Low-Dose Radiation-Induced Senescent Stromal Fibroblasts Render Nearby Breast Cancer Cells Radioresistant

Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Radiation Research (Impact Factor: 2.91). 10/2009; 172(3):306-13. DOI: 10.1667/RR1764.1
Source: PubMed


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.

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Available from: Kelvin K. Tsai
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    • "Thus there may be a bystander effect exerted by the senescent cells in this population on the androgen-refractory SB5 variants. This type of bystander effect has been previously reported and can be either growth-suppressive [71], [72] or growth-promoting [73]–[75] to varying degrees. Our co-mix experiments in this study (Figs. "
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    • "The SASP constitutes a myriad of proinflammatory cytokines and growth factors that can either facilitate or impede cancer progression depending on the cellular and/or microenvironmental context. A number of studies have demonstrated that senescent fibroblasts secrete factors that promote the growth of tumor cells (Olumi et al., 1999; Bavik et al., 2006; Tsai et al., 2009; Capparelli et al., 2012 "
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    • "Whether the irradiated cells that contribute to this plethora of inflammatory signals remain within the proliferative pool upon repair of damage or whether they become senescent is unknown however it is clear that even low doses of radiation induce SIPS and these cells subsequently secrete inflammatory cytokines, including IL-6 and IL-8 [27] [110] [133] [149] [150] [151] [152] [153]. Interestingly Tsai et al (2009) showed that stromal fibroblasts that were induced to senesce after low dose radiation exposure stimulated the proliferation of breast-carcinoma cells when co-cultured in the same medium [125] [130] [132] [133]. This potential relationship between exposure to radiation , cellular age and deleterious inflammatory (NTE) responses is further demonstrated by human and animal studies which show a correlation exists between the immunological imbalances caused as a result of exposure to radiation and, those effects which are seen in normal aged immune cells, implying ionising radiation may accelerate immunological ageing [154]. "
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