by Keyword: Tissue inhibitor
Duch, P, Diaz-Valdivia, N, Ikemori, R, Gabasa, M, Radisky, ES, Arshakyan, M, Gea-Sorli, S, Mateu-Bosch, A, Bragado, P, Carrasco, JL, Mori, H, Ramirez, J, Teixido, C, Reguart, N, Fillat, C, Radisky, DC, Alcaraz, J, (2022). Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma Matrix Biology 111, 207-225
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 metal-loproteinases. 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 micro-environment 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 adenocarci-noma (ADC) and squamous cell carcinoma (SCC), and defined the tumor-promoting effects of their interac-tion. 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-61/SMAD3 pathway in ADC-TAFs. Likewise, CD63 was upregulated in ADC compared to SCC cells. Genetic analyses revealed that TIMP-1 secreted by TGF-61-activated ADC-TAFs is both nec-essary 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 attenu-ated 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. (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
JTD Keywords: Angiogenesis, Cancer cells, Cancer-associated fibroblast, Cd63, Expression, Fibrosis, Hepatocellular-carcinoma, Metalloproteinases, Nintedanib, Prognostic-significance, Protein, Smad3, Squamous-cell carcinoma, Tgf-? 1, Tgf-β1, Timp-1, Tissue inhibitor, Tumor microenvironment
Chulia-Peris, L, Carreres-Rey, C, Gabasa, M, Alcaraz, J, Carretero, J, Pereda, J, (2022). Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play International Journal Of Molecular Sciences 23, 6894
Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP aactions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.
JTD Keywords: Basigin, Cd147, Cell-surface, Emmprin, Extracellular-matrix, Gelatinase-b, Gene-expression profiles, Growth-factor-beta, Immunoglobulin superfamily, Induced lung injury, Inducer emmprin, Mmps, Pulmonary fibrosis, Timps, Tissue inhibitor, Transforming growth-factor-beta-1