Integrative radiation carcinogenesis: interactions between cell and tissue responses to DNA damage.
Tissue function requires coordinated multicellular behavior as a consequence of diverse signals integrated through the tissue microenvironment; importantly, these cell-cell and cell-microenvironment interactions also actively suppress cancer. Ionizing radiation (IR) elicits a well-defined cellular response to DNA damage that mediates the fate of the individual cell, concomitantly with a less well-characterized overarching tissue stress response that coordinates the response of multiple cell types via microenvironment signaling. We have now shown that these programs to reestablish homeostasis intersect via mutual regulation by transforming growth factor beta1 (TGF beta 1), which acts as an extracellular sensor and signal of stress. In this review, the concept that this type of functional integration of cell and tissue stress response programs is essential to cancer suppression will be discussed. Our experiments using IR, and several recent studies that experimentally manipulate stromal TGF beta, show that disruption of microenvironment signaling actively promotes malignant progression. Understanding the dynamic interactions between tissue and cell stress responses will be necessary for an accurate assessment of cancer risk and may also provide targets for prevention.
Barcellos-Hoff
Mary Helen
MH
Department of Cancer Biology, Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94705, USA. mhbarcellos-hofff@lbl.gov
D000818:Animals; D002450:Cell Communication / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D009369:Neoplasms / Q000209:etiology*; D011839:Radiation, Ionizing; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53