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Nat Commun. 2016 Nov 9;7:13322. doi: 10.1038/ncomms13322.

Vasculogenic mimicry in small cell lung cancer.

Author information

  • 1Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
  • 2Computational Biology Support Team, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
  • 3The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
  • 4University of Southern California Dornsife, Los Angeles, California 90089-3301, USA.
  • 5Stanley Manne Children's Research Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
  • 6The Institute of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK.
  • 7RNA Biology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
  • 8Cancer Research UK, Lung Cancer Centre of Excellence, Manchester M20 4BX, UK.

Abstract

Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form 'endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (P<0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention.

PMID:
27827359
PMCID:
PMC5105195
DOI:
10.1038/ncomms13322
[PubMed - in process]
Free PMC Article
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