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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

MPs from activated endothelial cells support tumor pro-metastatic phenotype. a Schematic representation of the experimental design. b CCs were plated and counted every 2 days in presence or not of MPs from E4+ECs during 6 days. EC-MPs were able to sustain proliferation of CCs. c Wound closure assay showed that ECs-MPs improved the motility of CCs. d Breast CCs were treated with Doxorubicine (10 μM) and ovarian CCs with taxol (10 μM) in presence or absence of EC-MPs. EC-MPs induced chemoresistance of CCs to chemotherapy treatment. e Spheroids of CCs were grown in 3D media during 6 days, ECs-MPs sustained the proliferation of CCs spheres. f CCs were grown with or without MPs during 4 days. Prior to cytometry analysis, breast CCs were immunostained with CD44 and CD24. Gate of interest are represented with a star on the graph. EC-MPs increase the number of putative cancer stem cells in all CCs population
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Fig6: MPs from activated endothelial cells support tumor pro-metastatic phenotype. a Schematic representation of the experimental design. b CCs were plated and counted every 2 days in presence or not of MPs from E4+ECs during 6 days. EC-MPs were able to sustain proliferation of CCs. c Wound closure assay showed that ECs-MPs improved the motility of CCs. d Breast CCs were treated with Doxorubicine (10 μM) and ovarian CCs with taxol (10 μM) in presence or absence of EC-MPs. EC-MPs induced chemoresistance of CCs to chemotherapy treatment. e Spheroids of CCs were grown in 3D media during 6 days, ECs-MPs sustained the proliferation of CCs spheres. f CCs were grown with or without MPs during 4 days. Prior to cytometry analysis, breast CCs were immunostained with CD44 and CD24. Gate of interest are represented with a star on the graph. EC-MPs increase the number of putative cancer stem cells in all CCs population

Mentions: This suggests that the modulation of endothelial plasticity by CCs may be associated with a modulation of the MPs machinery and the constitution of an endothelial pro-tumoral niche. Therefore we investigated the functional effects of EC-MPs extracted from E4+ECs on cancer cells lines focusing on the following pro-metastatic properties: migration, proliferation, chemoresistance and stemness (Fig. 6a).Fig. 6


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)

MPs from activated endothelial cells support tumor pro-metastatic phenotype. a Schematic representation of the experimental design. b CCs were plated and counted every 2 days in presence or not of MPs from E4+ECs during 6 days. EC-MPs were able to sustain proliferation of CCs. c Wound closure assay showed that ECs-MPs improved the motility of CCs. d Breast CCs were treated with Doxorubicine (10 μM) and ovarian CCs with taxol (10 μM) in presence or absence of EC-MPs. EC-MPs induced chemoresistance of CCs to chemotherapy treatment. e Spheroids of CCs were grown in 3D media during 6 days, ECs-MPs sustained the proliferation of CCs spheres. f CCs were grown with or without MPs during 4 days. Prior to cytometry analysis, breast CCs were immunostained with CD44 and CD24. Gate of interest are represented with a star on the graph. EC-MPs increase the number of putative cancer stem cells in all CCs population
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig6: MPs from activated endothelial cells support tumor pro-metastatic phenotype. a Schematic representation of the experimental design. b CCs were plated and counted every 2 days in presence or not of MPs from E4+ECs during 6 days. EC-MPs were able to sustain proliferation of CCs. c Wound closure assay showed that ECs-MPs improved the motility of CCs. d Breast CCs were treated with Doxorubicine (10 μM) and ovarian CCs with taxol (10 μM) in presence or absence of EC-MPs. EC-MPs induced chemoresistance of CCs to chemotherapy treatment. e Spheroids of CCs were grown in 3D media during 6 days, ECs-MPs sustained the proliferation of CCs spheres. f CCs were grown with or without MPs during 4 days. Prior to cytometry analysis, breast CCs were immunostained with CD44 and CD24. Gate of interest are represented with a star on the graph. EC-MPs increase the number of putative cancer stem cells in all CCs population
Mentions: This suggests that the modulation of endothelial plasticity by CCs may be associated with a modulation of the MPs machinery and the constitution of an endothelial pro-tumoral niche. Therefore we investigated the functional effects of EC-MPs extracted from E4+ECs on cancer cells lines focusing on the following pro-metastatic properties: migration, proliferation, chemoresistance and stemness (Fig. 6a).Fig. 6

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