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The ATF6-EGF Pathway Mediates the Awakening of Slow-Cycling Chemoresistant Cells and Tumor Recurrence by Stimulating Tumor Angiogenesis.
- Source :
- Cancers; Jul2020, Vol. 12 Issue 7, p1772, 1p
- Publication Year :
- 2020
-
Abstract
- Slow-cycling cancer cells (SCCs) with a quiescence-like phenotype are believed to perpetrate cancer relapse and progression. However, the mechanisms that mediate SCC-derived tumor recurrence are poorly understood. Here, we investigated the mechanisms underlying cancer recurrence after chemotherapy, focusing on the interplay between SCCs and the tumor microenvironment. We established a preclinical model of SCCs by exposing non-small-cell lung cancer (NSCLC) cells to either the proliferation-dependent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) or chemotherapeutic drugs. An RNA sequencing analysis revealed that the established SCCs exhibited the upregulation of a group of genes, especially epidermal growth factor (EGF). Increases in the number of vascular endothelial growth factor receptor (VEGFR)-positive vascular endothelial cells and epidermal growth factor receptor (EGFR) activation were found in NSCLC cell line- and patient-derived xenograft tumors that progressed upon chemotherapy. EGFR tyrosine kinase inhibitors effectively suppressed the migration and tube formation of vascular endothelial cells. Furthermore, activating transcription factor 6 (ATF6) induced the upregulation of EGF, and its antagonism effectively suppressed these SCC-mediated events and inhibited tumor recurrence after chemotherapy. These results suggest that the ATF6-EGF signaling axis in SCCs functions to trigger the angiogenesis switch in residual tumors after chemotherapy and is thus a driving force for the switch from SCCs to actively cycling cancer cells, leading to tumor recurrence. [ABSTRACT FROM AUTHOR]
- Subjects :
- RNA analysis
ANTINEOPLASTIC agents
CANCER chemotherapy
CANCER relapse
CELL lines
CELL physiology
CELL receptors
CELLULAR signal transduction
DRUG resistance in cancer cells
EPIDERMAL growth factor
EPITHELIAL cells
GENES
LUNG cancer
TRANSCRIPTION factors
XENOGRAFTS
PROTEIN-tyrosine kinase inhibitors
CELL migration inhibition
FLUORESCENT dyes
PATHOLOGIC neovascularization
SEQUENCE analysis
Subjects
Details
- Language :
- English
- ISSN :
- 20726694
- Volume :
- 12
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- Cancers
- Publication Type :
- Academic Journal
- Accession number :
- 144873956
- Full Text :
- https://doi.org/10.3390/cancers12071772