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Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype.

Connor Y, Tekleab S, Nandakumar S, Walls C, Tekleab Y, Husain A, Gadish O, Sabbisetti V, Kaushik S, Sehrawat S, Kulkarni A, Dvorak H, Zetter B, R Edelman E, Sengupta S - Nat Commun (2015)

Bottom Line: Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis.The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits.These results lead us to define the notion of 'metastatic hijack': cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits.

View Article: PubMed Central - PubMed

Affiliation: Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. These results lead us to define the notion of 'metastatic hijack': cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits. Pharmacological perturbation of these nanoscale membrane bridges decreases metastatic foci in vivo. Targeting these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer.

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Temporal directed growth of heterotypic nanoscale membrane bridges from metastatic cancer cells to the endothelium(a–e) Representative SEM images show temporal growth of the nanoscale bridges from the epithelial cells towards the endothelial cells over a 24-h period. (c) High-resolution image of the region highlighted by the box in b shows directionality of growth from the cell surface in close proximity to the endothelium (open arrow) but not the opposing pole (closed arrow). (H1 and H2) High-magnification images of highlighted regions in d show the growth of the nanoscale connections that can both hover over or attach to the substratum, finally fusing with endothelial cells as seen in e high magnification by 24 h. (f) Graph shows the quantification of the growth of the nanoscale structures over time. (n>300 cells, 6 replicates per study).
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Figure 2: Temporal directed growth of heterotypic nanoscale membrane bridges from metastatic cancer cells to the endothelium(a–e) Representative SEM images show temporal growth of the nanoscale bridges from the epithelial cells towards the endothelial cells over a 24-h period. (c) High-resolution image of the region highlighted by the box in b shows directionality of growth from the cell surface in close proximity to the endothelium (open arrow) but not the opposing pole (closed arrow). (H1 and H2) High-magnification images of highlighted regions in d show the growth of the nanoscale connections that can both hover over or attach to the substratum, finally fusing with endothelial cells as seen in e high magnification by 24 h. (f) Graph shows the quantification of the growth of the nanoscale structures over time. (n>300 cells, 6 replicates per study).

Mentions: We next monitored the kinetics of formation of these intercellular nanostructures. The co-cultures of MDA-231 and endothelial cells were fixed at defined time points and imaged using an SEM. Consistent with previous observations, the cancer cells were found to attach with the endothelial cells, preferably in regions with additional cancer cells (Fig. 2). Interestingly, time-lapse analysis revealed that the nanoscale membrane projections develop from the metastatic cancer cells, from the surface in closest proximity to the endothelial tube, within 1.5 h of establishing the co-culture and evolving into stable intercellular structures over a 24-h period. Limited projections were observed from the opposite pole (away from endothelial cells) of the cancer cell (Fig. 2b), indicating that the formation of these structures occurred in a directed non-stochastic manner, consistent with a functional role. The peak lengths were reached between 15 and 20 h in co-culture (Fig. 2f).


Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype.

Connor Y, Tekleab S, Nandakumar S, Walls C, Tekleab Y, Husain A, Gadish O, Sabbisetti V, Kaushik S, Sehrawat S, Kulkarni A, Dvorak H, Zetter B, R Edelman E, Sengupta S - Nat Commun (2015)

Temporal directed growth of heterotypic nanoscale membrane bridges from metastatic cancer cells to the endothelium(a–e) Representative SEM images show temporal growth of the nanoscale bridges from the epithelial cells towards the endothelial cells over a 24-h period. (c) High-resolution image of the region highlighted by the box in b shows directionality of growth from the cell surface in close proximity to the endothelium (open arrow) but not the opposing pole (closed arrow). (H1 and H2) High-magnification images of highlighted regions in d show the growth of the nanoscale connections that can both hover over or attach to the substratum, finally fusing with endothelial cells as seen in e high magnification by 24 h. (f) Graph shows the quantification of the growth of the nanoscale structures over time. (n>300 cells, 6 replicates per study).
© Copyright Policy - open-access - permissions-link
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4697439&req=5

Figure 2: Temporal directed growth of heterotypic nanoscale membrane bridges from metastatic cancer cells to the endothelium(a–e) Representative SEM images show temporal growth of the nanoscale bridges from the epithelial cells towards the endothelial cells over a 24-h period. (c) High-resolution image of the region highlighted by the box in b shows directionality of growth from the cell surface in close proximity to the endothelium (open arrow) but not the opposing pole (closed arrow). (H1 and H2) High-magnification images of highlighted regions in d show the growth of the nanoscale connections that can both hover over or attach to the substratum, finally fusing with endothelial cells as seen in e high magnification by 24 h. (f) Graph shows the quantification of the growth of the nanoscale structures over time. (n>300 cells, 6 replicates per study).
Mentions: We next monitored the kinetics of formation of these intercellular nanostructures. The co-cultures of MDA-231 and endothelial cells were fixed at defined time points and imaged using an SEM. Consistent with previous observations, the cancer cells were found to attach with the endothelial cells, preferably in regions with additional cancer cells (Fig. 2). Interestingly, time-lapse analysis revealed that the nanoscale membrane projections develop from the metastatic cancer cells, from the surface in closest proximity to the endothelial tube, within 1.5 h of establishing the co-culture and evolving into stable intercellular structures over a 24-h period. Limited projections were observed from the opposite pole (away from endothelial cells) of the cancer cell (Fig. 2b), indicating that the formation of these structures occurred in a directed non-stochastic manner, consistent with a functional role. The peak lengths were reached between 15 and 20 h in co-culture (Fig. 2f).

Bottom Line: Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis.The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits.These results lead us to define the notion of 'metastatic hijack': cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits.

View Article: PubMed Central - PubMed

Affiliation: Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. These results lead us to define the notion of 'metastatic hijack': cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits. Pharmacological perturbation of these nanoscale membrane bridges decreases metastatic foci in vivo. Targeting these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer.

Show MeSH
Related in: MedlinePlus