Blocking the formation of radiation-induced breast cancer stem cells

Abstract

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.

Radiation induces the generation of cancer stem cells: A novel mechanism for cancer radioresistance

“…Furthermore, these induced breast CSCs exhibited resistance to radiation. This study confirmed that radiation induced the generation of CSCs, which was also reported by Wang et al (89). Additionally, Ghisolfi et al (47) demonstrated that radiation induced stem cell-like properties in non-stem hepatocarcinoma cells, as demonstrated by the findings that non-side population (CSC-depleted population) cells from HepG2 and Huh7 cells exhibited increased sphere formation and stemness gene expression after exposure to radiation.…”

An Epigenetic Reprogramming Strategy to Resensitize Radioresistant Prostate Cancer Cells

“…In agreement with this, recently published data showed that irradiation may induce reprogramming of differentiated breast and hepatocellular carcinoma cells (39)(40)(41). Consistent with these findings, we have previously shown that fractions of the cells positive for CSC markers, for example, ABCG2, CD133, ALDH activity were significantly enriched after fractionated irradiation that can be potentially attributed to cell selection as well as to cell induction mechanisms including both, accelerated proliferation and reprogramming (16,39,40). Notably, our data revealed that a single 4 Gy irradiation induces a prolonged effect on the clonogenic potential and expression of both CSC and EMT markers, which lasts for more than 6 weeks.…”

“…The populations of tumor cells with salient features of CSCs can be induced in vivo in response to the different microenvironmental stimuli, which include hypoxia, genetic alterations that trigger EMT, as well as cancer therapies (26,37,38). In agreement with this, recently published data showed that irradiation may induce reprogramming of differentiated breast and hepatocellular carcinoma cells (39)(40)(41). Consistent with these findings, we have previously shown that fractions of the cells positive for CSC markers, for example, ABCG2, CD133, ALDH activity were significantly enriched after fractionated irradiation that can be potentially attributed to cell selection as well as to cell induction mechanisms including both, accelerated proliferation and reprogramming (16,39,40).…”

The Role of Canonical Wnt Signaling in Regulating Radioresistance

“…In 2012, Lagadec et al observed that IR induced the enrichment of breast CSCs via promotion of stem cell-like properties in NSCCs [41]. These results were also demonstrated by Ghisolfi et al in hepatocellular carcinoma cells [42] and by Wang et al in breast cancer cells [42,43]. Thus, CSCs are involved in both intrinsic and acquired radioresistance.…”