling regulates the immunosuppressive activity of VEGF in T cells. J Immunol 193:3914–3924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaur S, Singh SP, Elkahloun AG, Wu W, Abu-Asab MS, Roberts DD (2014b) CD47-dependent immunomodulatory and angiogenic activities of extracellular vesicles produced by T cells. Matrix Biol 37:49–59

    Article  CAS  PubMed  Google Scholar 

  • Kaur S, Elkahloun AG, Singh SP, Chen QR, Meerzaman DM, Song T, Manu N, Wu W, Mannan P, Garfield SH, Roberts DD (2016) A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer. Oncotarget 7:10133–10152

    Article  PubMed  PubMed Central  Google Scholar 

  • Kibria G, Ramos EK, Lee KE, Bedoyan S, Huang S, Samaeekia R, Athman JJ, Harding CV, Lotvall J, Harris L, Thompson CL, Liu H (2016) A rapid, automated surface protein profiling of single circulating exosomes in human blood. Sci Rep 6:36502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M, Busch H, Boettcher M, Mougiakakos D, Reichardt W, Bronsert P, Brunton VG, Pilarsky C, Winkler TH, Brabletz S, Stemmler MP, Brabletz T (2017) The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 19:518–529

    Article  CAS  PubMed  Google Scholar 

  • Law RH, Zhang Q, Mcgowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC (2006) An overview of the serpin superfamily. Genome Biol 7:216

    Article  PubMed  PubMed Central  Google Scholar 

  • Lawson D, Harrison M, Shapland C (1997) Fibroblast transgelin and smooth muscle SM22alpha are the same protein, the expression of which is down-regulated in many cell lines. Cell Motil Cytoskeleton 38:250–257

    Article  CAS  PubMed  Google Scholar 

  • Lee TK, Cheung VC, Lu P, Lau EY, Ma S, Tang KH, Tong M, Lo J, Ng IO (2014) Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 60:179–191

    Article  CAS  PubMed  Google Scholar 

  • Ley K (2003) The role of selectins in inflammation and disease. Trends Mol Med 9:263–268

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J, Chao M, Weissman IL, Majeti R (2015) Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One 10:e0137345

    Article  PubMed  PubMed Central  Google Scholar 

  • Magenta A, Cencioni C, Fasanaro P, Zaccagnini G, Greco S, Sarra-Ferraris G, Antonini A, Martelli F, Capogrossi MC (2011) miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ 18:1628–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maile LA, Badley-Clarke J, Clemmons DR (2003) The association between integrin-associated protein and SHPS-1 regulates insulin-like growth factor-I receptor signaling in vascular smooth muscle cells. Mol Biol Cell 14:3519–3528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Majeti, R, Chao, MP, Alizadeh, AA, Pang, WW, Jaiswal, S, Gibbs, KD, Jr., Van Rooijen, N, Weissman, IL. (2009). CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell, 138, 286–299

  • Matlung HL, Szilagyi K, Barclay NA, Van Den Berg TK (2017) The CD47-SIRPalpha signaling axis as an innate immune checkpoint in cancer. Immunol Rev 276:145–164

    Article  CAS  PubMed  Google Scholar 

  • Matozaki T, Murata Y, Okazawa H, Ohnishi H (2009) Functions and molecular mechanisms of the CD47-SIRPalpha signalling pathway. Trends Cell Biol 19:72–80

    Article  CAS  PubMed  Google Scholar 

  • Minciacchi VR, You S, Spinelli C, Morley S, Zandian M, Aspuria PJ, Cavallini L, Ciardiello C, Reis Sobreiro M, Morello M, Kharmate G, Jang SC, Kim DK, Hosseini-Beheshti E, Tomlinson Guns E, Gleave M, Gho YS, Mathivanan S, Yang W, Freeman MR, Di Vizio D (2015) Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles. Oncotarget 6:11327–11341

    Article  PubMed  PubMed Central  Google Scholar 

  • Mitola S, Brenchio B, Piccinini M, Tertoolen L, Zammataro L, Breier G, Rinaudo MT, Den Hertog J, Arese M, Bussolino F (2006) Type I collagen limits VEGFR-2 signaling by a SHP2 protein-tyrosine phosphatase-dependent mechanism 1. Circ Res 98:45–54

