Jordi Alcaraz1, Josep Lluís Carrasco2, Laura Millares3, Iuliana-Cristiana Luis4, Francisco J Fernández-Porras4, Anabel Martínez-Romero5, Natalia Diaz-Valdivia4, Julio Sánchez De Cos6, Ramon Rami-Porta7, Luis Seijo8, Josep Ramírez9, María José Pajares10, Noemí Reguart11, Esther Barreiro12, Eduard Monsó13. 1. Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain. Electronic address: jalcaraz@ub.edu. 2. Unit of Biostatistics, Department of Basic Clinical Practice, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain. 3. CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Respiratory Medicine, Hospital Universitari Parc Taulí, Sabadell, Spain. 4. Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain. 5. CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Muscle Wasting and Cachexia in Chronic Respiratory Diseases and Lung Cancer, IMIM-Hospital del Mar, CEXS, UPF, PRBB, Barcelona, Spain. 6. CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Hospital San Pedro de Alcántara, Cáceres, Spain. 7. CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Hospital Universitari Mutua Terrassa, Terrassa, Spain. 8. Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Fundación Jímenez Díaz, Madrid, Spain. 9. Anatomopathology Department, Hospital Clínic de Barcelona, Barcelona, Spain. 10. Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA) and CIBERONC, Pamplona, Spain. 11. Medical Oncology Department, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain. 12. CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Muscle Wasting and Cachexia in Chronic Respiratory Diseases and Lung Cancer, IMIM-Hospital del Mar, CEXS, UPF, PRBB, Barcelona, Spain. 13. CIBER de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain; Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar, Spain; Respiratory Medicine, Hospital Universitari Parc Taulí, Sabadell, Spain; Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
Abstract
OBJECTIVES: Tumor associated fibroblasts (TAFs) are essential contributors of the progression of non-small cell lung cancer (NSCLC). Most lung TAFs exhibit an activated phenotype characterized by the expression of α-SMA and fibrillar collagens. However, the prognostic value of these activation markers in NSCLC remains unclear. MATERIAL AND METHODS: We conducted a quantitative image analysis of α-SMA immunostaining and picrosirius red staining of fibrillar collagens imaged by bright-field and polarized microscopy, respectively, using tissue microarrays with samples from 220 surgical patients, which elicited a percentage of positive staining area for each marker and patient. RESULTS: Kaplan-Meier curves showed that all TAF activation markers were significantly associated with poor survival, and their prognostic value was independent of TNM staging as revealed by multivariate analysis, which elicited an adjusted increased risk of death after 3 years of 129% and 94% for fibrillar collagens imaged with bright-field (p = 0.004) and polarized light (p = 0.003), respectively, and of 89% for α-SMA (p = 0.009). We also found a significant association between all TAF activation markers and tumor necrosis, which is often indicative of hypoxia, supporting a pathologic link between tumor desmoplasia and necrosis/hypoxia. CONCLUSIONS: Our findings identify patients with large histologic coverage of fibrillar collagens and α-SMA + TAFs to be at higher risk of recurrence and death, supporting that they could be considered for adjuvant therapy.
OBJECTIVES:Tumor associated fibroblasts (TAFs) are essential contributors of the progression of non-small cell lung cancer (NSCLC). Most lung TAFs exhibit an activated phenotype characterized by the expression of α-SMA and fibrillar collagens. However, the prognostic value of these activation markers in NSCLC remains unclear. MATERIAL AND METHODS: We conducted a quantitative image analysis of α-SMA immunostaining and picrosirius red staining of fibrillar collagens imaged by bright-field and polarized microscopy, respectively, using tissue microarrays with samples from 220 surgical patients, which elicited a percentage of positive staining area for each marker and patient. RESULTS: Kaplan-Meier curves showed that all TAF activation markers were significantly associated with poor survival, and their prognostic value was independent of TNM staging as revealed by multivariate analysis, which elicited an adjusted increased risk of death after 3 years of 129% and 94% for fibrillar collagens imaged with bright-field (p = 0.004) and polarized light (p = 0.003), respectively, and of 89% for α-SMA (p = 0.009). We also found a significant association between all TAF activation markers and tumor necrosis, which is often indicative of hypoxia, supporting a pathologic link between tumor desmoplasia and necrosis/hypoxia. CONCLUSIONS: Our findings identify patients with large histologic coverage of fibrillar collagens and α-SMA + TAFs to be at higher risk of recurrence and death, supporting that they could be considered for adjuvant therapy.
Authors: Marta Gabasa; Evette S Radisky; Rafael Ikemori; Giulia Bertolini; Marselina Arshakyan; Alexandra Hockla; Paula Duch; Ornella Rondinone; Alejandro Llorente; Maria Maqueda; Albert Davalos; Elena Gavilán; Alexandre Perera; Josep Ramírez; Pere Gascón; Noemí Reguart; Luca Roz; Derek C Radisky; Jordi Alcaraz Journal: Cancer Lett Date: 2021-03-06 Impact factor: 9.756