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  • Extracellular vesicles from genetically unstable, oncogene-driven cancer cells trigger micronuclei formation in endothelial cells.

Extracellular vesicles from genetically unstable, oncogene-driven cancer cells trigger micronuclei formation in endothelial cells.

Scientific reports (2020-05-24)
Shilpa Chennakrishnaiah, Thupten Tsering, Caroline Gregory, Nadim Tawil, Cristiana Spinelli, Laura Montermini, Nicolaos Karatzas, Saro Aprikian, Dongsic Choi, Ludger Klewes, Sabine Mai, Janusz Rak
ABSTRACT

Oncogenic transformation impacts cancer cell interactions with their stroma, including through formation of abnormal blood vessels. This influence is often attributed to angiogenic growth factors, either soluble, or associated with tumor cell-derived extracellular vesicles (EVs). Here we examine some of the cancer-specific components of EV-mediated tumor-vascular interactions, including the impact of genetic driver mutations and genetic instability. Cancer cells expressing mutant HRAS oncogene exhibit aberrations of chromatin architecture, aneuploidy, cytoplasmic chromatin deposition and formation of micronuclei with a non-random chromosome content. EVs released from such HRAS-driven cells carry genomic DNA, including oncogenic sequences, and transfer this material to endothelial cells while inducing abnormal formation of micronuclei, along with cell migration and proliferation. Micronuclei were also triggered following treatment with EVs derived from glioma cells (and stem cells) expressing EGFRvIII oncogene, and in both endothelial cells and astrocytes. EVs from HRAS and EGFRvIII-driven cancer cells carry 19 common proteins while EVs from indolent control cells exhibit more divergent proteomes. Immortalized endothelial cell lines with disrupted TP53 pathway were refractory to EV-mediated micronuclei induction. We suggest that oncogenic transformation and intercellular trafficking of cancer-derived EVs may contribute to pathological vascular responses in cancer due to intercellular transmission of genomic instability.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Hydrocortisone solution, 50 μM, sterile-filtered, BioXtra, suitable for cell culture
Sigma-Aldrich
Endothelial cell growth supplement from bovine neural tissue, ECGS, suitable for cell culture