Puig M.,University of Barcelona |
Puig M.,Institute dInvestigacions Biomediques August Pi i Sunyer |
Lugo R.,University of Barcelona |
Gabasa M.,University of Barcelona |
And 9 more authors.
Molecular Cancer Research | Year: 2015
The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serumconcentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues ofmatrix rigidity were driven by β1 integrin mechanosensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in β1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), β1 expression, and ERK1/2 (pT202/Y204) than ADC-TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or β1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs. Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells. ©2014 AACR.
Cyclooxigenase-2 levels are increased in the lung tissue and bronchial tumors of patients with chronic obstructive pulmonary disease [La ciclooxigenasa-2 esta regulada al alza en el pulmon y en los tumoresbronquiales de pacientes con enfermedad pulmonar obstructiva cronica]
Roca-Ferrer J.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS |
Roca-Ferrer J.,CIBER ISCIII |
Pujols L.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS |
Pujols L.,CIBER ISCIII |
And 11 more authors.
Archivos de Bronconeumologia | Year: 2011
Introduction: The expression of cyclooxygenase 2 (COX-2) is usually increased in inflammation and cancer. This study examines the expression of COX-2 in the lung of chronic obstructive pulmonary disease (COPD) patients with lung cancer. Methods: We studied 44 male patients with bronchial cancer (27 squamous carcinoma and 17 adenocarcinoma). Samples were obtained from the pulmonary parenchyma, from the bronchial mucosa adjacent to the tumor and from the tumor itself. Lung tissue specimens from 14 patients with pneumothorax were used as control. The mRNA and the COX-1 and COX-2 proteins were assessed by RT-PCR and Western blot, respectively. Results: COX-1 and COX-2 mRNA levels were significantly higher in the lung parenchyma of COPD patients than in the control subjects. COX-2 mRNA levels were also higher in the lung parenchyma than in both tumor and airway tissue samples procured from COPD patients. There were no differences in the COX-2 mRNA levels between squamous carcinoma and adenocarcinoma. In contrast, COX-2 protein levels were significantly higher in tumors than in lung parenchyma and airways. COX-2 protein levels were higher in adenocarcinoma compared with squamous carcinoma. Conclusion: This study shows that in COPD, the pathway of cyclooxygenase is activated and associated with an increase in the expression of COX-2 in lung tumors. These observations suggest that COX-2 is possibly involved in the association between COPD and cancer. © 2011 SEPAR.