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Cancer cell-endothelial intercellular transfer alters the endogenous miRNA profile and phenotype of recipient endothelial cells

ABSTRACT: Metastasis is a major cause of mortality, and remains a final frontier in the search for a cure for cancer. While there has been much research on the ‘seed’ (metastatic tumor cells) and the ‘soil’ (colonized host tissue), interactions between metastatic cancer cells and stromal endothelial cells, which occur at multiple stages during metastasis, are less well understood. 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 intercellular communication in vitro and in vivo, including horizontal transfer of microRNAs (miRNA). The communication between the tumor 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 syngeneic- and human xenograft-breast cancer models. Targeting the formation of these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE72679 | GEO | 2015/09/04

SECONDARY ACCESSION(S): PRJNA294652

REPOSITORIES: GEO

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Cancer cell-endothelial intercellular transfer alters the endogenous miRNA profile and phenotype of recipient endothelial cells

Project description:Metastasis is a major cause of mortality, and remains a final frontier in the search for a cure for cancer. While there has been much research on the ‘seed’ (metastatic tumor cells) and the ‘soil’ (colonized host tissue), interactions between metastatic cancer cells and stromal endothelial cells, which occur at multiple stages during metastasis, are less well understood. 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 intercellular communication in vitro and in vivo, including horizontal transfer of microRNAs (miRNA). The communication between the tumor 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 syngeneic- and human xenograft-breast cancer models. Targeting the formation of these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer. A miRNA microarray was used to evaluate the transport of endogenous microRNAs. The intercellular transfer-ve and intercellular transfer+ve samples were sorted from the same endothelial cell population with the only difference being the occurrence of intercellular transport. The heat map shows potential miRNA candidates for exogenous transfer on two independent biological replicates. These miRNA candidates were significantly up-regulated in the cells receiving transfer of intercellular contents. HUVECs that were not exposed to cancer cells were used as a baseline control.

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