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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 9

Administration of reserpine improves the outcomes of radio-/chemotherapies.

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Administration of reserpine improves the outcomes of radio-/chemotherapi...
(A) ELISA analysis of CD63 levels in the plasma from mice bearing B16F10 tumors of similar volume exposed or not to ionizing radiation (IR, 12 Gy), reserpine (1 mg/kg), or both. n = 4 for all groups. (B) Analysis of tumor volume in B16F10 tumors (inoculated s.c. at 1 × 105 cells/mouse) in WT mice treated with vehicle or reserpine (1 mg/kg) upon reaching 30 to 50 mm3. Three days later, vehicle- and reserpine-treated mice with similar tumor volumes underwent 12-Gy irradiation and continued their assigned vehicle or reserpine treatments 3 times per week (n = 4). (C) Kaplan-Meier survival analysis of B16F10 tumor–bearing mice treated as described in panel B until tumors reached 2000 mm3 (n = 4). (D) Quantification of total area of B16F10 metastatic load in lungs from mice described in panel B (n = 4). (E) Schematic of the experiments combining reserpine with FOLFOX treatment of orthotopically inoculated MC38 colon tumors. (F) Representative images and the mass of MC38 tumors from animals treated as in panel E. n = 5 for each group. (G) Representative images of livers from MC38 tumor–bearing mice described in panel E. Arrowheads show macroscopic metastatic lesions found in 8% of vehicle-treated animals, 57% of FOLFOX only–treated animals, and none of the animals that received reserpine (with or without FOLFOX). Data are shown as mean ± SEM. Statistical analysis was carried out using 1-way ANOVA with Tukey’s multiple-comparison test (A, D, and F), 2-way ANOVA with Tukey’s multiple-comparison test (B), or log-rank (Mantel-Cox) 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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