Formation of new blood vessels are critical for growth and metastasis of tumours. However, there is increasing evidence that many solid tumours can create functional vascular structures using tumour cells, a process known as vasculogenic mimicry (VM), which correlates with poor prognosis for cancer patients. We have identified the adhesion molecule desmoglein-2 (DSG2) as an important cadherin that promotes both angiogenesis and VM, where increased expression correlates with poor outcome for melanoma patients.
Growth of the mouse melanoma cell line B16-F10-GFP-P2A-luc is significantly reduced in mice with whole body loss-of-function Dsg2 (Dsg2lo/lo) when compared to control mice (WT). Histologically, melanomas from Dsg2lo/lo mice reveal restructured tumour vasculature and altered leukocyte content, with increased CD8+ T cells and reduced F4/80+ macrophages. To further explore this, we compared the supernatant from human bone marrow derived endothelial cells (TrHBMEC cell line) that were either DSG2-expressing or DSG2-negtiave and observed significant differences in an array of cytokines and chemokines.
Further investigation of the melanoma cells identified that VM competent melanoma cells (e.g. C32 and SK-MEL-28 cells) exhibited increased surface expression levels of known endothelial cell adhesion molecules (e.g. ICAM1) which could be further upregulated by TNFα. Using the parallel plate flow chamber and transwell migration assay, we identified that VM competent melanoma cells can mediate leukocyte recruitment, particularly monocytes. Monocyte adhesion is dependent on classical endothelial cell adhesion molecules as a decrease in monocyte adhesion under flow conditions when the adhesion molecule ICAM1 is reduced through siRNA knockdown. An interrogation of The Cancer Genome Atlas (TCGA) melanoma cohort revealed these adhesion molecules and chemokines are also expressed in melanoma patients, thereby highlighting the relevance of this study in human patients.
Our results suggest that DSG2 plays a role in regulating tumour vasculature and infiltration of leukocytes. Ongoing investigations aim to understand how modulating DSG2 and adhesion molecule expression can reshape tumour vasculature for improved disease outcome.