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Title: Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung
Author: Lugo, Roberto
Gabasa Ferràndez, Marta
Andriani, Francesca
Puig, Marta
Facchinetti, Federica
Ramírez Ruz, J. (José)
Gómez Caro, Abel
Pastorino, Ugo
Fuster Orellana, Gemma
Almendros López, Isaac
Gascón, Pere
Dávalos, Albert
Reguart, Noemí
Roz, Luca
Alcaraz Casademunt, Jordi
Keywords: Càncer de pulmó
Lung cancer
Issue Date: 30-Jun-2016
Publisher: Impact Journals
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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It is part of: Oncotarget, 2016, vol. (2nd revision)
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ISSN: 1949-2553
Appears in Collections:Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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