M15-02: Molecular pathogenesis of lung cancer and its precursor lesions

Abstract

Molecular pathogenesis of lung cancer and its precursor lesions From histological and biological perspectives, lung cancer is a complex neoplasm. It can be divided into centrally arising tumors arising from the major bronchi and their divisions (squamous cell and small cell carcinomas) and peripherally arising adenocarcinomas (mainly adenocarcinomas and large cell carcinomas). In the bronchi the stem cell is thought to be the basal cell (for squamous cell carcinomas) and neuroendocrine cells (for small cell carcinomas). A peripheral airway cell has been identified in the mouse, and apparently is the common origin for clara cells and type 2 pneumocytes which are believed to be the precursor cells for bronchioles and alveoli respectively. Although the sequential preneoplastic changes have been defined for centrally arising squamous carcinomas of the lung, they have been poorly documented for the other major forms of lung cancers, including small cell lung carcinoma and adenocarcinomas. There are three main morphologic forms of preneoplastic lesions recognized in the lung: squamous dysplasias, atypical adenomatous hyperplasia (AAH), and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. However, these lesions account for the development of only a subset of lung cancers. Of interest, many changes associated with peripheral adenocarcinomas including KRAS and EGFR mutations have been demonstrated in AAH lesions. Some oncogenes such as EGFR may be activated by both mutations and/or amplification. Preliminary studies indicate that mutation occurs first, followed by preferential amplification of the mutant locus. Several studies have provided information regarding the molecular characterization of lung preneoplastic changes, especially for squamous cell carcinoma. These molecular changes have been detected in the histologically normal and abnormal respiratory epithelium of smokers. They indicate that molecular changes appear very early in the lengthy preneoplastic process, even before histologically detectable changes. Many histologically detected preneoplastic lesions are very small in size (1-5 mm). The small size and difficulties of identifying such lesions complicates their study. Fluorescence endoscopy aids the identification of such lesions, although most are fixed in formalin and paraffin embedded, rendering molecular studies more difficult. Approaches to the study of small preneoplastic lesions include microdissection of the epithelium, morphometric studies, allelic losses, gene mutations and amplifications, protein expression by immunostaing or in situ hybridization, gene expression at RNA or protein levels etc. The advent of CT screening approaches for early detection of lung cancer has led to the identification of small ground glass opacity (GGO) type of lesions, some of which are AAH lesions. Thus these lesions can be biopsied or removed and information about their natural history obtained. The natural history of preneoplastic lesions is complex, and cancers may appear at sites previously biopsied and having minimal or no morphologic changes. Thus preneoplastic lesions may be indicators of smoke damaged epithelium with a greater propensity to progress to high grade lesions or invasive cancer, although the latter may not arise directly from morphologically identified lesions. Global approaches to studying preneoplasia include microarray expression data and comparative genomic hybridization. These techniques clearly demonstrate progressive changes from normal epithelium to dysplasia to CIS. CIS is also somewhat different from invasive squamous carcinomas. In addition, the bronchial epithelium of smokers and never smokers demonstrate many changes. A novel method to study preneoplasia is the introduction of tumor associated genes into bronchial immortalized preneoplastic cell cultures. Bronchial epithelial cultures are immortalized by infection with CDK2 and hTERT. Such cells are immortal but retain minimal cytogenetic and molecular changes. After introduction of oncogenes such as mutated KRAS or p53 knowcksown, or both, they develop morphologic and biologic features suggestive of preneoplastic respiratory epithelium. These altered cell lines demonstrate squamous dysplastic changes and the ability to invade the underlying matrix. However they usually lack tumorigenicity in mice. They appear to be useful models for studying preneoplasia. Advances in biology are providing insights into the complex and lengthy preneoplastic process. These advances may impact on prevention measures and identification of individuals at greatly increased risk.