Abstract 1103: An abnormally stiff microenvironment supports the overabundance of fibroblasts in non-small cell lung cancer.

Abstract

Abstract Breathing demands our lungs to be soft and elastic. In contrast, lung tumors exhibit an abnormal tissue hardening concomitantly with an altered lung architecture and function, which brings the mechanical microenvironment of the tumor closer to that of muscle or bone. This tissue hardening has been associated with the abundant reactive stroma rich in activated fibroblasts (also referred to as tumor associated fibroblasts or TAFs) that is a hallmark of non-small cell lung cancer (NSCLC). However, it remains unknown whether tissue hardening alone is sufficient to drive the abnormal abundance of fibroblasts in the stroma of NSCLC. To address this question, we cultured the human lung fibroblast cell line CCD-19Lu or primary human lung fibroblasts on collagen-coated polyacrylamide gels exhibiting normal- or tumor-like stiffness in the absence (0%) or presence (0.1%) of serum for 5 days. Primary cells were isolated from both tumor-free regions (referred to as control fibroblasts) or tumors of NSCLC patients diagnosed with either Adenocarcinoma (ADC, n=5) or Squamous Cell Carcinoma (SCC, n=5) histological subtypes. We observed a significantly higher density of CCD-19Lu fibroblasts in tumor-like gels compared to normal-like gels regardless the presence of serum. Similar results were obtained in both primary control fibroblasts and SCC-TAFs. In contrast, tumor-like gels induced a weaker density increase in ADC-TAFs. The increased fibroblast density in the tumor-like gels was associated with increased survival rather than proliferation, as revealed by a downregulation of caspase-3 and a rise in AKT phosphorylation. Our results indicate that extracellular hardening alone is sufficient to induce an increased density in lung fibroblasts by activating pro-survival pathways and suggest an abnormal response of ADC-TAFs to extracellular mechanical cues. Collectively these findings underline a major role of tissue hardening in the abnormal abundance of TAFs in NSCLC, particularly in the SCC subtype. These data may be useful in developing novel targeted therapies against the pro-survival effects of tissue hardening in SCC-TAFs, which act as co-conspirators of tumor progression. Citation Format: Marta Puig, Alícia Giménez, Roland Galgoczy, Roberto Lugo, Josep Ramírez, Abel Gómez-Caro, Pere Gascón, Noemí Reguart, Jordi Alcaraz. An abnormally stiff microenvironment supports the overabundance of fibroblasts in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1103. doi:10.1158/1538-7445.AM2013-1103