    Article  CAS  PubMed  Google Scholar 

  • Mouta Carreira C, Nasser SM, Di Tomaso E, Padera TP, Boucher Y, Tomarev SI, Jain RK (2001) LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res 61:8079–8084

    CAS  PubMed  Google Scholar 

  • Naito Y, Yoshioka Y, Yamamoto Y, Ochiya T (2017) How cancer cells dictate their microenvironment: present roles of extracellular vesicles. Cell Mol Life Sci 74:697–713

    Article  CAS  PubMed  Google Scholar 

  • Narizhneva NV, Razorenova OV, Podrez EA, Chen J, Chandrasekharan UM, Dicorleto PE, Plow EF, Topol EJ, Byzova TV (2005) Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium. FASEB J 19:1158–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neish AS, Williams AJ, Palmer HJ, Whitley MZ, Collins T (1992) Functional analysis of the human vascular cell adhesion molecule 1 promoter. J Exp Med 176:1583–1593

    Article  CAS  PubMed  Google Scholar 

  • Ohyashiki JH, Umezu T, Ohyashiki K (2016) Exosomes promote bone marrow angiogenesis in hematologic neoplasia: the role of hypoxia. Curr Opin Hematol 23:268–273

    Article  CAS  PubMed  Google Scholar 

  • Okumura N, Minamiyama R, Ho LT, Kay EP, Kawasaki S, Tourtas T, Schlotzer-Schrehardt U, Kruse FE, Young RD, Quantock AJ, Kinoshita S, Koizumi N (2015) Involvement of ZEB1 and Snail1 in excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy. Lab Investig 95:1291–1304

    Article  CAS  PubMed  Google Scholar 

  • Ou J, Li J, Pan F, Xie G, Zhou Q, Huang H, Liang H (2011) Endostatin suppresses colorectal tumor-induced lymphangiogenesis by inhibiting expression of fibronectin extra domain A and integrin alpha9. J Cell Biochem 112:2106–2114

    Article  CAS  PubMed  Google Scholar 

  • Palenski TL, Sorenson CM, Sheibani N (2013) Inflammatory cytokine-specific alterations in retinal endothelial cell function. Microvasc Res 89:57–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan BT, Johnstone RM (1983) Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33:967–978

    Article  CAS  PubMed  Google Scholar 

  • Park SY, Shi X, Pang J, Yan C, Berk BC (2013) Thioredoxin-interacting protein mediates sustained VEGFR2 signaling in endothelial cells required for angiogenesis. Arterioscler Thromb Vasc Biol 33:737–743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petrova PS, Viller NN, Wong M, Pang X, Lin GH, Dodge K, Chai V, Chen H, Lee V, House V, Vigo NT, Jin D, Mutukura T, Charbonneau M, Truong T, Viau S, Johnson LD, Linderoth E, Sievers EL, Maleki Vareki S, Figueredo R, Pampillo M, Koropatnick J, Trudel S, Mbong N, Jin L, Wang JC, Uger RA (2017) TTI-621 (SIRPalphaFc): a CD47-blocking innate immune checkpoint inhibitor with broad antitumor activity and minimal erythrocyte binding. Clin Cancer Res 23:1068–1079

    Article  CAS  PubMed  Google Scholar 

  • Pilzer D, Gasser O, Moskovich O, Schifferli JA, Fishelson Z (2005) Emission of membrane vesicles: roles in complement resistance, immunity and cancer. Springer Semin Immunopathol 27:375–387

    Article  CAS  PubMed  Google Scholar 

  • Raaz-Schrauder D, Ekici AB, Klinghammer L, Stumpf C, Achenbach S, Herrmann M, Reis A, Garlichs CD (2014) The proinflammatory effect of C-reactive protein on human endothelial cells depends on the FcgammaRIIa genotype. Thromb Res 133:426–432

    Article  CAS  PubMed  Google Scholar 

  • Roberts DD, Kaur S, Isenberg JS (2017) Regulation of cellular redox signaling by Matricellular proteins in vascular biology, immunology, and cancer. Antioxid Redox Signal 27:874–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruhul Amin AR, Machida K, Oshima K, Oo ML, Thant AA, Senga T, Matsuda S, Akhand AA, Maeda A, Kurosaki T, Hamaguchi M (2002) A role for SHPS-1/SIRPalpha1 in IL-1beta- and TNFalpha-dependent signaling. Oncogene 21:8871–8878

