Journal Article
. 2020 May; 10(1):8532.
doi: 10.1038/s41598-020-65640-7.

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

Shilpa Chennakrishnaiah 1 Thupten Tsering 1 Caroline Gregory 1 Nadim Tawil 1 Cristiana Spinelli 1 Laura Montermini 1 Nicolaos Karatzas 1 Saro Aprikian 1 Dongsic Choi 1 Ludger Klewes 2 Sabine Mai 2 Janusz Rak 3 
Affiliations
  • PMID: 32444772
  •     76 References
  •     2 citations

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.

A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities.
Kyoko Hida, Michael Klagsbrun.
Cancer Res, 2005 Apr 05; 65(7). PMID: 15805239
SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation.
Deepika Ahuja, M Teresa Sáenz-Robles, James M Pipas.
Oncogene, 2005 Nov 22; 24(52). PMID: 16299533
Highly Cited. Review.
In-gel digestion for mass spectrometric characterization of proteins and proteomes.
Andrej Shevchenko, Henrik Tomas, +2 authors, Matthias Mann.
Nat Protoc, 2007 Apr 05; 1(6). PMID: 17406544
Highly Cited.
Tumour suppression by p53: a role for the DNA damage response?
David W Meek.
Nat Rev Cancer, 2009 Sep 05; 9(10). PMID: 19730431
Highly Cited. Review.
Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors.
Tomoshige Akino, Kyoko Hida, +11 authors, Masanobu Shindoh.
Am J Pathol, 2009 Oct 31; 175(6). PMID: 19875502    Free PMC article.
Relevance of microscopic indicators of chromosomal instability in routine reporting of malignancies.
Alka Bhatia, Yashwant Kumar.
Diagn Cytopathol, 2013 Jun 12; 42(2). PMID: 23754835
Review.
Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles.
Jan Lötvall, Andrew F Hill, +12 authors, Clotilde Théry.
J Extracell Vesicles, 2014 Dec 30; 3. PMID: 25536934    Free PMC article.
Highly Cited.
Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier.
Naoomi Tominaga, Nobuyoshi Kosaka, +6 authors, Takahiro Ochiya.
Nat Commun, 2015 Apr 02; 6. PMID: 25828099    Free PMC article.
Highly Cited.
A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis.
Qiyu Feng, Chengliang Zhang, +6 authors, Richard A Cerione.
Nat Commun, 2017 Feb 17; 8. PMID: 28205552    Free PMC article.
Highly Cited.
The Microenvironmental Landscape of Brain Tumors.
Daniela F Quail, Johanna A Joyce.
Cancer Cell, 2017 Mar 16; 31(3). PMID: 28292436    Free PMC article.
Highly Cited. Review.
Exosomes maintain cellular homeostasis by excreting harmful DNA from cells.
Akiko Takahashi, Ryo Okada, +8 authors, Eiji Hara.
Nat Commun, 2017 May 17; 8. PMID: 28508895    Free PMC article.
Highly Cited.
Glioblastoma stem-like cells secrete the pro-angiogenic VEGF-A factor in extracellular vesicles.
Lucas Treps, Raul Perret, +2 authors, Julie Gavard.
J Extracell Vesicles, 2017 Aug 18; 6(1). PMID: 28815003    Free PMC article.
TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma.
Deguan Lv, Yanxin Li, +7 authors, Haizhong Feng.
Nat Commun, 2017 Nov 14; 8(1). PMID: 29129908    Free PMC article.
The Impact of Oncogenic EGFRvIII on the Proteome of Extracellular Vesicles Released from Glioblastoma Cells.
Dongsic Choi, Laura Montermini, +3 authors, Janusz Rak.
Mol Cell Proteomics, 2018 Jul 15; 17(10). PMID: 30006486    Free PMC article.
Plk1 overexpression induces chromosomal instability and suppresses tumor development.
Guillermo de Cárcer, Sharavan Vishaan Venkateswaran, +10 authors, Rocío Sotillo.
Nat Commun, 2018 Aug 03; 9(1). PMID: 30069007    Free PMC article.
Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma.
Tatyana Vagner, Cristiana Spinelli, +10 authors, Dolores Di Vizio.
J Extracell Vesicles, 2018 Aug 16; 7(1). PMID: 30108686    Free PMC article.
Highly Cited.
Defective Nuclear Lamina in Aneuploidy and Carcinogenesis.
Elizabeth R Smith, Callinice D Capo-Chichi, Xiang-Xi Xu.
Front Oncol, 2018 Dec 14; 8. PMID: 30524960    Free PMC article.
Review.
Lowering extracellular calcium content protects cells from arsenite-induced killing and micronuclei formation.
Y C Liu, H Huang.
Mutagenesis, 1996 Jan 01; 11(1). PMID: 8671719
Calcium-dependent nitric oxide production is involved in arsenite-induced micronuclei.
J R Gurr, F Liu, S Lynn, K Y Jan.
Mutat Res, 1998 Sep 05; 416(3). PMID: 9729339
Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis.
J Rak, Y Mitsuhashi, +4 authors, R S Kerbel.
Cancer Res, 1995 Oct 15; 55(20). PMID: 7553632
Highly Cited.
Leukocytes as a reservoir of circulating oncogenic DNA and regulatory targets of tumor-derived extracellular vesicles.
S Chennakrishnaiah, B Meehan, +9 authors, J Rak.
J Thromb Haemost, 2018 Jul 05; 16(9). PMID: 29971917
Size matters in nanoscale communication.
Andries Zijlstra, Dolores Di Vizio.
Nat Cell Biol, 2018 Feb 25; 20(3). PMID: 29476154    Free PMC article.
Highly Cited.
Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes.
Joanna Kowal, Guillaume Arras, +7 authors, Clotilde Théry.
Proc Natl Acad Sci U S A, 2016 Feb 10; 113(8). PMID: 26858453    Free PMC article.
Highly Cited.
Studying the Fate of Tumor Extracellular Vesicles at High Spatiotemporal Resolution Using the Zebrafish Embryo.
Vincent Hyenne, Shima Ghoroghi, +21 authors, Jacky G Goetz.
Dev Cell, 2019 Feb 13; 48(4). PMID: 30745140
Highly Cited.
Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape.
Fan Liu, Lan Wang, Fabiana Perna, Stephen D Nimer.
Nat Rev Cancer, 2016 May 26; 16(6). PMID: 27220480    Free PMC article.
Highly Cited. Review.
Autophagy mediates degradation of nuclear lamina.
Zhixun Dou, Caiyue Xu, +17 authors, Shelley L Berger.
Nature, 2015 Nov 03; 527(7576). PMID: 26524528    Free PMC article.
Highly Cited.
Selective elimination of acentric double minutes from cancer cells through the extrusion of micronuclei.
N Shimizu, T Shimura, T Tanaka.
Mutat Res, 2001 Feb 07; 448(1). PMID: 10751625
ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function.
Lyndsay Murrow, Ritu Malhotra, Jayanta Debnath.
Nat Cell Biol, 2015 Feb 17; 17(3). PMID: 25686249    Free PMC article.
Highly Cited.
Reassessment of Exosome Composition.
Dennis K Jeppesen, Aidan M Fenix, +12 authors, Robert J Coffey.
Cell, 2019 Apr 06; 177(2). PMID: 30951670    Free PMC article.
Highly Cited.
Barriers to horizontal cell transformation by extracellular vesicles containing oncogenic H-ras.
Tae Hoon Lee, Shilpa Chennakrishnaiah, +10 authors, Janusz Rak.
Oncotarget, 2016 Jul 21; 7(32). PMID: 27437771    Free PMC article.
Extracellular Vesicle-Mediated Bilateral Communication between Glioblastoma and Astrocytes.
Lisa Nieland, Liza M Morsett, +2 authors, Erik R Abels.
Trends Neurosci, 2020 Nov 26; 44(3). PMID: 33234347    Free PMC article.
Review.
Extracellular Vesicle Mediated Vascular Pathology in Glioblastoma.
Cristiana Spinelli, Nadim Tawil, +2 authors, Dongsic Choi.
Subcell Biochem, 2021 Mar 30; 97. PMID: 33779920