p53 and lung cancer.

The malignant transformation of pulmonary epithelial cells is the result of multistep accumulation of genetic and molecular alterations highly related to tobacco carcinogens, involving key mechanisms of proliferation and apoptosis. Clonal expansion is the net result of acceleration of cell division and inhibition of active cell death (apoptosis). Oncogene activation in lung cancer (ras, myc, autocrine growth factor loops) results in acceleration of cell division. More importantly, tumor suppressor genes inactivation (p53, Rb, cyclin-dependent-kinase-Inhibitor p16) at genetic, epigenetic, or post-translational level removes important constraints on cell division at G1-check-point increasing cell proliferation. p 53 inactivation, through loss of transcription function may abrogate both G1-arrest control and apoptosis, thus accelerating clonal expansion. It is the most frequent alteration in lung cancer (70% of genetic alterations) with some differentiation dependent differences. p53 missense mutation is highly concordant with p53 stabilization and immunoreactivity. However, 20% of mutations with null phenotype (no p53 protein) provides 20% of false negative using immunohistochemistry for evaluation of p53 mutations in lung cancer. Rare situations are described with wild type p53 stabilization. p53 mutational spectrum in lung cancer reveals some specificities: 3 hot spot codons (codon 157, 248, 273) are the main target of selective adduct formation from a defined chemical carcinogen of cigarette smoke (BP). p53 stabilized mutants proteins are the targets for immune recognition in patients, leading to secretion of p53 auto-antibodies, and can also elicit T-cell specific cytotoxicity in vitro. p53 was not proven to be of prognostical importance once the tumor has developed. However, p53 stabilization is one of the best predictor of progression and irreversitiblity of preneoplastic bronchial lesion overwhelming morphological changes such as severe dysplasia. Restoration of wild type p53 function through p53 gene therapy, immunotherapy or modification of carboxy terminal end enable new therapeutic intervention. Finally, target genes and proteins situated on the downstream pathway of p53 transcription appears to be the most important factors of growth acceleration or even cell dissemination in lung cancer (Rb and its phosphorylation pathway, Bax-Bc12 balance and matrix degrading enzymes UPA and inhibitor PAI). Their constitutive deregulation could by-pass wild type p53 functions. p53 pathway offers several targets for future gene therapy or modulation in the future in lung cancer.