Anti-VEGF-A Affects the Angiogenic Properties of Tumor-Derived Microparticles

Munster, Michal; Fremder, Ella; Miller, Valeria; Ben-Tsedek, Neta; Davidi, Shiri; Scherer, Stefan; Shaked, Yuval

doi:10.1371/journal.pone.0095983

Cited by 15 publications

(15 citation statements)

References 41 publications

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“…We speculate that these phenomena may be due to differences between cytotoxic drugs, which induce tumor cell apoptosis and anti-angiogenic agents, which inhibit endothelial cells instead of tumor cells and do not cause apoptosis. This is consistent with previous reports (21,22). The number of tumorderived microparticles (TMPs) was significantly increased in breast carcinoma cells exposed to paclitaxel chemotherapy compared to the number in untreated tumor cells (21), but treatment with anti-VEGF-A neutralizing antibodies, which is a cytostatic drug, did not lead to a significant change in the number of TMPs (22).…”

Section: Discussionsupporting

confidence: 92%

“…A previous study demonstrated that MM MVs exposed to bortezomib had lower expression levels of angiogenic factors, which limited the proliferation and migration of these endothelial cells (23). Similarly, another study showed that the expression level of VEGF-A was decreased in TMPs from breast carcinoma cells exposed to anti-VEGF-A antibody and thereby reduced the angiogenic potential (22). However, the impact of anti-angiogenic therapy with lenalidomide has not been elucidated; moreover, the effects of bortezomib-or lenalidomide-exposed MVs on the NF-κB activity of endothelial cells have not been reported.…”

Section: Discussionmentioning

confidence: 96%

“…One study demonstrated that tumor-derived microparticles (TMPs) from mammary carcinoma cells exposed to paclitaxel chemotherapy contributed to angiogenesis and tumor regrowth (21). However, another study showed that the neutralization of VEGF-A with anti-angiogenic drugs in cultured breast carcinoma cells blocked TMP-induced angiogenesis (22). There has been little research on the effect of drugs on MM MVs.…”

Section: Introductionmentioning

confidence: 99%

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Microvesicles shed from bortezomib-treated or lenalidomide-treated human myeloma cells inhibit angiogenesis inï¿½vitro

et al. 2018

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Angiogenesis plays a significant role in the pathogenesis of multiple myeloma (MM). Microvesicles (MVs), a type of extracellular vesicles, are known as important players in cell-to-cell communication. MM-derived MVs have exhibited the activity of promoting angiogenesis. Bortezomib and lenalidomide are important drugs for treating myeloma. Therefore, the aim of the present study was to investigate whether and how MVs secreted from human myeloma cells exposed to bortezomib and lenalidomide affect angiogenesis. RPMI-8226 human myeloma cells and human umbilical vein endothelial cells (HUVECs) were used. MVs were isolated from the drug-treated RPMI-8226 cells. The number of the MVs were analyzed with flow cytometry. The expression of pro-angiogenic factors was analyzed with PCR and ELISA. The angiogenic potential of HUVECs was examined. NF-κB activation was analyzed using PCR, immunofluorescent staining and western blotting assays. We showed that bortezomib treatment induced an increase in the number of MVs shed from myeloma cells, but the number of MVs was not significantly altered by lenalidomide. The expression levels of vascular endothelial growth factor (VEGF), interleukin 6 (IL-6) and basic fibroblast growth factor (bFGF) were reduced in the MVs from the RPMI-8226 cells exposed to bortezomib and lenalidomide. Consequently, these MVs exhibited reduced angiogenic potential, as evaluated by wound healing tests, Boyden chamber assays and tube formation assays. Co-culturing HUVECs with drug-treated MVs inhibited NF-κB activation in the HUVECs and reduced the secretion of pro-angiogenic factors. In conclusion, bortezomib and lenalidomide treatment of cultured myeloma cells can block MV-induced angiogenesis and hence provides another mechanism for anti-angiogenic therapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Microvesicles shed from bortezomib-treated or lenalidomide-treated human myeloma cells inhibit angiogenesis inï¿½vitro

