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Review
. 2017 Oct;108(10):1921-1926.
doi: 10.1111/cas.13336. Epub 2017 Aug 17.

Tumor endothelial cells accelerate tumor metastasis

Nako Maishi  1 , Kyoko Hida  1
Affiliations
Review

Tumor endothelial cells accelerate tumor metastasis

Nako Maishi et al. Cancer Sci. 2017 Oct.

Abstract

Tumor metastasis is the main cause of cancer-related death. Understanding the molecular mechanisms underlying tumor metastasis is crucial to control this fatal disease. Several molecular pathways orchestrate the complex biological cell events during a metastatic cascade. It is now well known that bidirectional interaction between tumor cells and their microenvironment, including tumor stroma, is important for tumor progression and metastasis. Tumor stromal cells, which acquire their specific characteristics in the tumor microenvironment, accelerate tumor malignancy. The formation of new blood vessels, termed as tumor angiogenesis, is a requirement for tumor progression. Tumor blood vessels supply nutrients and oxygen and also provide the route for metastasis. Tumor endothelial cells, which line tumor blood vessels, also exhibit several altered phenotypes compared with those of their normal counterparts. Recent studies have emphasized "angiocrine factors" that are released from tumor endothelial cells and promote tumor progression. During intravasation, tumor cells physically contact tumor endothelial cells and interact with them by juxtacrine and paracrine signaling. Recently, we observed that in highly metastatic tumors, tumor endothelial cells interact with tumor cells by secretion of a small leucine-rich repeat proteoglycan known as biglycan. Biglycan from tumor endothelial cells stimulates the tumor cells to metastasize. In the present review, we highlight the role of tumor stromal cells, particularly endothelial cells, in the initial steps of tumor metastasis.

Keywords: Angiocrine factor; biglycan; endothelial cell; metastasis; stromal cell.

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Figures

Figure 1
Figure 1
Steps in the development of tumor metastasis. (1) Tumor cells invade the surrounding stroma and extracellular matrix (ECM), (2) intravasate into the bloodstream, (3) survive in the circulation with anoikis resistance, (4) disseminate in the circulation and reach distant organs, (5) extravasate and invade into the parenchyma of distant tissues, (6) adapt to the new microenvironment and proliferate to form metastatic colonization. Stromal cells have important roles in metastasis dissemination. TEC, tumor endothelial cell.
Figure 2
Figure 2
Tumor microenvironment is formed by tumor and stromal cells and extracellular matrix (ECM). CAF, cancer‐associated fibroblast; TAM, tumor‐associated macrophage.
Figure 3
Figure 3
Biglycan is highly expressed in tumor endothelial cells (TEC) in highly metastatic tumors. (a) Biglycan expression in mouse normal skin tissues and indicated tumors dissected from mouse. (b) Bisulfite sequencing analysis of the biglycan promoter in endothelial cells (EC). White and black circles indicate unmethylated and methylated CpG dinucleotides, respectively. Reprinted from Maishi et al.,39 with permission from Sci Rep. HM‐TEC, highly metastatic tumor‐derived endothelial cell; LM‐TEC, low metastatic tumor‐derived endothelial cell; NEC, normal endothelial cell.
Figure 4
Figure 4
Promotion of tumor metastasis by tumor endothelial cells (TEC) through biglycan secretion. Tumor cells and the microenvironment develop TEC. In turn, these educated TEC express high levels of biglycan with epigenetic modification. TEC‐biglycan stimulates Toll‐like receptor (TLR)‐expressing tumor cells to metastasize by activation of nuclear factor‐kappa B (NF‐κB) and extracellular signal‐regulated kinase (ERK) signaling. Reprinted from Maishi et al.,39 with permission from Sci Rep.
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