Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma.
Adenocarcinoma of Lung
/ genetics
Animals
Cancer-Associated Fibroblasts
/ metabolism
Carcinoma, Squamous Cell
/ metabolism
Fibroblasts
/ metabolism
Humans
Lung Neoplasms
/ genetics
Mice
Tetraspanin 30
/ metabolism
Tissue Inhibitor of Metalloproteinase-1
/ genetics
Transforming Growth Factor beta1
/ metabolism
Tumor Microenvironment
CD63
Cancer-associated fibroblast
Fibrosis
SMAD3
TGF-β1
TIMP-1
Tumor microenvironment
Journal
Matrix biology : journal of the International Society for Matrix Biology
ISSN: 1569-1802
Titre abrégé: Matrix Biol
Pays: Netherlands
ID NLM: 9432592
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
14
10
2021
revised:
10
06
2022
accepted:
29
06
2022
pubmed:
6
7
2022
medline:
9
9
2022
entrez:
5
7
2022
Statut:
ppublish
Résumé
Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of extracellular matrix turnover that has been traditionally regarded as a potential tumor suppressor owing to its inhibitory effects of matrix metalloproteinases. Intriguingly, this interpretation has been challenged by the consistent observation that increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types including lung cancer, supporting a tumor-promoting function. However, how TIMP-1 is dysregulated within the tumor microenvironment and how it drives tumor progression in lung cancer is poorly understood. We analyzed the expression of TIMP-1 and its cell surface receptor CD63 in two major lung cancer subtypes: lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), and defined the tumor-promoting effects of their interaction. We found that TIMP-1 is aberrantly overexpressed in tumor-associated fibroblasts (TAFs) in ADC compared to SCC. Mechanistically, TIMP-1 overexpression was mediated by the selective hyperactivity of the pro-fibrotic TGF-β1/SMAD3 pathway in ADC-TAFs. Likewise, CD63 was upregulated in ADC compared to SCC cells. Genetic analyses revealed that TIMP-1 secreted by TGF-β1-activated ADC-TAFs is both necessary and sufficient to enhance growth and invasion of ADC cancer cells in culture, and that tumor cell expression of CD63 was required for these effects. Consistently, in vivo analyses revealed that ADC cells co-injected with fibroblasts with reduced SMAD3 or TIMP-1 expression into immunocompromised mice attenuated tumor aggressiveness compared to tumors bearing parental fibroblasts. We also found that high TIMP1 and CD63 mRNA levels combined define a stronger prognostic biomarker than TIMP1 alone. Our results identify an excessive stromal TIMP-1 within the tumor microenvironment selectively in lung ADC, and implicate it in a novel tumor-promoting TAF-carcinoma crosstalk, thereby pointing to TIMP-1/CD63 interaction as a novel therapeutic target in lung cancer.
Identifiants
pubmed: 35787446
pii: S0945-053X(22)00089-0
doi: 10.1016/j.matbio.2022.06.009
pmc: PMC9667815
mid: NIHMS1840088
pii:
doi:
Substances chimiques
CD63 protein, human
0
TIMP1 protein, human
0
Tetraspanin 30
0
Tissue Inhibitor of Metalloproteinase-1
0
Transforming Growth Factor beta1
0
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
207-225Subventions
Organisme : NCI NIH HHS
ID : R01 CA258274
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM132100
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare no competing interests.
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