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Neutrophils Promote Aerogenous Spread of Lung Adenocarcinoma with Bronchioloalveolar Carcinoma Features

Authors' Affiliations: Services de ¹ Pneumologie, ² Anatomie-Pathologique, and ³ Cytologie et Biologie Tumorale, AP-HP, Hôpital Tenon and ⁴ Laboratoire de Biologie Cellulaire et d'Immunopathologie Pulmonaire, UFR Pierre et Marie Curie, Université Paris VI, Paris, France

Requests for reprints: Jacques Cadranel, Service de Pneumologie et Réanimation Respiratoire, Hôpital Tenon, 4 rue de la Chine 75970, Paris Cedex 20, France. Phone: 33-1-56-01-65-31; Fax: 33-1-56-01-69-68; E-mail: jacques.cadranel{at}tnn.ap-hop-paris.fr.

Purpose: Adenocarcinoma with bronchioloalveolar carcinoma (BAC) features is a subtype of non–small cell lung cancers characterized by an intense inflammatory reaction composed of macrophages and neutrophils and by a distinct natural history with intrapulmonary spread leading to death due to respiratory failure. We hypothesized that neutrophils could promote aerogenous spread of lung adenocarcinoma with BAC features.

Experimental Design: We examined the effect of neutrophils on A549 cell line detachment in vitro and we quantified desquamation of tumor cells on tumor tissue (n = 25) and on matched bronchioloalveolar lavage (n = 17) in vivo in a series of patients with adenocarcinoma with BAC features.

Results: Neutrophils induced A549 detachment mediated by signals through cell-to-cell contact. Detached A549 cells were still viable and able to proliferate in vitro. Neutralization studies identified several membrane-bound molecules involved in detachment (i.e., intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, tumor necrosis factor /tumor necrosis factor receptor inhibitor, interleukin-1 /interleukin-1 receptor, and neutrophil elastase). In tumor tissue, shedding was detected in all samples, with a median shedding score of 42% (range, 4-95%). Micropapillary clusters were detected in 23 of the 25 tumor tissue samples, with a median micropapillary score of 1.40 (range, 0-2.1), and tumor cells were detected in 7 of 17 lavages. The micropapillary score was associated with a high neutrophil count in bronchioloalveolar lavage (P = 0.051). The shedding cell percentage was a significant factor in shorter survival (P = 0.034, univariate Cox analysis).

Conclusions: Tumor shedding is induced by neutrophils. It is a significant factor of shorter survival and may be an important event in adenocarcinoma progression.