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Review
. 2019 Oct 28;26(1):86.
doi: 10.1186/s12929-019-0580-3.

Active roles of dysfunctional vascular endothelium in fibrosis and cancer

Tien Hsu  1   2 , Hieu-Huy Nguyen-Tran  3 , Maria Trojanowska  4
Affiliations
Review

Active roles of dysfunctional vascular endothelium in fibrosis and cancer

Tien Hsu et al. J Biomed Sci. .

Abstract

Chronic inflammation is the underlying pathological condition that results in fibrotic diseases. More recently, many forms of cancer have also been linked to chronic tissue inflammation. While stromal immune cells and myofibroblasts have been recognized as major contributors of cytokines and growth factors that foster the formation of fibrotic tissue, the endothelium has traditionally been regarded as a passive player in the pathogenic process, or even as a barrier since it provides a physical divide between the circulating immune cells and the inflamed tissues. Recent findings, however, have indicated that endothelial cells in fact play a crucial role in the inflammatory response. Endothelial cells can be activated by cytokine signaling and express inflammatory markers, which can sustain or exacerbate the inflammatory process. For example, the activated endothelium can recruit and activate leukocytes, thus perpetuating tissue inflammation, while sustained stimulation of endothelial cells may lead to endothelial-to-mesenchymal transition that contributes to fibrosis. Since chronic inflammation has now been recognized as a significant contributing factor to tumorigenesis, it has also emerged that activation of endothelium also occurs in the tumor microenvironment. This review summarizes recent findings characterizing the molecular and cellular changes in the vascular endothelium that contribute to tissue fibrosis, and potentially to cancer formation.

Keywords: Cancer vasculature; Endothelial cells; Fibrosis; Inflammation.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Proposed relationship between activated vasculatures found in injured tissue, inflammatory disease, fibrotic disease, and cancer. Injured tissue activates endothelium, which undergoes inflammatory responses and structural changes, including proliferation, loss of pericyte coverage, decreased junctional components and increased immune cell adhesion, that facilitate neoangiogenesis (shown as a sprout) and extravasation. In normal wound healing, inflammation-induced neoangiogenesis eventually ceases and the vessel undergoes pruning, and the tissue returns to homeostasis. In chronic inflammatory conditions, either the injury is never resolved, resulting in continued angiogenesis and chronic inflammatory disease, or the endothelium undergoes rarefaction and EndoMT, resulting in excessive repair and fibrotic disease. Cancer vasculature, while also considered a result of chronic inflammation, exhibits characteristics found in both inflammatory disease and fibrotic disease
Fig. 2
Fig. 2
Summary of interaction between tumor and tumor-associated vasculature. Tumor cells can induce inflammatory response in myofibroblasts, tissue resident immune cells, and endothelial cells (black arrows). Both tumor cells and activated stromal cells can induce neoangiogenic response. Inflammation-activated endothelial cells in turn can respond by secreting cytokines to activate other stromal cells, and express adhesion molecules (red and blue short bars) that allow capture of circulating immune cells (green), and facilitate their extravasation. Activated endothelial cells, which lack coverage of perivascular cells, can also inhibit primary tumor growth while promoting metastasis
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