Cell function in complex three dimensional tissues is coordinated by soluble signaling peptides and by small molecules within the context of insoluble scaffolding provided by the extracellular matrix. Tissue interactions, mediated by the extracellular matrix and growth factors, can actively suppress malignant behavior by epithelial cells. Conversely, atypical interactions can become active participants in carcinogenesis. The dynamic interaction between target cells and the various cellular constituents of tissues is a novel target for therapeutics (Erickson and Barcellos-Hoff, 2003). Ionizing radiation (IR), a prototypic mutagen and carcinogen, as a consequence of medical, occupational and environmental exposure, rapidly and persistently alters tissue interactions (Barcellos-Hoff, Park and Wright, 2005). The challenge in predicting low dose/fluence radiation health effects in humans is to understand how cellular responses occurring in a multicellular context are integrated to produce an organismal response. Identifying when and how tissue alterations contribute to the action of IR as a carcinogen may provide a ‘back door’ to inhibiting its carcinogenic potential, as well as a better understanding of how normal tissues suppress carcinogenesis.

Transforming growth factor 1ß (TGFß) is a prominent player in the response to IR, which in turn has revealed new aspects of its biology. An orchestrated multicellular response IR is important for rapid restoration of homeostasis and long-term prevention of cancer but it is unclear whether factors outside the cell influence DNA damage response. We have shown that TGFß1, a pleiotropic cytokine, is essential for epithelial cells to mount the canonical DNA damage response (Ewan, 2002a). Irradiated Tgfß1 null murine epithelial cells fail to undergo cell cycle arrest or apoptosis in response to irradiation in vivo. Recent cell culture experiments demonstrate that this response is restricted to epithelial cells and can be reversed by TGFß addition. A direct and specific requirement for TGFß in the genotoxic stress program provides a vital link between cell fate and tissue integrity.

In normal mammary gland, TGFß specifically inhibits the proliferative potential of mammary epithelial cells in response to ovarian steroids. TGFß immunolocalization revealed striking epithelial heterogeneity during mammary stages characterized by proliferation (Ewan 2002b). Many cells downregulate TGFß at estrus, consistent with its action as a growth inhibitor, but some mammary epithelial cells maintain prominent TGFß1 activation. This observation suggested the possibility that TGFß acts to restrain such cells from proliferating particularly in the presence of ovarian steroids. We found that TGFß1-positive and steroid hormone receptor co-localize in an epithelial subpopulation and that TGFß depletion specifically affects proliferation of hormone receptor positive cells (Ewan, 2005).

The laboratory’s current focus is to study the multiple and complex mechanisms of regulation by TGFß of epithelial function physiologically and in response to IR, and the consequences of its ultimate loss of function during carcinogenesis. The goal is to better understand how tissues integrate information across multiple scales of organization and to use this information in modeling critical events in carcinogenesis.