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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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 3

The angiostatic role of CH25H in the tumor microenvironment.

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The angiostatic role of CH25H in the tumor microenvironment. (A) A repre...
(A) A representative image of B16F10-TdTomato tumors and surrounding blood vessels in GFP+ WT and GFP+ Ch25h–/– mice. (B) Representative image of blood vessels (green) and CH25H (red) in normal stroma and colorectal cancer stroma. Scale bar: 100 μm. (C) Scatterplot of quantitative stromal CH25H protein expression levels in normal adjacent stroma and tumor stroma (Cohort 1). (D) Kaplan-Meier survival analysis of CRC stromal CH25H protein levels, dichotomized into high and low CH25H expression, indicating increased risk of recurrence with loss of CH25H protein levels (Cohort 2). (E) Scatterplot of quantitative CH25H protein levels within the endothelium of normal adjacent stroma and CRC tumor stroma (Cohort 3, left panel) and the validation of endothelial CH25H expression levels between paired samples of normal adjacent stroma and CRC stroma (Cohort 4, right panel). (F) Analysis of CD31+ ECs in B16F10 tumors (s.c., 1 × 106 cells/mouse) of comparable volume grown for approximately 2 weeks in WT (n = 4) and Ch25h–/– (n = 5) mice. Scale bar: 100 μm. (G) Quantification of data from experiment described in panel F. Data averaged from 5 random fields in sections from each of 4 or 5 animals are shown. (H) Representative image (left) of colocalization of blood vessels (red) and lectin+ (green) area in tumor from WT and Ch25h–/– mice after injection with FITC-lectin (i.v., 100 μg/mouse). Quantification (right) of FITC-positive area (n = 5 for each group) of the images. Scale bar: 50 μm. (I) qPCR analysis of relative expression indicated genes in B16F10 (n = 5) and MC38 (n = 6) tumor tissues from WT and Ch25h–/– mice. For each gene, mRNA levels in WT tumors were defined as 1.0. Data are presented as mean ± SEM. Statistical significance was determined by 2-tailed Student’s t test (C, E, and G–I) or log-rank (Mantel-Cox) test (D). Experiments were performed independently at least 3 times.