264 Vasculogenic mimicry in small cell lung cancer

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 (Po0.025). 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.

Targeting angiogenesis in small cell lung cancer

“…VM has been observed in SCLC, where it is driven by vascular endothelial (VE)-cadherin and it is correlated with poor survival (75). Interestingly, VE-cadherin expression has been demonstrated in SCLC circulating tumor cells as well, therefore indicating that VM may have a role in metastases formation (76).…”

Supervillin promotes tumor angiogenesis in liver cancer

“…The development of vasculogenic mimicry (VM) is similar to that of endothelium-dependent vessels (EDVs) (6,8). Vascular endothelial-cadherin (VE-cadherin), epithelial cell kinase (EphA2), phosphoinositide 3-kinase-α (PI3K-α), matrix metalloproteinases (MMPs), laminin 5 (Ln-5) γ2 chain, hypoxia-inducible factor-1α (HIF-1α), focal adhesion kinase (FAK) and p38 (9)(10)(11)(12)(13) are proteins and signaling pathways that promote cell proliferation, migration, invasion and matrix remodeling during VM formation (6). For example, VE-cadherin induces EphA2 phosphorylation by modulating the interaction of EphA2 with its membrane-bound ligand.…”