Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade

Abstract

The lymphatic vasculature is essential for tissue fluid homeostasis and cancer metastasis, although the molecular mechanisms involved remain poorly characterized. Endothelin-1 (ET-1) axis plays a crucial role in angiogenesis and tumorigenesis. Here, we first report that ET-1 acts as a lymphangiogenic mediator. We performed in vitro and in vivo studies and show that lymphatic endothelial cells produce ET-1, ET-3, and express the endothelin B receptor (ET B R). In these cells, ET-1 promotes proliferation, invasiveness, vascular-like structures formation, and phosphorylation of AKT and p42/44 mitogen-activated protein kinase through ET B

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

“…To this end, we implanted Matrigel containing p17, ET-1 (positive control), or PBS (negative control) into the dorsal subcutaneous tissue of C57BL/6 mice. 27 As shown in Figure 6, immunostaining of Matrigel plugs with polyclonal Ab to lymphatic vessel endothelial receptor-1 identified pronounced lymphatic vessel formation in those containing p17 and ET-1 compared with Matrigel controls. Staining was confined within discrete areas at the boundaries with the surrounding murine tissue.…”

“…32,33 Members of the ET-1 axis are frequently overexpressed in many solid tumors, 34,35 and their expression has been correlated with increased lymphatic dissemination. 27 In a recent article, we described the capability of ET-1 to promote lymphangiogenesis and migration of LECs through a mechanism mediated by ET B R-ET-1-driven effects being completely abrogated in the presence of the specific ET B R antagonist BQ788. 27 Therefore, the finding that ET-1 was increased in the supernatant of LN-LECs after p17 stimulation led us to hypothesize a role of the ET-1/ET B R axis in p17-driven lymphangiogenic activity of LN-LECs.…”

“…27 Moreover, we found that ET-1 exerts a potent lymphangiogenic activity by interacting with ET B R. 27 We investigated whether p17-induced capillarylike structure formation and migration were mediated by ET-1 by selectively blocking ET B R with specific ET B R antagonist BQ788. As shown in Figure 5A, p17-induced capillary-like structure formation was significantly inhibited in the presence of specific ET B R antagonist BQ788.…”

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

“…Therefore, we can hypothesize that other mechanisms activated by ET B R, heterogeneously expressed on tumor cells as well as on endothelial cells, might also contribute to sensitize tumor cells to chemotherapy. Therefore, macitentan, interfering with ET A R and with ET B R, might offer a more efficacious "two-hit" therapeutic strategy because it might target aggressive EOC cells, disabling multiple signaling circuits activated by ET A R in a b-arr1-dependent manner, and microenvironment-associated elements expressing ET B R (10)(11)(12)(13)(14)(15)33). The activity of macitentan in EOC preclinical models associated with a well-tolerated toxicity profile, suggest that this approved small molecule can be used in a clinical setting for future development of combination regimens aimed at sensitizing tumor to chemotherapeutics.…”

“…Indeed, ET B R signaling is capable to impair antitumor immunity by preventing T-cell recruitment to tumors (10,11). In addition, ET B R plays a role in inducing tumor angiogenesis and lymphangiogenesis by inducing in blood and lymphatic endothelial cell proliferation, survival, and migration (12,13). Hence, ET A R and ET B R, which are heterogeneously expressed in EOC cells (14,15), have emerged as key targets for cancer therapy.…”