Abstract
BackgroundThe tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood.MethodsWe have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro.ResultsUpon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression.ConclusionThe identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.
Highlights
The tumour microenvironment is a critical regulator of malignant cancer progression
To dissect the mechanisms and to clarify whether secreted factors from endothelial cells are sufficient to influence the migratory potential of the cancer cells without cell-cell contact, we pre-exposed the cancer cell lines to human umbilical vein endothelial cells conditioned medium (HUVEC-CM) for 4 days
PC-3 prostate cancer cells showed the same response to HUVEC-CM (Fig. 1a, b), while MCF7 breast cancer cells and H460 lung cancer cells did not show any change in their migratory potential
Summary
The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood. Endothelial cells are critical for tissue homeostasis [23]. They are among the longest-living cells in the body remaining quiescent over years. Endothelial cells might exert a similar effect during tumour growth and progression, not by serving as static structural cells of perfused vessels but by actively modulating the tumour microenvironment and tumour cells, which may have profound effects on cancer fate. Several tumour-promoting factors originating from endothelial cells have been shown to increase cancer cell proliferation [24]
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