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

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

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 6

Angiostatic and antitumorigenic effects of reserpine in solid tumors.

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Angiostatic and antitumorigenic effects of reserpine in solid tumors. (A...
(A) qPCR analysis of relative Angpt2 mRNA levels in B16F10 tumors from WT and Ch25h–/– mice treated with vehicle or reserpine (1 mg/kg, i.p. every other day for 4 days). n = 5 for each group. (B) Representative immunofluorescence images and quantification of CD31-positive areas in B16F10 tumors from WT and Ch25h–/– mice (n = 5 for each group) treated with vehicle or reserpine as described in panel A. Scale bar: 100 μm. (C) Growth of human HCT116 tumors (inoculated s.c. at 5 × 106 cells/mouse) in NSG mice treated with vehicle or reserpine (1 mg/kg) every other day. n = 5 for each group. (D) Representative immunofluorescence image (upper) of CD31 staining of HCT116 tumors from NSG mice treated with vehicle or reserpine. Quantification (bottom) of CD31-positive areas and average distance of blood vessels. Quantification averaged from 5 random fields in sections from each of 5 animals is shown (n = 5 for each group). Scale bar: 100 μm. (E) Analysis of B16F10 tumor growth (inoculated s.c. at 1 × 106 cells/mouse) in WT and Ch25h–/– mice (n = 5 for each group) followed by vehicle or reserpine treatment (1 mg/kg, i.p. every other day). (F) Analysis of B16F10 tumor mass on day 15 of the experiment described in panel E. (G) Analysis of B16F10 tumor mass on day 15 after inoculation (s.c. at 1 × 106 cells/mouse) into indicated mice (n = 5 for each group) followed by vehicle or reserpine treatment (1 mg/kg, i.p. every other day). Data are presented as mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Tukey’s multiple-comparison test (A, B, F, and G), 2-way ANOVA with Tukey’s multiple-comparison test (C and E), or 2-tailed Student’s t test (D). NS, not significant. Experiments were performed independently at least 3 times.