Exosomal Thrombospondin-1 Disrupts the Integrity of Endothelial Intercellular Junctions to Facilitate Breast Cancer Cell Metastasis

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2019 Dec 11

PMID 31817450

Citations 19

Authors

Junyu Cen

Lingyun Feng

Huichuan Ke

Lifeng Bao

Lin Z Li

Yoshimasa Tanaka

Jun Weng

Li Su

Affiliations

Soon will be listed here.

Abstract

Transendothelial migration of malignant cells plays an essential role in tumor progression and metastasis. The present study revealed that treating human umbilical vein endothelial cells (HUVECs) with exosomes derived from metastatic breast cancer cells increased the number of cancer cells migrating through the endothelial cell layer and impaired the tube formation of HUVECs. Furthermore, the expression of intercellular junction proteins, including vascular endothelial cadherin (VE-cadherin) and zona occluden-1 (ZO-1), was reduced significantly in HUVECs treated with carcinoma-derived exosomes. Proteomic analyses revealed that thrombospondin-1 (TSP1) was highly expressed in breast cancer cell MDA-MB-231-derived exosomes. Treating HUVECs with TSP1-enriched exosomes similarly promoted the transendothelial migration of malignant cells and decreased the expression of intercellular junction proteins. TSP1-down regulation abolished the effects of exosomes on HUVECs. The migration of breast cancer cells was markedly increased in a zebrafish in vivo model injected with TSP1-overexpressing breast cancer cells. Taken together, these results suggest that carcinoma-derived exosomal TSP1 facilitated the transendothelial migration of breast cancer cells via disrupting the intercellular integrity of endothelial cells.

Citing Articles

Cancer cells impact the microrheology of endothelial cells during physical contact or through paracrine signalling.

Kefala G, Tsvirkun D, Laurent V, Verdier C Sci Rep. 2025; 15(1):8064.

PMID: 40055419 PMC: 11889160. DOI: 10.1038/s41598-025-92422-w.

Recent Advances and Mechanism of Nanomaterials Promoting Tumor Metastasis.

Wang W, Pang X, Dong M, Li R, Liu Z, Liang Y Environ Health (Wash). 2024; 1(6):367-382.

PMID: 39474052 PMC: 11503957. DOI: 10.1021/envhealth.3c00132.

Enigmatic exosomal connection in lung cancer drug resistance.

Patra S, Sahoo R, Biswal S, Panda S, Biswal B Mol Ther Nucleic Acids. 2024; 35(2):102177.

PMID: 38617976 PMC: 11015513. DOI: 10.1016/j.omtn.2024.102177.

Protein cargo in extracellular vesicles as the key mediator in the progression of cancer.

Hanelova K, Raudenska M, Masarik M, Balvan J Cell Commun Signal. 2024; 22(1):25.

PMID: 38200509 PMC: 10777590. DOI: 10.1186/s12964-023-01408-6.

Progress in cancer neuroscience.

Lan Y, Zou S, Wang W, Chen Q, Zhu Y MedComm (2020). 2023; 4(6):e431.

PMID: 38020711 PMC: 10665600. DOI: 10.1002/mco2.431.

References

Tzeng H, Tsai C, Yen Y, Cheng H, Chen Y, Pu S . Dysregulation of Rab37-Mediated Cross-talk between Cancer Cells and Endothelial Cells via Thrombospondin-1 Promotes Tumor Neovasculature and Metastasis. Clin Cancer Res. 2017; 23(9):2335-2345. DOI: 10.1158/1078-0432.CCR-16-1520. View

Benn A, Bredow C, Casanova I, Vukicevic S, Knaus P . VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling. J Cell Sci. 2015; 129(1):206-18. PMC: 4732303. DOI: 10.1242/jcs.179960. View

Yuan A, Farber E, Rapoport A, Tejada D, Deniskin R, Akhmedov N . Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One. 2009; 4(3):e4722. PMC: 2648987. DOI: 10.1371/journal.pone.0004722. View

Dvorak H, Weaver V, Tlsty T, Bergers G . Tumor microenvironment and progression. J Surg Oncol. 2011; 103(6):468-74. PMC: 3277953. DOI: 10.1002/jso.21709. View

Firlej V, Mathieu J, Gilbert C, Lemonnier L, Nakhle J, Gallou-Kabani C . Thrombospondin-1 triggers cell migration and development of advanced prostate tumors. Cancer Res. 2011; 71(24):7649-58. DOI: 10.1158/0008-5472.CAN-11-0833. View

