Ionizing Radiation Affects Cancer Frequency and Characteristics by Acting on the Microenvironment
Background: For more than a quarter century the scientific rationale for extrapolating radiation health effects has been underpinned by biophysical target theory. Fundamental to target theory is that the effect (e.g., DNA damage, mutation, cancer) is proportional to dose based on interaction of energy with biological targets, specifically DNA.
However, the biology following ionizing radiation is more than just DNA damage, repair, or misrepair. Cellular responses to ionizing radiation can affect phenotype, cell interactions, lineage commitment, differentiation and genomic stability, all of which have been widely documented in cultured cells and many observed in vivo. This class of non-targeted effects induced by radiation has been grouped together because they occur in cells that have not incurred direct energy deposition, so-called bystander phenomenon, or are not mediated by a mutational mechanism such as radiation-induced genomic instability, or are phenotypes exhibited in the daughters of irradiated cells. Although the mechanisms behind some phenomena are unclear, critical signals and pathways are identified in others.
Results: A study published in the May 2011 issue of Cancer Cell challenges the notion that DNA damage and mutations are the primary actions of radiation as a carcinogen. A research team funded by the DOE Low Dose Program and led by Mary Helen Barcellos-Hoff, New York University School of Medicine, showed that non-targeted effects following doses of 10 cGy or more do affect the latency and frequency of cancer. They used a mouse model in which the mouse mammary epithelium is removed prior to host irradiation and subsequently replaced with an un-irradiated mammary epithelium that underwent normal ductal outgrowth. When transplanted with a normal epithelium, no tumors developed over the course of a year, indicating that host irradiation and/or transplantation is insufficient to promote cancer. But when the transplanted epithelium was primed by deletion of the tumor suppressor p53, most outgrowths gave rise to mammary tumors within a year.
Host irradiation before transplantation altered the timing, frequency, and type of cancer. Notably, mice irradiated with very high doses (400 cGy) actually developed 20% fewer breast cancers within the period. The authors showed that high doses cause ovarian insufficiency, which occurs in women receiving >5 Gy radiation to the ovaries, which decreases proliferation in the tissue. However, at lower doses (10-100 cGy), host irradiation accelerated cancer development.
Methods: Using systems biology approaches, the authors identified two mechanisms of radiation action. The induction of transforming growth factor-beta (TGF-β)—a protein that controls proliferation, cellular differentiation, and other functions in cells—was shown to be essential for the decreased latency observed in irradiated mice, but not in Tgfb1 heterozygote irradiated mice. The second effect was to induce signals mediated by the notch-signaling pathway that increase stem cell number and thereby increase the development of estrogen-receptor negative breast cancer. Notably, breast cancers that are both early age at diagnosis and estrogen-receptor negative are significantly increased in radiation-preceded breast cancer.
Why it matters: These studies show that 1) non-targeted effects are important to cancer risk following high dose radiation, 2) cell signaling is critical to cancer latency, and 3) such signals can be identified and interrupted. While this action of radiation as a promoter is less well studied, particularly in the context of recent developments in multicellular biology of carcinogenesis, it has significant implications. Just as radiation damage to DNA elicits a dramatic transition in signaling state within a cell, cellular response to radiation in tissues generates distinct signals that modify phenotype and tissue composition, presumably directed towards maintenance of tissue function and restoration of homeostasis, except when combined with neoplastically primed cells.
Reference: Nguyen DH, HA Oketch-Rabah, I Illa-Bochaca, FC Geyer, JS Reis-Filho, J-H Mao, SA Ravani, J Zavadil, AD Borowsky, DJ Jerry, KA Dunphy, JH Seo, S Haslam, D Medina, and MH Barcellos-Hoff. 2011. "Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type." Cancer Cell 19(5):640-651.