Aberrant extracellular signaling induced by ionizing radiation and its role in carcinogenesis

Abstract

Multicellular organisms orchestrate the behavior of individual cells via extracellular signaling through the microenvironment. The lines of communication are diverse, ranging from the insoluble scaffold of the extracellular matrix, permeated with small, diffusible molecules of cytokines to the cell surface that is structured by adhesion receptors and gap junctions forming communication channels between cells. Ionizing radiation elicits rapid and persistent changes in extracellular signaling, as exemplified in our studies of the irradiated mammary gland by the rapid and persistent activation of transforming growth factor-β1. We have shown that such events can contribute to radiation's carcinogenic action in experiments in which nonirradiated, preneoplastic mammary epithelial cells are transplanted to an irradiated stroma, in which significantly larger tumors arose more frequently. In recent studies, we analyzed the effect of radiation on extracellular signaling in human mammary cells using a three-dimensional culture model. Preliminary data indicate that the progeny of irradiated cells, i.e., survivors, display aberrant morphogenesis and cell–cell interactions, resulting in behaviors characteristic of malignancy in this model. We hypothesized that under certain conditions, radiation exposure prevents normal cell interactions, which in turn could predispose susceptible cells to genomic instability.