Chiang S, Cabrera R, Segall J . Tumor cell intravasation. Am J Physiol Cell Physiol. 2016; 311(1):C1-C14. PMC: 4967137. DOI: 10.1152/ajpcell.00238.2015. View

Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki J . Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem. 2013; 288(48):34343-51. PMC: 3843049. DOI: 10.1074/jbc.M113.480822. View

Hannafon B, Carpenter K, Berry W, Janknecht R, Dooley W, Ding W . Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA). Mol Cancer. 2015; 14:133. PMC: 4504101. DOI: 10.1186/s12943-015-0400-7. View

Regev-Rudzki N, Wilson D, Carvalho T, Sisquella X, Coleman B, Rug M . Cell-cell communication between malaria-infected red blood cells via exosome-like vesicles. Cell. 2013; 153(5):1120-33. DOI: 10.1016/j.cell.2013.04.029. View

10.

Muramatsu F, Kidoya H, Naito H, Sakimoto S, Takakura N . microRNA-125b inhibits tube formation of blood vessels through translational suppression of VE-cadherin. Oncogene. 2012; 32(4):414-21. DOI: 10.1038/onc.2012.68. View

11.

Sweetwyne M, Murphy-Ullrich J . Thrombospondin1 in tissue repair and fibrosis: TGF-β-dependent and independent mechanisms. Matrix Biol. 2012; 31(3):178-86. PMC: 3295861. DOI: 10.1016/j.matbio.2012.01.006. View

12.

Gao Q, Chen K, Gao L, Zheng Y, Yang Y . Thrombospondin-1 signaling through CD47 inhibits cell cycle progression and induces senescence in endothelial cells. Cell Death Dis. 2016; 7(9):e2368. PMC: 5059850. DOI: 10.1038/cddis.2016.155. View

13.

Rezaei M, Cao J, Friedrich K, Kemper B, Brendel O, Grosser M . The expression of VE-cadherin in breast cancer cells modulates cell dynamics as a function of tumor differentiation and promotes tumor-endothelial cell interactions. Histochem Cell Biol. 2017; 149(1):15-30. DOI: 10.1007/s00418-017-1619-8. View

14.

Dejana E, Tournier-Lasserve E, Weinstein B . The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell. 2009; 16(2):209-21. DOI: 10.1016/j.devcel.2009.01.004. View

15.

Liu J, Miao G, Wang B, Zheng N, Ma L, Chen X . Chlamydia pneumoniae infection promotes monocyte transendothelial migration by increasing vascular endothelial cell permeability via the tyrosine phosphorylation of VE-cadherin. Biochem Biophys Res Commun. 2018; 497(2):742-748. DOI: 10.1016/j.bbrc.2018.02.145. View

16.

Muramatsu F, Kidoya H, Naito H, Hayashi Y, Iba T, Takakura N . Plakoglobin maintains the integrity of vascular endothelial cell junctions and regulates VEGF-induced phosphorylation of VE-cadherin. J Biochem. 2017; 162(1):55-62. DOI: 10.1093/jb/mvx001. View

17.

Kazerounian S, Yee K, Lawler J . Thrombospondins in cancer. Cell Mol Life Sci. 2008; 65(5):700-12. PMC: 2752021. DOI: 10.1007/s00018-007-7486-z. View

18.

Bachurski D, Schuldner M, Nguyen P, Malz A, Reiners K, Grenzi P . Extracellular vesicle measurements with nanoparticle tracking analysis - An accuracy and repeatability comparison between NanoSight NS300 and ZetaView. J Extracell Vesicles. 2019; 8(1):1596016. PMC: 6450530. DOI: 10.1080/20013078.2019.1596016. View

19.

Lee S, Rouhi P, Jensen L, Zhang D, Ji H, Hauptmann G . Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model. Proc Natl Acad Sci U S A. 2009; 106(46):19485-90. PMC: 2780785. DOI: 10.1073/pnas.0909228106. View

20.

Li H, Shi X, Liu J, Hu C, Zhang X, Liu H . The soluble fragment of VE-cadherin inhibits angiogenesis by reducing endothelial cell proliferation and tube capillary formation. Cancer Gene Ther. 2010; 17(10):700-7. DOI: 10.1038/cgt.2010.26. View