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

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.

Intercellular transfer of HLA‐G: its potential in cancer immunology

“…The biogenesis and release of exosomes could be impaired by dimethyl amiloride and inactivation of the small GTP‐binding protein ARF6, respectively . Additionally, the formation of TnTs could be inhibited by mTOR signalling inhibitors metformin and everolimus, and cytoskeletal inhibitors docetaxel and latrunculin A as previously reported . Second, post‐transcriptional RNA interference by HLA‐G‐specific miRNAs (such as miR‐148, miR‐152, miR‐548q and miR‐628‐5p) has been demonstrated to reduce HLA‐G expression and recover NK cell lysis of tumor cells .…”

“…70,71 Additionally, the formation of TnTs could be inhibited by mTOR signalling inhibitors metformin and everolimus, and cytoskeletal inhibitors docetaxel and latrunculin A as previously reported. 72,73 Second, post-transcriptional RNA interference by HLA-G-specific miRNAs (such as miR-148, miR-152, miR-548q and miR-628-5p) has been demonstrated to reduce HLA-G expression and recover NK cell lysis of tumor cells. 74 Third, the masking of either HLA-G or receptor ILTs with specific blocking antibodies could be a promising strategy for HLA-G/ILTs-based target therapy.…”

Extracellular Vesicles: Unique Intercellular Delivery Vehicles

“…1) include direct cell-to-cell contact with both ligand-receptor signaling and transport of small molecules, including miRNAs, across gap junctions [14]. Cells separated by short distances can also pass macromolecules, organelles, and nuclei through “tunneling” nanotubes [15], and microtubes [16]. …”

Tumor penetrating peptides for improved drug delivery

“…Another interesting possibility, entirely speculative at this point, is transport through micro- or nanotubes. It has been shown that tumor cells form tube-like conduits among themselves and to endothelial cells, and that that cellular macromolecules can be transported from one cell to another through these conduits [29,30,31]. The transport though these tube conduits has been found to be more effective than exosome transport, at least over short distances [30], so this mechanism could explain the effectiveness and speed of the trans-tissue transport by the CendR pathway [25].…”