An Animal Model for Studying the Sequence of Precursor Lesions that Characterise the Development of Bronchialoalveolar Carcinoma

Rationale: Analogous to the adenoma-adenocarcinoma sequence in the colon, it has been proposed that bronchioloalveolar carcinoma (BAC) in the lung arises from adenomatous hyperplasia (AH) that progresses throughout atypical adenomatous hyperplasia (AAH) to BAC. However, the data supporting the preneoplastic nature of these lesions in the lung are largely circumstantial and are mainly based upon the association of these changes at the histological examination. Methods and Results: In this study we show that the loss of function of NK1 receptor (either due to a pharmacological or to genetic manipulation) results in the development of BAC in mice after intratracheal instillation of bleomycin (0.3 μg /50 μl saline solution). We also demonstrate that a series of precursor lesions characterize the development of the BAC. The preneoplastic nature of these changes has been also ascertained. In particular, staining for proliferation markers (PCNA and Ki-67) increases with increasing atypia when a decrease of the tumor suppressor factor FHIT is demonstrated. The correlation between p53 and p21 is lost during the AH-BAC sequence. In addition, the loss function of NK1 receptor results in a delay of DNA strand breaks recovery in response to bleomycin administration. The data obtained strongly suggest a role for NK1 receptor in a cell death pathway involving Nur77 and some members of the Bcl2 family. Conclusions: These observations open the way to identify the signalling pathways crucial for BAC and to test new therapeutic interventions.