Journal article
Regulation of intercellular biomolecule transfer–driven tumor angiogenesis and responses to anticancer therapies
The Journal of clinical investigation, Vol.131(10), pp.1-16
05/15/2021
DOI: 10.1172/JCI144225
PMCID: PMC8121529
PMID: 33998600
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.
Details
- Title: Subtitle
- Regulation of intercellular biomolecule transfer–driven tumor angiogenesis and responses to anticancer therapies
- Creators
- Zhen Lu - University of PennsylvaniaAngelica Ortiz - University of PennsylvaniaIoannis I. Verginadis - University of PennsylvaniaAmy R. Peck - University of PennsylvaniaFarima Zahedi - University of PennsylvaniaChristina Cho - University of PennsylvaniaPengfei Yu - University of PennsylvaniaRachel M. DeRita - University of PennsylvaniaHongru Zhang - University of PennsylvaniaRyan Kubanoff - University of PennsylvaniaYunguang Sun - Medical College of WisconsinAndrew T. Yaspan - Medical College of WisconsinElise Krespan - University of PennsylvaniaDaniel P. Beiting - University of PennsylvaniaEnrico Radaelli - University of PennsylvaniaSandra W. Ryeom - University of PennsylvaniaJ. Alan Diehl - Case Western Reserve UniversityHallgeir Rui - Medical College of WisconsinConstantinos Koumenis - University of PennsylvaniaSerge Y. Fuchs - University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.131(10), pp.1-16
- DOI
- 10.1172/JCI144225
- PMID
- 33998600
- PMCID
- PMC8121529
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Grant note
- CA247803,CA240814,CA165997 / ;
- Language
- English
- Date published
- 05/15/2021
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984949510502771
Metrics
3 Record Views