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

Abstract

We have shown that ionizing radiation, a known carcinogen of human breast, elicits rapid, persistent, and global changes in the mammary microenvironment as evidenced by altered extracellular matrix composition and growth factor activities. To address whether these events contribute to radiogenic carcinogenesis, we evaluated the effect of irradiated mammary stroma on the neoplastic potential of COMMA-D mammary epithelial cells. Although COMMA-D cells harbor mutations in both alleles of p53, they are nontumorigenic when injected s.c. into syngeneic hosts. Unirradiated COMMA-D cells transplanted to mammary fat pads cleared previously of epithelia preferentially formed tumors in irradiated hosts. Tumor incidence at 6 weeks was 81% +/- 12 SE when animals were irradiated with 4 Gy, 3 days prior to transplantation, compared 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. Furthermore, tumors were significantly larger (243.1 +/- 61.3 mm3 versus 30.8 +/- 8.7 mm3) and arose more quickly (100% by 6 weeks versus 39% over 10 weeks in sham hosts) in fat pads in irradiated hosts. The contribution of local 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 microenvironment can contribute to neoplastic progression in vivo. Disruption of solid tissue interactions is a heretofore unrecognized activity of ionizing radiation as a carcinogen.