Several molecular changes frequently present in lung adenocarcinomas are also present in AAH lesions, and they are further evidence that AAH may represent true preneoplastic lesions (Figure 5.3).
The most important finding is the presence of KRAS(codon 12) mutations in up to 39% of AAHs,
which are also a relatively frequent alteration in lung adenocarcinomas [15,56]. Other molecular
alterations detected in AAH are overexpression of Cyclin D1 (∼70%), p53 (ranging from 10 to
58%), survivin (48%), and HER2/neu (7%) proteins overexpression [15,57,58]. Some AAH le-
sions have demonstrated LOH in chromosomes 3p (18%), 9p (p16INK4a, 13%), 9q (53%), 17q, and 17p (TP53, 6%), changes that are frequently detected in lung adenocarcinomas [59,60]. A study on lung adenocarcinoma with synchronous multiple AAHs showed frequent LOH of tuberous sclerosis complex (TSC)-associated regions (TSC1 at 9q,53%, and TSC2 at 16p, 6%), suggesting that theseare candidate loci for tumor suppressor gene in asubset of adenocarcinomas of the lung [60]. Activation of telomerase expressed by expression of
human telomerase RNA component (hTERC) and telomerase reverse transcriptase (hTERT) mRNA, has been detected in 27–78% of AAH lesions, depending in their atypia level [61]. Recently, it has been shown that loss of LKB1, a serine/threoninekinase that functions as a tumor suppressor gene, isfrequent in lung adenocarcinomas (25%) and AAH (21%) with severe cytological atypia, while it is rare in mild atypical AAH lesions (5%), suggesting that
LKB1 inactivation may play a role in the AAH progression to malignancy [62].
Several mouse models have been developed to better study various oncogenic molecular signaling pathways and the sequence of molecular events involved in the pathogenesis of peripheral lung tumors, and to test novel chemopreventive agents [63]. The KRAS oncogenic mouse model is characterized for the development of peripheral alveolar type of proliferations, including AAH, adenoma,and adenocarcinoma [63]. Using this mouse model,
several important findings that need to be further validated in human tissues have been reported.Kim et al. [64] identified the potential stem cell population (expressing Clara cells-specific protein and surfactant protein-C, termed bronchioalveolar stem cell, BASC) that maintains the bronchiolar Clara cells and alveolar cells of the distal respiratory epithelium and which could be considered the precursors of lung KRAS neoplastic lesions in
mice. Wislez et al. [50] provided evidence that the expansion of lung adenocarcinoma precursors
induced by oncogenic KRAS requires mammalian target of rapamycin (mTOR)-dependent signalingand, most importantly, that inflammation-related host factors, including factors derived from macrophages, play a critical role in mice adenocarcinoma progression. Recent findings reported by Collado et al. [65], suggest that KRAS oncogeneinduced senescence may help to restrict tumor progression of lung peripheral lesions in mice. They discovered that a substantial number of cells in mice premalignant alveolar type of lesions undergooncogene-induced senescence, but the cells that escape senescence by loss of oncogene-induced senescence effectors, such as p16INK4a or p53,progress to malignancy. Thus, senescence is a defining feature of premalignant lung lesions, but not invasive tumors.
Pathogenesis of lung adenocarcinoma
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