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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 4

The ICBT-driven activation of endothelial cells is controlled by CH25H.

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The ICBT-driven activation of endothelial cells is controlled by CH25H.
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(A) Volcano plot (upper) and Gene Ontology (GO, bottom) analyses of gene expression in Ch25h–/– mouse lung ECs treated as indicated. BP, Biological Process; MF, Molecular Function; CC, Cellular Component; TF, transcription factors. (B) Heatmap analysis of gene expression from panel A. (C) Western blot analysis of TIE2 levels/phosphorylation in indicated ECs treated with MC38 TEVs (20 μg/mL for 12 hours). (D) qPCR analysis of Angpt2 expression (n = 3 ) in indicated ECs pretreated with vehicle or reserpine (10 μM for 8 hours) or cyclosporin A (0.25 μM for 24 hours) followed by PBS or TEVs (20 μg/mL for 12 hours). (E) ELISA analysis of ANGPT2 in supernatant of indicated ECs from panel D. (F) Tube formation by indicated ECs treated with VEGF165 (20 ng/mL) or MC38 tumor cell–conditioned media (TCM) or TCM –TEV (TEV-free tumor cell–conditioned media) or TCM with addition of anti-ANGPT2 neutralizing antibody as in Supplemental Figure 4C. Data averaged from 3 random fields in each of 5 wells were quantified. (G) Proliferation of indicated ECs exposed to MC38-derived TEVs (20 μg/mL) for 9 days. (H) Tube formation by indicated ECs treated (or not) with MC38-derived TEVs (20 μg/mL for 12 hours) in the presence or absence of anti-ANGPT2 antibody (60 ng/mL). Representative images (left) and quantified data (n = 5 for each group) averaged from 3 random fields in each of the 5 wells are shown. Scale bar: 100 μm. (I) Tube formation by Ch25h–/– ECs transduced with empty (Ctrl) or CH25H-expressing lentivirus (for 48 hours) or treated with vehicle or 25-hydroxycholesterol (25HC, 4 μM for 4 hours) and then exposed or not to MC38 TEVs (20 μg/mL for 12 hours). Data are presented as mean ± SEM. Statistical analysis was performed by 1-way ANOVA with Tukey’s multiple-comparison test (D–F, H, and I) or 2-way ANOVA with Tukey’s multiple-comparison test (G). NS, not significant. Experiments were performed independently at least 3 times.

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