Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells

We have shown that ionizing radiation, a known carcinogen of human breast, elicits rapid, persistent, and global changes in the mammary microenvironme nt as evidenced by altered extracellular matrix composition and growth fact or activities. To address whether these events contribute to radiogenic car cinogenesis, we evaluated the effect of irradiated mammary stroma on the ne oplastic potential of COMMA-D mammary epithelial cells. Although COMMA-D ce lls harbor mutations in both alleles of p53, they are nontumorigenic when i njected s.c. into syngeneic hosts. Unirradiated COMMA-D cells transplanted to mammary fat pads cleared previously of epithelia preferentially formed t umors in irradiated hosts. Tumor incidence at 6 weeks was 81% +/- 12 SE whe n animals were irradiated with 4 Gy, 3 days prior to transplantation, compa red with 19% +/- 2 SE (P < 0.005) in sham-irradiated hosts. This effect was evident when cells were transplanted 1 to 14 days after irradiation. Furth ermore, tumors were significantly larger (243.1 +/- 61.3 mm(3) versus 30.8 +/- 8.7 mm(3)) and arose more quickly (100% by 6 weeks versus 39% over 10 w eeks in sham hosts) in fat pads in irradiated hosts. The contribution of lo cal versus systemic effects was evaluated using hemibody (left versus right ) irradiation; tumors formed only in fat pads on the irradiated side. These data indicate that radiation-induced changes in the stromal microenvironme nt can contribute to neoplastic progression in vivo. Disruption of solid ti ssue interactions is a heretofore unrecognized activity of ionizing radiati on as a carcinogen.