Mechanism of radiation carcinogenesis: βigH3, COX-2 and beyond

.Although radiation is a well-established human carcinogen, the mechanism of radiation carcinogenesis remains unknown. Using immortalized human bronchial cell models irradiated with graded doses of either 150 keV/μm alpha particles or 1 GeV/nucleon 56Fe ions, there is evidence that transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Cell fusion studies indicated that radiation-induced tumorigenic phenotype in BEP2D cells could be completely suppressed by fusion with non-tumorigenic BEP2D cells. Using cDNA arrays, we have shown that the βigH3 gene is consistently down-regulated by 6–7 fold among tumorigenic cells when compared with controls. Ectopic expression of βigH3 in tumor cells significantly inhibits in vivo tumor growth in nude mice relative to parental tumor cells infected with vector controls. The observation that cells not directly hit by alpha particles, but in the vicinity of one that is, contribute to the mutagenic and oncogenic transformation effects of ionizing radiation represents a paradigm shift in our understanding of the essential target of radiation exposure. Recent evidence suggests that the cyclooxygenase-2 (COX-2) signaling cascade plays an essential role in the bystander process and may contribute to the neoplastic signals necessary for the oncogenic process induced by ionizing radiation.