et al. 2018

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“…In a different study, the anti-VEGF-A antibody B20 reduced the level of VEGF-A enclosed in breast cancer cell-secreted microparticles and these vesicles were unable to activate endothelial cells and could not promote BM-derived pro-angiogenic cell colonization [87]. In addition, exosomes derived from hematological tumor cells such as chronic myelogenous leukemia cells and MM cells also contribute to angiogenesis [88–91].…”

Section: Effect Of Tumor-derived Evs On Bm-derived Cellsmentioning

confidence: 99%

Extracellular vesicle cross-talk in the bone marrow microenvironment: implications in multiple myeloma

et al. 2016

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The bone marrow (BM) represents a complex microenvironment containing stromal cells, immune cells, osteoclasts, osteoblasts, and hematopoietic cells, which are crucial for the immune response, bone formation, and hematopoiesis. Apart from soluble factors and direct cell-cell contact, extracellular vesicles (EVs), including exosomes, were recently identified as a third mediator for cell communication. Solid evidence has already demonstrated the involvement of various BM-derived cells and soluble factors in the regulation of multiple biological processes whereas the EV-mediated message delivery system from the BM has just been explored in recent decades. These EVs not only perform physiological functions but can also play a role in cancer development, including in Multiple Myeloma (MM) which is a plasma cell malignancy predominantly localized in the BM. This review will therefore focus on the multiple functions of EVs derived from BM cells, the manipulation of the BM by cancer-derived EVs, and the role of BM EVs in MM progression.

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“…Although traditionally thought of as signaling mediated primarily through soluble factors, the role of microvesicles and in particular TMVs in paracrine signaling through the horizontal transfer of bioactive molecules, is becoming more and more appreciated. The transfer of pro‐angiogenic cargos, for example, including EGFRvIII, VEGF, TGF‐β, and miRNA 1246 can significantly impact tumorigenesis . TMV‐mediated signaling can also serve to form a robust pro‐tumorigenic niche by signaling to and activating fibroblasts in the tumor microenvironment.…”

Section: Current Perspectives On Tmv Formation Cargo Enrichment Andmentioning

confidence: 99%

Tumor‐derived microvesicles in the tumor microenvironment: How vesicle heterogeneity can shape the future of a rapidly expanding field

2015

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Information transmission from tumor cells to non-tumor cells in the surrounding microenvironment via microvesicles is a more recently studied form of intercellular signaling that can have a marked impact on the tumor microenvironment. Tumor-derived microvesicles (TMVs) are packed with information including signaling proteins and nucleic acids, and can be taken up by target cells, enabling paracrine signaling. While previous research has focused on how vesicles released from pathologic cells differ from normal cells, the heterogeneity that exists within the TMV population itself is not fully characterized, and only beginning to be appreciated. In this review, we summarize current understanding of the biogenesis and roles of shed TMVs in the tumor microenvironment, and speculate on the consequences for tumor cell signaling in light of the hypothesis that there exists variance within the TMV population. The analysis of differential signaling upon cell-TMV interactions provides insights into potential mechanisms of intercellular communication.

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Anti-VEGF-A Affects the Angiogenic Properties of Tumor-Derived Microparticles

Cited by 15 publications

References 41 publications

Microvesicles shed from bortezomib-treated or lenalidomide-treated human myeloma cells inhibit angiogenesis inï¿½vitro

Microvesicles shed from bortezomib-treated or lenalidomide-treated human myeloma cells inhibit angiogenesis inï¿½vitro

Extracellular vesicle cross-talk in the bone marrow microenvironment: implications in multiple myeloma

Tumor‐derived microvesicles in the tumor microenvironment: How vesicle heterogeneity can shape the future of a rapidly expanding field

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