Expression of B-RAF V600E in Type II Pneumocytes Causes Abnormalities in Alveolar Formation, Airspace Enlargement and Tumor Formation in Mice

Abstract

Growth factor induced signaling cascades are key regulatory elements in tissue development, maintenance and regeneration. Perturbations of these cascades have severe consequences, leading to developmental disorders and neoplastic diseases. As a major function in signal transduction, activating mutations in RAF family kinases are the cause of human tumorigenesis, where B-RAF V600E has been identified as the prevalent mutant. In order to address the oncogenic function of B-RAF V600E, we have generated transgenic mice expressing the activated oncogene specifically in lung alveolar epithelial type II cells. Constitutive expression of B-RAF V600E caused abnormalities in alveolar epithelium formation that led to airspace enlargements. These lung lesions showed signs of tissue remodeling and were often associated with chronic inflammation and low incidence of lung tumors. The inflammatory cell infiltration did not precede the formation of the lung lesions but was rather accompanied with late tumor development. These data support a model where the continuous regenerative process initiated by oncogenic B-RAF-driven alveolar disruption provides a tumor-promoting environment associated with chronic inflammation.

Enhanced Phenotypic Alterations of Alveolar Type II Cells in Response to Aflatoxin G1‐Induced Lung Inflammation

“…Activated AT‐II cells by inflammatory cytokines can upregulate the surface marker MHC‐II or COX‐2, inducing the differentiation of regulatory T cells (Tregs) (Ragazzo et al, ; Lo et al, ; Gereke et al, ). Thus, understanding the phenotypic alterations of AT‐II cells in response to AFG 1 ‐induced inflammation is especially important considering that activated AT‐II cells are involved in lung carcinogenesis in several animal models (Li et al, ; Zanucco et al, ).…”

“…We also found that AFG 1 induces ultrastructural and functional impairment in rat AT‐II cells in vitro and vivo (Shen et al, ). Activated AT‐II cells have been shown to be involved in lung carcinogenesis in several animal models (Li et al, ; Zanucco et al, ). Those findings further confirm that AT‐II cells serve as a potential progenitor cells and may play a critical role in Aflatoxin‐induced lung tumorigenesis (Massey et al, ; Guindon et al, ).…”

Early differential responses elicited by BRAFV600E in adult mouse models

“…The RAS-pathway also induces small mother against decapentaplegic-3 (SMAD3) [24,25] and STAT3 [26,27], two transcriptions factors whose phosphorylated versions (pSMAD3, pSTAT3) activate p21 CIP1 gene [28][29][30][31]. Unexpectedly, we found no changes in the percentage of pSMAD3-positive cells among adenomas and non-tumor alveolar areas from both BRAF V600E mice and controls (Supplementary Fig.…”