Biologie des cancers bronchiques

The bronchial multistep carcinogenesis is a cascade of molecular genetic alterations responsible for the histological continuum from squamous metaplasia to invasive bronchial carcinoma. These genetic alterations are responsible for the acquired properties of the transformed bronchial cell that lead to an invasive cancer. Many genes involved in the control of G1-S transition are mutated in lung cancer, such as the tumor suppressor genes Rb, p16, p14ARF and p53. The later is an actual cellular gatekeeper at the crossroads of DNA repair control and apoptosis signaling, this process being activated when carcinogene-induced DNA alterations are irreversible. Other genes regulating apoptosis pathways are often altered in lung cancer such as RasSF1, the main tumor suppressor gene on 3p chromosome and the DAP kinase gene. Genes that are responsible for growth factors self sufficiency of bronchial cancer cells code for tyrosine kinase receptors to growth factors (EGF-R, HGF-R, erbB2 etc.) and can be amplified and/or mutated in lung carcinomas. Other genes promoting growth factors self sufficiency code for intra-cellular proliferative signal transduction proteins such as the GTPase Ras or the serine threonine kinase Raf, both mutated in a subset of adenocarcinomas. Many of these genes are also involved in angiogenesis signaling that is critical for tumor growth. At last, genes coding for cell adhesion and cell motility proteins are frequently altered in lung cancer. These are genes coding for receptors to extra-cellular matrix, for components of this matrix, for matrix proteases or their inhibitors, for cytoplasmic regulators of actin cytoskeleton, or secreted proteins controlling cell migration and therefore cancer cell metastasis. Such a molecular dissection of cell signalization involved in bronchial carcinogenesis will lead in a near future to the design of “biological modifiers” interfering with those signalizations. These “ targeted” inhibitors could be the bona fide candidates to be used in human therapeutics, as pro-apoptotic, anti-metastatic, or antigiogenic agents. They probably will take place in multi-modal therapeutic strategies, associated to classical cytotoxic chemotherapy, radiotherapy or as adjuvant treatments after surgery, in order to avoid tumoural relapses.