Vasculogenic Mimicry in Small Cell Lung Cancer

BackgroundSmall cell lung cancer (SCLC) accounts for ~15% of lung cancer cases worldwide and despite initial responses to chemotherapy, most patients relapse with drug resistant disease. Targeting tumour vasculature in SCLC produced disappointing results and angiogenesis-independent tumour vascularisation pathways, including vasculogenic mimicry (VM), warrant further investigation. VM is the ability of aggressive tumour cells to form fluid conducting vascular channel-like structures. We sought to determine the role of VM in SCLC and explore the function of VE-Cadherin, a VM-associated protein in vitro and in SCLC Circulating Tumour Cells (CTCs).MethodVM was evaluated using CD31/periodic acid-Schiff (PAS) staining in a tissue micro-array (TMA) from 41 limited stage SCLC chemo-naive patients and in tumours from 11 Circulating Tumour Cell (CTC) Derived Explant (CDX) models1. Laser Capture Microdissection (LCM) and Copy Number Analysis (CNA) were performed on CDX samples which were enriched for VM. The role of VE-Cadherin in VM was evaluated in vitro and in ISET filtered CTCs stained by IF for DAPI, CD45, cytokeratin and VE-Cadherin. ResultsIn the TMA, VM score >10% correlated with poor OS (13.0 v 23.8 months, log rank p=0.025). VM was present in CDX models and CNA confirmed its SCLC origin. VM cells exhibited a distinct molecular signature. In vitro VE-Cadherin was essential for network formation in Matrigel and 37/38 SCLC patients contained a sub-population of VE-Cadherin expressing CTCs where the VM score ranged from 0 - 100% (median 11%, mean 21%).ConclusionWe present the first evidence of VM in SCLC which correlates with poor OS and with findings in other cancers. VM is present in CDX models and CNA confirms that VM vessels originate from tumour, and bear a unique molecular signature. VE-Cadherin is required in SCLC for VM in vitro and VE-Cadherin co-expression was found in CTC sub-populations in SCLC.