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Angiogenesis

Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma

Key Points

  • The molecular 'signature' of aggressive melanoma cells is illustrative of an undifferentiated cell with a gene-expression profile that is similar to that of embryonic-like cells.

  • Vasculogenic mimicry describes the ability of aggressive melanoma cells to express endothelium-associated genes and form extracellular matrix (ECM)-rich vasculogenic-like networks in three-dimensional culture. These networks recapitulate embryonic vasculogenesis, and they have been detected in human aggressive tumours.

  • Vasculogenic mimicry in melanoma involves several signalling molecules that are also involved in embryonic vasculogenesis, including vascular endothelial (VE)-cadherin, erythropoietin-producing hepatocellular carcinoma-A2 (EPHA2), phosphatidylinositol 3-kinase, focal adhesion kinase, matrix metalloproteinases and laminin 5 γ2-chain.

  • The biological implications of vasculogenic mimicry in vivo are unclear, but recent studies indicate that the formation of vasculogenic-like networks that are rich in laminin could serve as an intratumoral fluid-conducting meshwork.

  • Vasculogenic mimicry has been observed in non-melanoma tumour types, including carcinomas of the breast, prostate, ovary and lung, synoviosarcoma, rhabdomyosarcoma and phaeochromocytoma, and in cytotrophoblasts forming the placenta.

  • Endostatin, an angiogenesis inhibitor, abrogates endothelial-cell-driven angiogenesis, but not vasculogenic mimicry, in melanomas.

  • Identification of the pathways that regulate this undifferentiated, highly plastic phenotype could lead to the development of new therapeutic strategies for cancer.

Abstract

The gene-expression profile of aggressive cutaneous and uveal melanoma cells resembles that of an undifferentiated, embryonic-like cell. The plasticity of certain types of cancer cell could explain their ability to mimic the activities of endothelial cells and to participate in processes such as neovascularization and the formation of a fluid-conducting, matrix-rich meshwork. This ability has been termed 'vasculogenic mimicry'. How does vasculogenic mimicry contribute to tumour progression, and can it be targeted by therapeutic agents?

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Figure 1: Vasculogenesis, angiogenesis and tumour-cell vasculogenic mimicry.
Figure 2: The vasculogenic-mimicry signalling cascade.
Figure 3: The melanoma fluid-conducting ECM meshwork.
Figure 4: The differential effects of endostatin (an angiogenesis inhibitor) on endothelial cells compared with melanoma cells in three-dimensional gels of collagen I in vitro.

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Acknowledgements

We gratefully acknowledge the critical review of this manuscript by T. Weingeist, and are most appreciative for grants from the National Cancer Institute at the National Institutes of Health for supporting the work discussed in this article.

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Correspondence to Mary J. C. Hendrix.

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DATABASES

Cancer.gov

melanoma

LocusLink

CD31

CD34

CDH5

EPHA2

ephrin-A1

FAK

LAMC2

LYVE1

MCAM

MITF

MMP2

MT1-MMP

NOTCH4

TFPI1

TFPI2

tyrosinase

TYRP1

VEGF-C

FURTHER INFORMATION

Blood flow in aggressive human melanoma xenografts

ScienceDaily — never-before-seen look deep inside cancerous tumors

The University of Illinois at Chicago Uveal Melanoma Research Program

Glossary

PERIODIC ACID SCHIFF STAIN

(PAS stain). A histochemical assay used to identify extracellular matrix, on the basis of the presence of glycogen and related mucopolysaccharides.

MELANOCYTE

A type of cell derived from the neural crest that is specialized to produce the pigment melanin. Melanocytes are commonly found in the skin and retina.

BLOOD LAKES

Areas of haemorrhage generally lacking an endothelial-cell lining that are often seen in histological sections of high-grade neoplasms.

COLOUR DOPPLER IMAGING

(CDI). An ultrasonographic method that allows simultaneous two-dimensional structural imaging and evaluation of blood flow. Originally developed to aid the analysis of cardiac function, tissue colour Doppler imaging is a technique in which the velocity of myocardial movement towards the transducer is displayed in a colour-coded form on myocardial images. This technology can be adapted to monitor the effects of antivascular therapies on the blood flow in a tumour.

LASER-CAPTURE MICRODISSECTION

(LCM). Energy from a low-power laser fitted to an inverted microscope is used to melt a thin vinyl film to precise locations on a tissue section to bind targeted cells. After the appropriate cells have been selected, the film and adherent cells are removed for gene-expression studies.

GLEASON GRADE

A grade of one (low grade) to five (high grade) is assigned to tumour-biopsy samples, based on how the cells look and how they are arranged. A lower Gleason grade indicates well-differentiated tumour cells, with a poor potential to spread. A higher Gleason grade indicates a poorly differentiated tumour, with a higher potential to spread.

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Hendrix, M., Seftor, E., Hess, A. et al. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3, 411–421 (2003). https://doi.org/10.1038/nrc1092

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