Original Article

Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208

Xi-wei Ji, Run-tao Li, Zai-quan Li, Liang Li, Xue-yan Shao, Si-yuan Wang, Yin Yuan, Tian-yan Zhou, Wei Lu
DOI: 10.1038/aps.2013.156


Yan LIU1, 2, #, Xiao-jian ZHU1, #, Chen ZENG1, Pin-hui WU1, Hong-xiang WANG3, Zhi-chao CHEN1, *, Qiu-bai LI1, *
1Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 2Department of Hematology, Affiliated Hospital of Taishan Medical College, Taian 271000, China; 3Department of Hematology, Wuhan Central Hospital, Wuhan 430022, China

Aim: To investigate whether human multiple myeloma (MM) cells secrete microvesicles (MVs) and whether the MVs secreted from MM cells (MM-MVs) promote angiogenesis.
Methods: RPMI8226 human MM cells and EA.hy926 human umbilical vein cells were used. MVs isolated from RPMI 8226 cells were characterized under laser confocal microscopy, electron microscopy and with flow cytometry. The fusion of MM-MVs and EA.hy926 cells was studied under confocal microscopy, and the transfer of CD138 to EA.hy926 cells was demonstrated with flow cytometry. The proliferation, invasion and tube formation of EA.hy926 cells in vitro were evaluated using MTT, transwell migration and tube formation assays, respectively. The vasculization of EA.hy926 cells in vivo was studied using Matrigel plug assay. The expression of IL-6 and VEGF was analyzed with PCR and ELISA.

Results: MM-MVs from the RPMI 8226 cells had the characteristic cup-shape with diameter of 100–1000 nm. Most of the MM-MVs expressed phosphatidylserine and the myeloma cell marker CD138, confirming that they were derived from myeloma cells. After added to EA.hy926 cells, the MM-MVs transferred CD138 to the endothelial cells and significantly stimulated the endothelial cells to proliferate, invade, secrete IL-6 and VEGF, two key angiogenic factors of myeloma, and form tubes in vitro and in vivo.

Conclusion: Our results confirm the presence of MVs in MM cells and support the idea that MM-MVs are newfound mediators for myeloma angiogenesis and may serve as a therapeutic target to treat MM.

Keywords: microvesicle; multiple myeloma; CD138; IL-6; VEGF; angiogenesis; endothelial cell

This research was supported by grants from the National Natural Science Foundation of China (81272624 and 81071943). We would like to thank the Flow Cytometry Lab of Tongji Medical College for the detection and the analysis of the surface markers of the MM-MVs.
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail qiubai.li@yahoo.com (Qiu-bai LI); chenzc2001@yahoo.com.cn (Zhi-chao CHEN)
Received 2013-07-22 Accepted 2013-09-03

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