Metronomic chemotherapy offsets HIFα induction upon maximum-tolerated dose in metastatic cancers.
HIF-1
breast cancer
colon cancer
hypoxia
low-dose metronomic
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 09 2020
07 09 2020
Historique:
received:
07
09
2019
revised:
21
06
2020
accepted:
23
06
2020
pubmed:
21
7
2020
medline:
19
8
2021
entrez:
21
7
2020
Statut:
ppublish
Résumé
Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.
Identifiants
pubmed: 32686360
doi: 10.15252/emmm.201911416
pmc: PMC7507002
doi:
Banques de données
GEO
['GSE28722', 'GSE3494', 'GSE2034']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e11416Subventions
Organisme : Gouvernement du Canada|Canadian Institutes of Health Research (CIHR)
ID : PJT 364411
Pays : International
Organisme : Canadian Breast Cancer Foundation
Pays : International
Organisme : UCD Ad Astra Fellows Programme
Pays : International
Organisme : CIHR
Pays : Canada
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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