MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence.
Animals
Cancer-Associated Fibroblasts
/ enzymology
Carcinoma, Large Cell
/ enzymology
Cell Line, Tumor
Cell Proliferation
Cellular Senescence
Coculture Techniques
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
/ enzymology
Matrix Metalloproteinase 1
/ genetics
Mice, Nude
Oxidative Stress
Paracrine Communication
Receptor, PAR-1
/ genetics
Signal Transduction
Transforming Growth Factor beta1
/ genetics
Tumor Burden
Cancer-associated fibroblasts
MMP1
TGF-β
lung cancer
senescence
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
01 06 2021
01 06 2021
Historique:
received:
20
11
2020
revised:
09
01
2021
accepted:
28
01
2021
pubmed:
9
3
2021
medline:
21
10
2021
entrez:
8
3
2021
Statut:
ppublish
Résumé
Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-β1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-β1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs.
Identifiants
pubmed: 33684534
pii: S0304-3835(21)00052-5
doi: 10.1016/j.canlet.2021.01.028
pmc: PMC8026696
mid: NIHMS1683888
pii:
doi:
Substances chimiques
Receptor, PAR-1
0
TGFB1 protein, human
0
Transforming Growth Factor beta1
0
MMP1 protein, human
EC 3.4.24.7
Matrix Metalloproteinase 1
EC 3.4.24.7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-12Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM132100
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
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