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Review
. 2016 Mar;159:83-92.
doi: 10.1016/j.pharmthera.2016.01.006. Epub 2016 Jan 22.

Tumor Cell Vascular Mimicry: Novel Targeting Opportunity in Melanoma

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Free PMC article
Review

Tumor Cell Vascular Mimicry: Novel Targeting Opportunity in Melanoma

Mary J C Hendrix et al. Pharmacol Ther. .
Free PMC article

Abstract

In 1999, the American Journal of Pathology published an article, entitled "Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry" by Maniotis and colleagues, which ignited a spirited debate for several years and earned the journal's distinction of a "citation classic" (Maniotis et al., 1999). Tumor cell vasculogenic mimicry (VM), also known as vascular mimicry, describes the plasticity of aggressive cancer cells forming de novo vascular networks and is associated with the malignant phenotype and poor clinical outcome. The tumor cells capable of VM share the commonality of a stem cell-like, transendothelial phenotype, which may be induced by hypoxia. Since its introduction as a novel paradigm for melanoma tumor perfusion, many studies have contributed new findings illuminating the underlying molecular pathways supporting VM in a variety of tumors, including carcinomas, sarcomas, glioblastomas, astrocytomas, and melanomas. Of special significance is the lack of effectiveness of angiogenesis inhibitors on tumor cell VM, suggesting a selective resistance by this phenotype to conventional therapy. Facilitating the functional plasticity of tumor cell VM are key proteins associated with vascular, stem cell, extracellular matrix, and hypoxia-related signaling pathways--each deserving serious consideration as potential therapeutic targets and diagnostic indicators of the aggressive, metastatic phenotype. This review highlights seminal findings pertinent to VM, including the effects of a novel, small molecular compound, CVM-1118, currently under clinical development to target VM, and illuminates important molecular pathways involved in the suppression of this plastic, aggressive phenotype, using melanoma as a model.

Keywords: CVM-1118; Melanoma; Transendothelial phenotype; Tumor cell plasticity; Vascular mimicry; Vascular mimicry pathways.

Conflict of interest statement

Conflict of interest statement: Mary Hendrix, Elisabeth Seftor, and Richard Seftor, hold patents on Nodal, Lefty and Notch4 therapeutics; Du-Shieng Chien, Yi-Wen Chu, and Jun-Tzu Chao are employees of TaiRx, Inc., where CVM-1118 is currently under development.

Figures

Fig. 1
Fig. 1
Schematic model of signaling pathways implicated in tumor cell vascular 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), tumor microenvironment (purple), and hypoxia signaling pathways (blue). Molecules shaded with two different colors demonstrate overlap between major VM signaling pathways. Involvement of Gal3 and IL-8 in VM has been previously reviewed (Mourand-Zeidan et al., 2008). Question marks indicate the potential involvement of a protein and/or downstream effector protein or proteins in modulating VM in aggressive cancer cells, for which the underlying signaling pathway or pathways are not yet clearly defined. (Redrawn and modified from Seftor et al., 2012.)
Fig. 2
Fig. 2
Flow cytometric analysis (Guava) was used to determine viability, proliferation and apoptosis of 1 × 105 human melanoma cells without (Control) and after treatment with 1, 10 and 50 nM CVM-1118 for 24, 48 and 72 hr.
Fig. 3
Fig. 3
Human melanoma cells were cultured in 3-dimensional Matrigel matrices without (Control) or with 1, 10 and 50 nM CVM-1118. After 24 hr, four images per treatment were digitally captured and representative images shown here. These images were then converted to binary images (as shown) and analyzed using the Angiosys software to determine the average number of junctions and average total tubule length per field for the four images per parameter. Statistically significant changes (p<0.05) are marked with an * in the bar graphs. (Magnification 100×; scale bar = 100 μm.)
Fig. 4
Fig. 4
Diagram of signaling pathways associated with VM that are affected by CVM-1118. After treating human melanoma cells with CVM-1118, changes in the mRNA, protein expression and phosphorylation of specific members of these different pathways were examined by q-RT-PCR, Western blot analyses, and the R&D Systems Proteome Profiler Antibody Arrays (i.e. Human Apoptosis, Human Phospho-Kinase, Human Phospho-MAPK and Human Cell Stress Arrays).

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