Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications

Abstract

Tumor cell vasculogenic mimicry (VM) describes the functional plasticity of aggressive cancer cells forming de novo vascular networks, thereby providing a perfusion pathway for rapidly growing tumors, transporting fluid from leaky vessels, and/or connecting with endothelial-lined vasculature. The underlying induction of VM seems to be related to hypoxia, which may also promote the plastic, transendothelial phenotype of tumor cells capable of VM. Since its introduction in 1999 as a novel paradigm for melanoma tumor perfusion, many studies have contributed new insights into the underlying molecular pathways supporting VM in a variety of tumors, including melanoma, glioblastoma, carcinomas, and sarcomas. In particular, critical VM-modulating genes are associated with vascular (VE-cadherin, EphA2, VEGF receptor 1), embryonic and/or stem cell (Nodal, Notch4), and hypoxia-related (hypoxia-inducible factor, Twist1) signaling pathways. Each of these pathways warrants serious scrutiny as potential therapeutic, vascular targets, and diagnostic indicators of plasticity, drug resistance, and the aggressive metastatic phenotype.

Figure 1

Schematic model of signaling pathways implicated in tumor cell vasculogenic mimicry (VM). Only signaling molecules which have been specifically modulated using antisense oligonucletides, small inhibitory RNAs, blocking antibodies, small molecule inhibitors, or transient transfections are depicted -- demonstrating their ability to directly affect VM, and are categorized as vascular (red), embryonic/stem cell (green), and hypoxia signaling pathways (blue). Molecules shaded with two different colors demonstrate overlap between major VM signaling pathways. Proteins in grey play a quintessential role in VM formation and matrix remodeling (21). Question marks indicate the potential involvement of a protein and/or downstream effector proteins in modulating VM in aggressive cancer cells - - where the underlying signaling pathway(s) are not as yet clearly defined. (A portion of this schematic model was used in our previous publication; 9)