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Microparticles mediated cross-talk between tumoral and endothelial cells promote the constitution of a pro-metastatic vascular niche through Arf6 up regulation.

Pasquier J, Thawadi HA, Ghiabi P, Abu-Kaoud N, Maleki M, Guerrouahen BS, Vidal F, Courderc B, Ferron G, Martinez A, Al Sulaiti H, Gupta R, Rafii S, Rafii A - Cancer Microenviron (2014)

Bottom Line: Our data show that MPs from mesenchymal-like cell lines (MDA-MB231, SKOV3 and APOCC) were able to promote an activation of endothelial cells through Akt phosphorylation, compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7).The endothelial activation was associated to increased Arf6 expression and MPs secretion.Such cross-talk may play a role in perfusion independent role of the endothelium.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.

ABSTRACT
The tumor stroma plays an essential role in tumor growth, resistance to therapy and occurrence of metastatic phenotype. Tumor vessels have been considered as passive conducts for nutrients but several studies have demonstrated secretion of pro-tumoral factors by endothelial cells. The failure of anti-angiogenic therapies to meet expectations raised by pre-clinical studies prompt us to better study the cross-talk between endothelial and cancer cells. Here, we hypothesized that tumor cells and the endothelium secrete bio-active microparticles (MPs) participating to a functional cross-talk. We characterized the cancer cells MPs, using breast and ovarian cancer cell lines (MCF7, MDA-MB231, SKOV3, OVCAR3 and a primary cell lines, APOCC). Our data show that MPs from mesenchymal-like cell lines (MDA-MB231, SKOV3 and APOCC) were able to promote an activation of endothelial cells through Akt phosphorylation, compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7). The MPs from mesenchymal-like cells contained increased angiogenic molecules including PDGF, IL8 and angiogenin. The endothelial activation was associated to increased Arf6 expression and MPs secretion. Endothelial activation functionalized an MP dependent pro-tumoral vascular niche promoting cancer cells proliferation, invasiveness, stem cell phenotype and chemoresistance. MPs from cancer and endothelial cells displayed phenotypic heterogeneity, and participated to a functional cross-talk where endothelial activation by cancer MPs resulted in increased secretion of EC-MPs sustaining tumor cells. Such cross-talk may play a role in perfusion independent role of the endothelium.

No MeSH data available.


Related in: MedlinePlus

Mensenchymal MPs are able to induce endothelial activation. a HUVECs were incubated with MPs from each cancer cells lines during 30 min and Akt activation was analyzed by confocal microscopy and flow cytometry. Prior to confocal microscopy HUVECs were stained with WGA red and nuclei were tagged with DAPI. Only MPs from MDA and SKOV3 were able to induce Akt phosphorylation in HUVECs. Scale bar 20 μm. b Western blot for Phospho-Akt (Ser473) confirmed that only MPs from MDA, SKOV3 and APOCC are able to induce phosphorylation of Akt in HUVECS. C. Human angiogenesis array of MPs contents from an E-MPs (MCF7), iM-MPs (MCF7 treated with TGFβ) and M-MPs (MDA) model. The significant protein modification were cut from the full membrane (Supplementary Figure 4) and represent in the top panel. The bottom panel represents the relative quantification of the dot pixel density
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Fig4: Mensenchymal MPs are able to induce endothelial activation. a HUVECs were incubated with MPs from each cancer cells lines during 30 min and Akt activation was analyzed by confocal microscopy and flow cytometry. Prior to confocal microscopy HUVECs were stained with WGA red and nuclei were tagged with DAPI. Only MPs from MDA and SKOV3 were able to induce Akt phosphorylation in HUVECs. Scale bar 20 μm. b Western blot for Phospho-Akt (Ser473) confirmed that only MPs from MDA, SKOV3 and APOCC are able to induce phosphorylation of Akt in HUVECS. C. Human angiogenesis array of MPs contents from an E-MPs (MCF7), iM-MPs (MCF7 treated with TGFβ) and M-MPs (MDA) model. The significant protein modification were cut from the full membrane (Supplementary Figure 4) and represent in the top panel. The bottom panel represents the relative quantification of the dot pixel density

Mentions: Akt phosphorylation is known to be involved in EC proliferation, migration and tube formation [36]. Our findings and a recent study by Kawamoto et al. propose that M-MPs could activate Akt phosphorylation in HUVECs [16]. In concordance with the functional experiments, confocal microscopy and western blot confirmed that only M-MPs and iM-MPs induced Akt phosphorylation in HUVECs (Fig. 4a-b and Supplementary figure 4).Fig. 4


Microparticles mediated cross-talk between tumoral and endothelial cells promote the constitution of a pro-metastatic vascular niche through Arf6 up regulation.

