Abnormal abundance of senescent fibroblasts in the tumor stroma of non-small cell lung cancer patients

Senescence has been previously regarded as protective against tumor growth. However, there is evidence that senescent cells observed in the tumor stroma may support cancer progression. The presence of senescent stromal cells in non-small cell lung cancer (NSCLC) remains poorly defined. To address this question, we examined senescent associated signatures in primary cultures of human fibroblasts obtained from 3 major NSCLC subtypes (adenocarcinoma/ADC, squamous cell carcinoma/SCC, large cell carcinoma/LCC) or paired controls. The senescence-associated beta-galactosidase (beta-gal) assay was negative in >90% of control fibroblasts (11/12). Likewise, tumor-assocaited fibroblasts (TAFs) from either ADC or SCC were negative for beta-gal assay in 80% of patients (4/5), whereas <10% were beta-gal positive in the remaining 20% of patients. In contrast, beta-gal positive TAFs were observed in 100% of LCC patients (3/3), with an average of ∼30% positive TAFs. In agreement with these findings, LCC TAFs were poorly or non-responsive to serum stimulation in terms of cell cycle progression. These results suggest that the senescent phenotype is absent in normal fibroblasts, and abnormally and specifically present in lung fibroblasts from LCC patients, which may contribute to the progression of LCC.