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

Abstract

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.

Response to low-dose X-irradiation is p53-dependent in a papillary thyroid carcinoma model system

“…Perhaps the low number of nuclei that exhibit DNA damage and the slight increase in the levels of Bcl-2 and Akt at low doses contribute to this effect. Another feature of senescent cells is an alteration in their secretory profile which has been reported at low doses of radiation (0.2 Gy) with noticeable effects on the microenvironment (45). This SASP has been deemed an important player in the tissue microenvironment and in the maintenance of the senescent state in cells (46,47).…”

Tumor Microenvironment and Differential Responses to Therapy

“…Similar to cytotoxic drugs, radiation-induced DNA damage can drive fibroblasts into senescence and promote a secretome that includes high levels of TGF-b ligands, VEGF-A, and various cytokines (Freund et al 2010;Acosta et al 2013). Crucially, media conditioned by senescent fibroblasts confers radioresistance (Tsai et al 2009). Increased levels of TGF-b are a common feature of the microenvironment following radiation, although it should be noted that fibroblasts may not be the only source of TGF-b.…”

“…Increased levels of TGF-b are a common feature of the microenvironment following radiation, although it should be noted that fibroblasts may not be the only source of TGF-b. Increased TGFb levels can affect the subsequent progression of residual disease, thereby undermining the long-term efficacy of the therapy (Tsai et al 2009). Further, the immune-suppressive effects of TGF-b can prevent an effective immune response being triggered against the cancer cell debris that results from the cells killed by radiotherapy.…”

The radiobiology of laser-driven particle beams: focus on sub-lethal responses of normal human cells

“…In hadrontherapy patients, the role of SIPS is still undetermined [55,56]. In addition, because senescing cells remain metabolically active [46], a Senescence -Associated Secretory Phenotype (SAPS) has been identified whose effect on neighboring primary cancer cells is controversial as secretion of factors released by cells undergoing SIPS has been associated with either the inhibition or the promotion of proliferation/invasiveness [57][58][59]. Therefore, sub-lethal effects clearly play a role as important as tumor local control in determining the successful outcome of cancer radiation treatment.…”