Multiple steps occur in the development of squamous carcinoma in the bronchial epithelium. Oncogenic signals convert normal bronchial epithelium into hyperplastic, metaplastic and dysplastic lesions. After these pre-malignant stages, lung cancer develops as a carcinoma in situ, and then emerges as an overt squamous cell carcinoma (Figure as below).

While hyperplasia and squamous metaplasia are reversible changes, dysplasia and CIS are changes linked to the growth of squamous cell lung carcinomas. Adenocarcinomas occur with changes such as atypical adenomatous hyperplasia in peripheral airway cells, although the malignant potential of these lesions has not been proven. For SCLC, no specific preneoplastic changes have been described.

Carcinogens in cigarette smoke are the main initiators of lung cancer that induce multiple genetic alterations through the formation of DNA adducts. Molecular changes in bronchial epithelium last long after one has stopped smoking, and smoking seems to cause a dose-related proliferation in bronchial epithelia.

Tumour suppressor genes (TSG) act like brakes and prevent a cell from growing aberrantly. These genes prevent the damaged cells from growing or they repair the damage. If they mutate, their function is lost, leading to aberrant proliferation that leads to cancer. Examples of TSGs mutating in lung cancers include p53, retinoblastoma (Rb), p16 and O6-methylguanine DNA methyltransferase (MGMT). In contrast to TSGs, oncogenes are genes that are responsible for normal cellular growth. In cancers, the genes are often hyper-activated leading to uncontrolled growth, and they can be considered as accelerators. Some examples include K-ras, c-Myc and cyclin D1.

Alterations in TSGs and oncogenes are believed to cause genomic instability, which is important in the early stages of cancer development. K-ras gene mutations were one of the earliest molecular abnormalities detected in lung cancer. Mutant K-ras and p53 genes are often found in the sputum and fluid of bronchioalveolar lavage a few months before diagnosis of cancer. Hence, molecular strategies may detect the presence of neoplastic cells in patients with early-stage lung carcinomas.

Evidence shows that perturbation of cellular signalling and genetic alterations in regulators of cellular processes would lead to the carcinogenesis and progression of lung cancer. The chronology and catalogue of genes that are required to fully transform normal epithelium varies among different histological entities. In the near future, the mapped human genome sequence and emerging new technologies will give the complete picture of lung cancer biology and revolutionise prevention, diagnosis and treatment.

A/Prof. Kanaga Sabapathy
Principal Investigator, Laboratory of Carcinogenesis