Pasquier J, Thawadi HA, Ghiabi P, Abu-Kaoud N, Maleki M, Guerrouahen BS, Vidal F, Courderc B, Ferron G, Martinez A, Al Sulaiti H, Gupta R, Rafii S, Rafii A - Cancer Microenviron (2014)

Mensenchymal MPs are able to induce endothelial activation. a HUVECs were incubated with MPs from each cancer cells lines during 30 min and Akt activation was analyzed by confocal microscopy and flow cytometry. Prior to confocal microscopy HUVECs were stained with WGA red and nuclei were tagged with DAPI. Only MPs from MDA and SKOV3 were able to induce Akt phosphorylation in HUVECs. Scale bar 20 μm. b Western blot for Phospho-Akt (Ser473) confirmed that only MPs from MDA, SKOV3 and APOCC are able to induce phosphorylation of Akt in HUVECS. C. Human angiogenesis array of MPs contents from an E-MPs (MCF7), iM-MPs (MCF7 treated with TGFβ) and M-MPs (MDA) model. The significant protein modification were cut from the full membrane (Supplementary Figure 4) and represent in the top panel. The bottom panel represents the relative quantification of the dot pixel density
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4150875&req=5

Fig4: Mensenchymal MPs are able to induce endothelial activation. a HUVECs were incubated with MPs from each cancer cells lines during 30 min and Akt activation was analyzed by confocal microscopy and flow cytometry. Prior to confocal microscopy HUVECs were stained with WGA red and nuclei were tagged with DAPI. Only MPs from MDA and SKOV3 were able to induce Akt phosphorylation in HUVECs. Scale bar 20 μm. b Western blot for Phospho-Akt (Ser473) confirmed that only MPs from MDA, SKOV3 and APOCC are able to induce phosphorylation of Akt in HUVECS. C. Human angiogenesis array of MPs contents from an E-MPs (MCF7), iM-MPs (MCF7 treated with TGFβ) and M-MPs (MDA) model. The significant protein modification were cut from the full membrane (Supplementary Figure 4) and represent in the top panel. The bottom panel represents the relative quantification of the dot pixel density
Mentions: Akt phosphorylation is known to be involved in EC proliferation, migration and tube formation [36]. Our findings and a recent study by Kawamoto et al. propose that M-MPs could activate Akt phosphorylation in HUVECs [16]. In concordance with the functional experiments, confocal microscopy and western blot confirmed that only M-MPs and iM-MPs induced Akt phosphorylation in HUVECs (Fig. 4a-b and Supplementary figure 4).Fig. 4

Bottom Line: Our data show that MPs from mesenchymal-like cell lines (MDA-MB231, SKOV3 and APOCC) were able to promote an activation of endothelial cells through Akt phosphorylation, compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7).The endothelial activation was associated to increased Arf6 expression and MPs secretion.Such cross-talk may play a role in perfusion independent role of the endothelium.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.

ABSTRACT
The tumor stroma plays an essential role in tumor growth, resistance to therapy and occurrence of metastatic phenotype. Tumor vessels have been considered as passive conducts for nutrients but several studies have demonstrated secretion of pro-tumoral factors by endothelial cells. The failure of anti-angiogenic therapies to meet expectations raised by pre-clinical studies prompt us to better study the cross-talk between endothelial and cancer cells. Here, we hypothesized that tumor cells and the endothelium secrete bio-active microparticles (MPs) participating to a functional cross-talk. We characterized the cancer cells MPs, using breast and ovarian cancer cell lines (MCF7, MDA-MB231, SKOV3, OVCAR3 and a primary cell lines, APOCC). Our data show that MPs from mesenchymal-like cell lines (MDA-MB231, SKOV3 and APOCC) were able to promote an activation of endothelial cells through Akt phosphorylation, compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7). The MPs from mesenchymal-like cells contained increased angiogenic molecules including PDGF, IL8 and angiogenin. The endothelial activation was associated to increased Arf6 expression and MPs secretion. Endothelial activation functionalized an MP dependent pro-tumoral vascular niche promoting cancer cells proliferation, invasiveness, stem cell phenotype and chemoresistance. MPs from cancer and endothelial cells displayed phenotypic heterogeneity, and participated to a functional cross-talk where endothelial activation by cancer MPs resulted in increased secretion of EC-MPs sustaining tumor cells. Such cross-talk may play a role in perfusion independent role of the endothelium.

No MeSH data available.


Related in: MedlinePlus