FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4.
EMBO Mol Med
; 16(5): 1063-1090, 2024 May.
Article
in En
| MEDLINE
| ID: mdl-38589650
ABSTRACT
Cancer cells re-program normal lung endothelial cells (EC) into tumor-associated endothelial cells (TEC) that form leaky vessels supporting carcinogenesis. Transcriptional regulators that control the reprogramming of EC into TEC are poorly understood. We identified Forkhead box F1 (FOXF1) as a critical regulator of EC-to-TEC transition. FOXF1 was highly expressed in normal lung vasculature but was decreased in TEC within non-small cell lung cancers (NSCLC). Low FOXF1 correlated with poor overall survival of NSCLC patients. In mice, endothelial-specific deletion of FOXF1 decreased pericyte coverage, increased vessel permeability and hypoxia, and promoted lung tumor growth and metastasis. Endothelial-specific overexpression of FOXF1 normalized tumor vessels and inhibited the progression of lung cancer. FOXF1 deficiency decreased Wnt/ß-catenin signaling in TECs through direct transcriptional activation of Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs through endothelial-specific nanoparticle delivery of Fzd4 cDNA rescued Wnt/ß-catenin signaling in TECs, normalized tumor vessels and inhibited the progression of lung cancer. Altogether, FOXF1 increases tumor vessel stability, and inhibits lung cancer progression by stimulating FZD4/Wnt/ß-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has promise for future therapies in NSCLC.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Endothelial Cells
/
Forkhead Transcription Factors
/
Frizzled Receptors
/
Lung Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
EMBO Mol Med
Journal subject:
BIOLOGIA MOLECULAR
Year:
2024
Document type:
Article
Affiliation country:
Publication country:
ALEMANHA
/
ALEMANIA
/
DE
/
DEUSTCHLAND
/
GERMANY