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. 2023 Mar 22;9(12):eadd5028. doi: 10.1126/sciadv.add5028

Fig. 10. Endogenous TRAIL DcRs favor metastatic spread.

Fig. 10.

(A) Number of ink-contrasted lung metastasis 12 days after i.v. injection of E0771 cells in constitutive DcR1/2 WT (Dcr1/2+/+) and KO (Dcr1/2−/−) mice. (B and C) mRNA expression of Tnfrsf23 (DcR1) (B) and Tnfrsf22 (DcR2) (C) in ECs, NK cells, CD8+ T cells, and neutrophils sorted from perfused lungs of tumor-free WT mice. (D) Number of ink-contrasted lung metastasis 11 days after i.v. injection of E0771 cells in chimeras obtained from the reciprocal bone marrow transplantation of constitutive DcR1/2 WT (Dcr1/2+/+) and KO (Dcr1/2−/−) mice. Arrows indicate genotypes of the bone marrow donor → recipient mice. (E and F) Graphical abstract. (E) Steady-state, high TRAIL in ECs. In steady state, endothelial TRAIL holds DR5 intracellularly and prevents its activation in quiescent ECs, thereby supporting cell survival, quiescence, and a resting anti-inflammatory/antiadhesive state. Together, this ensures the stability of the vascular barrier. (F) PMN, low TRAIL in ECs. Tampering with TRAIL in the PMN by transcriptional down-regulation in response to tumor-derived factors (i.e., VEGF-A, PlGF, and others) or by DcR-mediated entrapment liberates DR5. The increased availability of DR5 at the cell surface is sufficient to trigger its activation in a ligand-independent manner. As a result, vascular integrity is compromised by the occurring EC apoptosis and NF-κB/p38–mediated stickiness, favoring immune cell recruitment and ICAM1/E-Selectin–mediated cancer cell adhesion. Together, this process promotes cancer cell dissemination and metastasis in distant organs. All graphs show means ± SEM. *P < 0.05; **P < 0.01.