Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma.

Autor: Duch P; Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona 08036, Spain., Díaz-Valdivia N; Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona 08036, Spain., Ikemori R; Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona 08036, Spain., Gabasa M; Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona 08036, Spain; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona 08036, Spain., Radisky ES; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, United States., Arshakyan M; Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona 08036, Spain., Gea-Sorlí S; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 08029, Spain., Mateu-Bosch A; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 08029, Spain., Bragado P; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, 28040, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain., Carrasco JL; Unit of Biostatistics, Department of Basic Clinical Practice, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain., Mori H; Center for Immunology and Infectious Diseases, University of California Davis, Davis, CA 95616, United States., Ramírez J; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona 08036, Spain; Pathology Service, Hospital Clínic de Barcelona, Barcelona 08036, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid 28029, Spain., Teixidó C; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain; Pathology Service, Hospital Clínic de Barcelona, Barcelona 08036, Spain., Reguart N; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain., Fillat C; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 08029, Spain; Department of Medicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain., Radisky DC; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, United States., Alcaraz J; Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona 08036, Spain; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona 08036, Spain; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona 08028, Spain. Electronic address: jalcaraz@ub.edu.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2022 Aug; Vol. 111, pp. 207-225. Date of Electronic Publication: 2022 Jul 02.
DOI: 10.1016/j.matbio.2022.06.009
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare no competing interests.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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