期刊
CANCER CELL
卷 19, 期 5, 页码 640-651出版社
CELL PRESS
DOI: 10.1016/j.ccr.2011.03.011
关键词
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资金
- DOD-BCRP
- Breakthrough Breast Cancer
- Department of Energy, Office of Biological and Environment Research
- National Institute of Environmental Health Sciences [U01 ES/CA 012801, 012800]
- National Cancer Institute of the National Institutes of Health
Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from tumors arising in nonirradiated hosts. Molecular and genetic approaches show that TGF beta mediated tumor acceleration. Tumor molecular signatures implicated TGF beta, and genetically reducing TGF beta abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGF beta independent and linked to mammary stem cell activity. Thus, the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms.
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