Abstract 2282: K-RasV12 Bone Marrow Cell Reconstitution Causes Lung Cancer in Wild Type Mice

Abstract The potential of recruited bone-marrow-derived cells (BMDCs) to act as a source of malignancy was disputed for a long time. A role for BMDCs in tissue repair has also been proposed, since these cells are capable of homing to the lung and differentiating into multiple epithelial cell lineages so thus contributing in lung tissue repair and regeneration. We tested the ability of bone marrow cells containing an inducible oncogene to initiate lung adenocarcinoma. Since the role of the K-Ras gene in lung cancer is well known, for our experimental strategy, we used a mouse model expressing oncogenic K-RasV12 (K-Ras+/V12RERTert/ert). This model generates a specific neoplastic phenotype induced by the K-RasV12 mutation. Mice usually develop lung tumors with complete penetrance evolving from hyperplasia, through adenoma, to adenocarcinoma, when the oncogene expression is induced by 4-hydroxitamoxifen (4-OHT) administration. Following lethal irradiation, wild-type mice were transplanted with donor bone marrow cells derived from K-RasV12 mice and, once the bone marrow was reconstituted, treated with 4-OHT. Mice were monitored and sacrificed at subsequent post-induction time points (0, 3.5, 5.5, 8.5, 11, 13.5, 15, and 16 months) and lungs and peripheral blood were collected. Analysis of the H&E-stained lung sections from both reconstituted K-RasV12 and control mice revealed diffuse hyperplasia, possibly due to irradiation. Epithelial lesions, adenomas and/or adenocarcinomas, were detected in 4 out of 8 K-RasV12-reconstituted animals at 3.5, 5.5, 13.5 and 15 months post oncogene induction while no lesions were detected in the control group (transplanted but not induced mice). In addition, the K-Ras implication on the origin of the tumor was confirmed by X-Gal staining of lung lesions in reconstituted mice. In our model, -geo is indeed a marker protein coexpressed along with the same K-RasV12 transcript by a bicistronic strategy. Our results suggest a direct implication of BMDCs in lung epithelial tumor development and emphasize the need of further studies to dissect the mechanisms regulating BMDCs’ recruitment to injured tissues and their role in tumor initiation and/or progression. Citation Format: Elena Belloni, Ines Martin-Padura, Elvira Gerbino, Stefania Orecchioni, Fulvia Fusar-Imperatore, Paola Marighetti, Giovanni Bertalot, Pier Giuseppe Pelicci, Francesco Bertolini. K-RasV12 bone marrow cell reconstitution causes lung cancer in wild type mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2282. doi:10.1158/1538-7445.AM2015-2282