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Regulation of intercellular biomolecule transfer–driven tumor angiogenesis and responses to anticancer therapies
Zhen Lu, … , Constantinos Koumenis, Serge Y. Fuchs
Zhen Lu, … , Constantinos Koumenis, Serge Y. Fuchs
Published May 17, 2021
Citation Information: J Clin Invest. 2021;131(10):e144225. https://doi.org/10.1172/JCI144225.
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Research Article Oncology Vascular biology Article has an altmetric score of 1

Regulation of intercellular biomolecule transfer–driven tumor angiogenesis and responses to anticancer therapies

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Abstract

Intercellular biomolecule transfer (ICBT) between malignant and benign cells is a major driver of tumor growth, resistance to anticancer therapies, and therapy-triggered metastatic disease. Here we characterized cholesterol 25-hydroxylase (CH25H) as a key genetic suppressor of ICBT between malignant and endothelial cells (ECs) and of ICBT-driven angiopoietin-2–dependent activation of ECs, stimulation of intratumoral angiogenesis, and tumor growth. Human CH25H was downregulated in the ECs from patients with colorectal cancer and the low levels of stromal CH25H were associated with a poor disease outcome. Knockout of endothelial CH25H stimulated angiogenesis and tumor growth in mice. Pharmacologic inhibition of ICBT by reserpine compensated for CH25H loss, elicited angiostatic effects (alone or combined with sunitinib), augmented the therapeutic effect of radio-/chemotherapy, and prevented metastatic disease induced by these regimens. We propose inhibiting ICBT to improve the overall efficacy of anticancer therapies and limit their prometastatic side effects.

Authors

Zhen Lu, Angelica Ortiz, Ioannis I. Verginadis, Amy R. Peck, Farima Zahedi, Christina Cho, Pengfei Yu, Rachel M. DeRita, Hongru Zhang, Ryan Kubanoff, Yunguang Sun, Andrew T. Yaspan, Elise Krespan, Daniel P. Beiting, Enrico Radaelli, Sandra W. Ryeom, J. Alan Diehl, Hallgeir Rui, Constantinos Koumenis, Serge Y. Fuchs

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Figure 2

Stromal CH25H restricts growth of solid tumors.

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Stromal CH25H restricts growth of solid tumors.
(A) Growth of B16F10-TdT...
(A) Growth of B16F10-TdTomato tumors (inoculated s.c. at 1 × 106 cells/mouse) in GFP+ WT and GFP+ Ch25h–/– mice. n = 4–5 for each group. (B) Representative images and quantification of tumor mass on day 15 from the experiment described in panel A. (C) Growth of MH6499c4 pancreatic ductal adenocarcinoma tumors (inoculated s.c. at 1 × 105 cells/mouse) in WT and Ch25h–/– mice. n = 12–13 for each group. (D) Growth of MC38 colon adenocarcinoma tumors (inoculated s.c. at 1 × 106 cells/mouse) in WT (n = 8) and Ch25h–/– (n = 13) mice. (E) Representative images and quantification of mass of MC38 colon adenocarcinoma tumors at 40 days after orthotopic inoculation of 5 × 105 cells into the cecum of WT (n = 5) or Ch25h–/– (n = 4) mice. (F) Representative images and quantification for in vivo luciferase analysis in male WT (n = 8) and Ch25h–/– (n = 9) mice, which were inoculated into prostatic glands with TRAMP-C2-luc prostate cells (1 × 106). Data are presented as mean ± SEM. Statistical analysis was performed using 2-way ANOVA with Tukey’s multiple-comparison test (A, C, D, and F) or 2-tailed Student’s t test (B and E). Experiments were performed independently at least 3 times.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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