Regulation of intercellular biomolecule transfer-driven tumor angiogenesis and responses to anticancer therapies.
Animals
Endothelial Cells
/ enzymology
Gene Knockdown Techniques
HCT116 Cells
Humans
Mice
Mice, Knockout
Neoplasm Metastasis
Neoplasm Proteins
/ antagonists & inhibitors
Neoplasms, Experimental
/ drug therapy
Neovascularization, Pathologic
/ drug therapy
Reserpine
/ pharmacology
Steroid Hydroxylases
/ antagonists & inhibitors
Sunitinib
/ pharmacology
Colorectal cancer
Endothelial cells
Oncology
Vascular Biology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
17 05 2021
17 05 2021
Historique:
received:
11
09
2020
accepted:
23
03
2021
entrez:
17
5
2021
pubmed:
18
5
2021
medline:
6
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33998600
pii: 144225
doi: 10.1172/JCI144225
pmc: PMC8121529
doi:
pii:
Substances chimiques
Neoplasm Proteins
0
Reserpine
8B1QWR724A
Steroid Hydroxylases
EC 1.14.-
cholesterol 25-hydroxylase
EC 1.14.99.38
Sunitinib
V99T50803M
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P01 CA165997
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA240814
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA247803
Pays : United States
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