    Article  CAS  PubMed  Google Scholar 

  • Sadallah S, Eken C, Martin PJ, Schifferli JA (2011) Microparticles (ectosomes) shed by stored human platelets downregulate macrophages and modify the development of dendritic cells. J Immunol 186:6543–6552

    Article  CAS  PubMed  Google Scholar 

  • St Hill CA (2011) Interactions between endothelial selectins and cancer cells regulate metastasis. Front Biosci (Landmark Ed) 16:3233–3251

    Article  CAS  Google Scholar 

  • Thery C, Duban L, Segura E, Veron P, Lantz O, Amigorena S (2002) Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol 3:1156–1162

    Article  CAS  PubMed  Google Scholar 

  • Tian T, Zhu YL, Zhou YY, Liang GF, Wang YY, Hu FH, Xiao ZD (2014) Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J Biol Chem 289:22258–22267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tkach M, Thery C (2016) Communication by extracellular vesicles: where we are and where we need to go. Cell 164:1226–1232

    Article  CAS  PubMed  Google Scholar 

  • Tsai RK, Rodriguez PL, Discher DE (2010) Self inhibition of phagocytosis: the affinity of 'marker of self' CD47 for SIRPalpha dictates potency of inhibition but only at low expression levels. Blood Cells Mol Dis 45:67–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    Article  CAS  PubMed  Google Scholar 

  • Wendler F, Favicchio R, Simon T, Alifrangis C, Stebbing J, Giamas G (2017) Extracellular vesicles swarm the cancer microenvironment: from tumor-stroma communication to drug intervention. Oncogene 36:877–884

    Article  CAS  PubMed  Google Scholar 

  • Witz IP (2006) Tumor-microenvironment interactions: the selectin-selectin ligand axis in tumor-endothelium cross talk. Cancer Treat Res 130:125–140

    Article  CAS  PubMed  Google Scholar 

  • Zahr A, Alcaide P, Yang J, Jones A, Gregory M, Dela Paz NG, Patel-Hett S, Nevers T, Koirala A, Luscinskas FW, Saint-Geniez M, Ksander B, D'amore PA, Argueso P (2016) Endomucin prevents leukocyte-endothelial cell adhesion and has a critical role under resting and inflammatory conditions. Nat Commun 7:10363

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Zhang W, Li Y, Alvarez A, Li Z, Wang Y, Song L, Lv D, Nakano I, Hu B, Cheng SY, Feng H (2016) SHP-2-upregulated ZEB1 is important for PDGFRalpha-driven glioma epithelial-mesenchymal transition and invasion in mice and humans. Oncogene 35:5641–5652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou L, Isenberg JS, Cao Z, Roberts DD (2006) Type I collagen is a molecular target for inhibition of angiogenesis by endogenous thrombospondin-1. Oncogene 25:536–545

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (DDR). We thank Kavya Ravikanti, Marlen Castro Hernandez, Jana’e Waugh and Weiwei Wu for technical assistance.

Author information

Authors and Affiliations

  1. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10 Room 2S235, 10 Center Drive MSC1500, Bethesda, MD, 20892-1500, USA

    Sukhbir Kaur & David D. Roberts

  2. Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Abdel G. Elkahloun

  3. Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20982, USA

    Satya P. Singh

  4. Section of Intercellular Interactions, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20982, USA

    Anush Arakelyan

Authors
  1. Sukhbir Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abdel G. Elkahloun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satya P. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anush Arakelyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David D. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DDR and SK designed the research, SK, AG, SPS, AA performed experiments. SK, DDR, SPS and AG analyzed and interpreted the data. SK and DDR wrote the manuscript.

Corresponding author

Correspondence to David D. Roberts.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Electronic supplementary material

ESM 1

(PDF 475 kb)

ESM 2

(PDF 373 kb)

ESM 3

(PDF 524 kb)

ESM 4

(PDF 600 kb)

ESM 5

(PDF 395 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaur, S., Elkahloun, A.G., Singh, S.P. et al. A function-blocking CD47 antibody modulates extracellular vesicle-mediated intercellular signaling between breast carcinoma cells and endothelial cells. J. Cell Commun. Signal. 12, 157–170 (2018). https://doi.org/10.1007/s12079-017-0428-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-017-0428-0

Keywords

Search

Navigation