Journal Article

Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma

Sánchez-García, Isidro, Francoz, Sarah, Vicente-Dueñas, Carolina, Mainardi, Sara, Mijimolle, Nieves, Barbacid, Mariano

2014

Overview

Ubiquitous expression of a resident K-Ras ᴳ¹²ⱽ oncogene in adult mice revealed that most tissues are resistant to K-Ras oncogenic signals. Indeed, K-Ras ᴳ¹²ⱽ expression only induced overt tumors in lungs. To identify these transformation-permissive cells, we induced K-Ras ᴳ¹²ⱽ expression in a very limited number of adult lung cells (0.2%) and monitored their fate by X-Gal staining, a surrogate marker coexpressed with the K-Ras ᴳ¹²ⱽ oncoprotein. Four weeks later, 30% of these cells had proliferated to form small clusters. However, only SPC ⁺ alveolar type II (ATII) cells were able to form hyperplastic lesions, some of which progressed to adenomas and adenocarcinomas. In contrast, induction of K-Ras ᴳ¹²ⱽ expression in lung cells by intratracheal infection with adenoviral-Cre particles generated hyperplasias in all regions except the proximal airways. Bronchiolar and bronchioalveolar duct junction hyperplasias were primarily made of CC10 ⁺ Clara cells. Some of them progressed to form benign adenomas. However, only alveolar hyperplasias, exclusively made up of SPC ⁺ ATII cells, progressed to yield malignant adenocarcinomas. Adenoviral infection induced inflammatory infiltrates primarily made of T and B cells. This inflammatory response was essential for the development of K-Ras ᴳ¹²ⱽ–driven bronchiolar hyperplasias and adenomas, but not for the generation of SPC ⁺ ATII lesions. Finally, activation of K-Ras ᴳ¹²ⱽ during embryonic development under the control of a Sca1 promoter yielded CC10 ⁺, but not SPC ⁺, hyperplasias, and adenomas. These results, taken together, illustrate that different types of lung cells can generate benign lesions in response to K-Ras oncogenic signals. However, in adult mice, only SPC ⁺ ATII cells were able to yield malignant adenocarcinomas.

• Publisher: National Academy of Sciences
• Subject: Acinar cells / Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Adenocarcinoma of Lung / Adenoma / Adenoviridae - metabolism / adults / Alleles / Animals / B lymphocytes / Biological Sciences / Bronchioles - metabolism / Carcinoma, Non-Small-Cell Lung - metabolism / Cell Biology / Cell growth / Cell Proliferation / Cell Separation / Cell Transformation, Neoplastic / Cells / embryogenesis / Embryonic growth stage / Flow Cytometry / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genes, ras / Giant cells / Hyperplasia / Inflammation / Lesions / Lung - cytology / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lungs / Mice / Mice, Transgenic / oncogene proteins / Oncogenes / Promoter Regions, Genetic / Pulmonary alveoli / Pulmonary Alveoli - metabolism / ras Proteins - metabolism / Signal Transduction / Stem Cells - cytology / tissues / Tumors