Key result
Aberrant TIMP-1 overexpression in tumor-associated fibroblasts promotes lung adenocarcinoma progression through interaction with CD63 on cancer cells.
Why the study?
Although increased TIMP-1 expression is associated with poor prognosis in lung cancer, how it is dysregulated within the tumor microenvironment and drives tumor progression is poorly understood.
Does reducing SMAD3 or TIMP-1 expression in tumor-associated fibroblasts attenuate tumor aggressiveness in lung adenocarcinoma models?
Does reducing SMAD3 or TIMP-1 expression in tumor-associated fibroblasts attenuate tumor aggressiveness in lung adenocarcinoma models?
TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression in lung adenocarcinoma via CD63 interaction, presenting a potential therapeutic target.
Challenges TIMP-1 tumor-suppressor view in lung cancer; leaves open its therapeutic targeting.
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.
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Duch et al. (2022) studied Lung adenocarcinoma and squamous cell carcinoma. TIMP-1 and CD63 expression vs. Reduced expression or squamous cell carcinoma was evaluated on Tumor progression and aggressiveness. Aberrant TIMP-1 overexpression in tumor-associated fibroblasts promotes lung adenocarcinoma progression through interaction with CD63 on cancer cells.
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