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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 7

Combination of reserpine and antiangiogenic therapy.

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Combination of reserpine and antiangiogenic therapy.
(A) Schematic of tr...
(A) Schematic of treatment of MC38 tumor–bearing mice with sunitinib, reserpine, or their combination. (B) Representative immunofluorescence images and quantification of angiogenesis parameters in MC38 tumors from WT mice treated as in panel A (n = 5 for each group). Scale bar: 100 μm. (C) Analysis of MC38 tumor volume in WT mice treated as in panel A (n = 5 for each group). (D) Analysis of mass of MC38 tumors in WT mice on day 25 of the experiment described in panel C (n = 5 for each group). Data are presented as mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Tukey’s multiple-comparison test (B and D) or 2-way ANOVA with Tukey’s multiple-comparison test (C). NS, not significant. Experiments were performed independently at least 3 times.

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

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