Oncotarget

Research Papers:

Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung

Roberto Lugo, Marta Gabasa, Francesca Andriani, Marta Puig, Federica Facchinetti, Josep Ramírez, Abel Gómez-Caro, Ugo Pastorino, Gemma Fuster, Isaac Almendros, Pere Gascón, Albert Davalos, Noemí Reguart, Luca Roz and Jordi Alcaraz _

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Oncotarget. 2016; 7:82324-82337. https://doi.org/10.18632/oncotarget.10327

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Abstract

Roberto Lugo1, Marta Gabasa1, Francesca Andriani2, Marta Puig1,3, Federica Facchinetti2, Josep Ramírez4, Abel Gómez-Caro5, Ugo Pastorino6, Gemma Fuster6,7, Isaac Almendros1, Pere Gascón3,7, Albert Davalos8, Noemí Reguart3,7, Luca Roz2, Jordi Alcaraz1,9

1Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain

2Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori INT, Milano, Italy

3Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain

4Anatomopathology Unit, Hospital Clínic de Barcelona, Barcelona, Spain

5Thoracic Surgery Unit, Hospital Clínic de Barcelona, Barcelona, Spain

6Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

7Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

8Buck Institute for Age Research, Novato, CA, US

9CIBER de Enfermedades Respiratorias, Madrid, Spain

Correspondence to:

Jordi Alcaraz, email: jalcaraz@ub.edu

Keywords: lung cancer, large cell carcinoma, cancer associated fibroblast, senescence, invasion

Received: November 09, 2015    Accepted: June 12, 2016    Published: June 30, 2016

ABSTRACT

Senescence in cancer cells acts as a tumor suppressor, whereas in fibroblasts enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of cancer subtypes. However, the presence of senescent TAFs in lung cancer remains undefined. We examined senescence in TAFs from primary lung cancer and paired control fibroblasts from unaffected tissue in three major histologic subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Three independent senescence markers (senescence-associated beta-galactosidase, permanent growth arrest and spreading) were consistently observed in cultured LCC-TAFs only, revealing a selective premature senescence. Intriguingly, SCC-TAFs exhibited a poor growth response in the absence of senescence markers, indicating a dysfunctional phenotype rather than senescence. Co-culturing normal fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to render fibroblasts senescent through oxidative stress, indicating that senescence in LCC-TAFs is driven by heterotypic signaling. In addition, senescent fibroblasts provided selective growth and invasive advantages to LCC cells in culture compared to normal fibroblasts. Likewise, senescent fibroblasts enhanced tumor growth and lung dissemination of tumor cells when co-injected with LCC cells in nude mice beyond the effects induced by control fibroblasts. These results define the subtype-specific aberrant phenotypes of lung TAFs, thereby challenging the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless of their subtype. Importantly, because LCC often distinguishes itself in the clinic by its aggressive nature, we argue that senescent TAFs may contribute to the selective aggressive behavior of LCC tumors.


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