Abstract
Tumors can develop a blood supply not only by promoting angiogenesis but also by forming vessel-like structures directly from tumor cells, known as vasculogenic mimicry (VM). Understanding mechanisms that regulate VM is important, as these might be exploitable to inhibit tumor progression. Here, we reveal the adhesion molecule desmoglein 2 (DSG2) as a novel mediator of VM in melanoma. Analysis of patient-derived melanoma cell lines and tumor tissues, and interrogation of The Cancer Genome Atlas (TCGA) data, revealed that DSG2 is frequently overexpressed in primary and metastatic melanomas compared to normal melanocytes. Notably, this overexpression was associated with poor clinical outcome. DSG2+ melanoma cells self-organized into tube-like structures on Matrigel, indicative of VM activity, which was inhibited by DSG2 knockdown or treatment with a DSG2-blocking peptide. Mechanistic studies revealed that DSG2 regulates adhesion and cell-cell interactions during tube formation, but does not control melanoma cell viability, proliferation or motility. Finally, analysis of patient tumors revealed a correlation between DSG2 expression, VM network density and expression of VM-associated genes. These studies identify DSG2 as a key regulator of VM activity in human melanoma and suggest this molecule might be therapeutically targeted to reduce tumor blood supply and metastatic spread.
Highlights
Without access to a blood supply, solid tumors cannot grow more than a few millimeters in diameter [1]
In desmoglein 2 (DSG2)+ cell lines, immunofluorescence microscopy revealed diffuse distribution of DSG2 over cell membranes as well as intracellularly, within perinuclear puncta (Figure 1D). This was in contrast to the localization of DSG2 at cell-cell junctions in HaCat keratinocytes, where DSG2 is an integral component of desmosomes, and the absence of DSG2 immunostaining in the LOX-IMV1 cell line, which lacks DSG2 gene and protein expression. These results demonstrate that (i) in contrast to other desmosomal cadherins, expression of DSG2 is relatively frequent amongst melanoma cell lines, (ii) differences in DSG2 gene expression are reflected at the level of protein expression and (iii) DSG2 protein displays a non-desmosomal distribution in melanoma cells
The results presented far demonstrate that DSG2 is overexpressed in a large fraction of melanomas compared to normal melanocytes, and that this www.impactjournals.com/oncotarget overexpression is associated with poor clinical outcome
Summary
Without access to a blood supply, solid tumors cannot grow more than a few millimeters in diameter [1]. In animal models, inhibiting VM in solid cancers leads to improved survival [16, 17], and a recent study found that breast cancer clones with the highest capacity to enter the vasculature and establish metastasis were those most efficient at generating VM networks [18]. Together, these findings highlight the biological and clinical significance of VM. The molecular mechanisms that regulate VM are not well understood, pathways associated with vasculogenesis, embryogenesis and hypoxia have been implicated [3, 4]
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