Low-dose radiation-induced senescent stromal fibroblasts render nearby breast cancer cells radioresistant.
In addition to cell cycle arrest, DNA repair or/and apoptosis, ionizing radiation can also induce premature senescence, which could lead to very different biological consequences depending on the cell type. We show in this report that low-dose radiation-induced senescent stromal fibroblasts stimulate proliferation of cocultured breast carcinoma cells. Such effects of senescent fibroblasts appear to result from their ability to induce the expression in carcinoma cells of mitotic genes and subsequent mitotic division. The elevated proliferation of breast carcinoma cells correlates with resistance to radiation as well as to adriamycin. Of interest is the observation that exposure to lower doses (<20 cGy) augments the ability of senescent fibroblasts to promote the survival of cocultured breast carcinoma cells. The resistance appears to be mediated partially by the Akt pathway, because expression of a dominant negative Akt mutant in breast carcinoma cells results in a partial reversal of the radioresistance. The ability of fibroblasts to modulate the radiosensitivity of nearby carcinoma cells implicates the importance of targeting the stroma during therapy.
Tsai
Kelvin K C
KK
Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Stuart
Jeremy
J
Chuang
Yao-Yu Eric
YY
Little
John B
JB
Yuan
Zhi-Min
ZM
D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D024201:Bystander Effect / Q000528:radiation effects*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000528:radiation effects*; D006801:Humans; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000528:radiation effects*; D017154:Stromal Cells / Q000473:pathology / Q000528:radiation effects