Radiation‐Induced Reprogramming of Breast Cancer Cells

Lagadec, Chann; Vlashi, Erina; Donna, Lorenza Della; Dekmezian, Carmen; Pajonk, Frank

doi:10.1002/stem.1058

Cited by 349 publications

(367 citation statements)

References 33 publications

(45 reference statements)

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“…23,24 In breast cancer, IR induces Notch 56 and stem-like phenotype, including Notch-dependent upregulation of Oct-4. 57 Notch signaling can also activate EMT. 58 Together with other evidence, 59-61 our data support an emerging concept that IR promotes a phenotypic switch towards EMT and stem-like traits in epithelial tumors, also consistent with the intriguing yet mechanistically unclear resistance of cancer stem-like cells to genotoxic treatments.…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

et al. 2014

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Fractionated ionizing radiation combined with surgery or hormone therapy represents the first-choice treatment for medium to high-risk localized prostate carcinoma. One of the main reasons for the failure of radiotherapy in prostate cancer is radioresistance and further dissemination of surviving cells. In this study, exposure of four metastasis-derived human prostate cancer cell lines (DU145, PC-3, LNCaP and 22RV1) to clinically relevant daily fractions of ionizing radiation (35 doses of 2 Gy) resulted in generation of two radiation-surviving populations: adherent senescent-like cells expressing common senescenceassociated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2 and Nanog. While a subset of the radiation-surviving adherent cells resumed proliferation shortly after completion of the irradiation regimen, the non-adherent cells started to proliferate only on their reattachment several weeks after the radiation-induced loss of adhesion. Like the parental non-irradiated cells, radiation-surviving re-adherent DU145 cells were tumorigenic in immunocompromised mice. The radiation-induced loss of adhesion was dependent on expression of Snail, as siRNA/shRNA-mediated knockdown of Snail prevented cell detachment. On the other hand, survival of the non-adherent cells required active Erk signaling, as chemical inhibition of Erk1/2 by a MEK-selective inhibitor or Erk1/2 knockdown resulted in anoikis-mediated death in the non-adherent cell fraction. Notably, whereas combined inhibition of Erk and PI3K-Akt signaling triggered cell death in the non-adherent cell fraction and blocked proliferation of the adherent population of the prostate cancer cells, such combined treatment had only marginal if any impact on growth of control normal human diploid cells. These results contribute to better understanding of radiation-induced stress response and heterogeneity of human metastatic prostate cancer cells, document treatment-induced plasticity and phenotypically distinct cell subsets, and suggest the way to exploit their differential sensitivity to radiosensitizing drugs in overcoming radioresistance. Cell Death and Differentiation (2015) 22, 898-911; doi:10.1038/cdd.2014.97; published online 11 July 2014Prostate carcinoma (CaP) is the most frequent type of cancer in men, and the sixth cause of cancer-associated death in men worldwide. 1 Despite the advances in diagnosis and therapy of CaP, the mortality has remained almost unchanged for the last decades. Currently, the most successful treatment for localized CaP is prostatectomy with postoperative fractionated radiotherapy, significantly improving metastasis-free and overall survival, where the median of a 15-year survival is around 47% of patients. 2,3 The rest of the patients develop a metastatic disease that is incurable due to the resistance of CaP to androgen ablation, radiotherapy and chemotherapy. Therefore, understanding the mechanisms of radioresistance and chemoresista...

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Section: Discussionmentioning

confidence: 99%

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

et al. 2014

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“…Others have reported that sa-β-gal-positivity is also compatible with polylploid cells (induced by DNA chemotherapy) undergoing de-polyploidization and surviving [13,16]. Overcoming the tetraploidy barrier in TP53 mutants, boosting the self-renewal network [25,26] -can likely convert tumor cells into CSCs or stabilize them. Moreover, paradoxically, genotoxically challenged TP53 mutant tumor cells, which uncouple DNA replication from cell division and undergo mitotic slippage possessing both DNA DSBs and Ki67 expression ( Figure 6A).…”

Section: The Role Of Autophagy In Preventing Terminal Senescencementioning

confidence: 99%

“…Many gene modules of ESC are found active in various cancers [20], in turn, aggressive tumors express the markers of ESC or germ cells [21][22][23][24]. Third, tumors also acquire epigenetic proiles of ESC under genotoxic [25][26][27][28] or hypoxic conditions [29], in association with overcoming the tetraploidy barrier. So, epigenetically, CSCs of highly de-diferentiated tumors possess many features of ESC.…”

Section: Biological Features Of Cell Senescence: What Is Clear and Whmentioning

confidence: 99%

Accelerated Senescence of Cancer Stem Cells: A Failure to Thrive or a Route to Survival?

Ērenpreisa¹,

Salmiņa²,

Cragg³

2017

Senescence - Physiology or Pathology

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Accelerated senescence of cancer stem cells (CSCs) represents an adaptive response allowing withstand cell death. TP53, the pivotal tumor suppressor plays an important role in this process by inducing a prolonged dual state with senescence and self-renewal as potential outcomes. Molecularly, this is achieved by activating both OCT4A (POU5F1) and p21CIP1. OCT4A suppresses the excessive activity of p21 preventing the immediate precipitation of apoptosis or terminal senescence. It persists as long as suicient cellular energy remains; generated through autophagy, itself sequestrating p16INK4A in the cytoplasm. As such, autophagic capacity is the botleneck of these TP53-dependent senescence reversal processes, as well terminal senescence will follow if DNA damage is not ultimately repaired. In TP53 mutants the CSC-like state is boosted by stressed cells overcoming the tetraploidy barrier.These cells acquire additional DNA repair capacity through mitotic slippage and entrance to a sequence of ploidy cycles, allowing repair and sorting DNA damage, ultimately facilitating the genesis of mitotically competent daughter cells following inal depolyploidisation. Again, autophagy is required to fuel this process. More detailed knowledge of these arcane processes anticipates the provision of anti-cancer drug targets, such as AURORA B kinase and Survivin, which ensure mitotic slippage and the continuity of ploidy cycles.

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“…It has been shown that resveratrol induces cell death in some cancer cells by changing the proteins of the Bcl-2 family [119]. The inhibition of anti-apoptotic proteins of the Bcl-2 family, and activation of pro-apoptotic proteins such as Bad, Bak or Bax, by resveratrol has also been shown to be a mechanism for caspase activation and cytochrome c release [120,121].…”

Section: Anti-tumor-promotion Activitymentioning

confidence: 99%

Chemically-Induced DNA Damage, Mutagenesis, and Cancer

2018

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Radiation‐Induced Reprogramming of Breast Cancer Cells

Cited by 349 publications

References 33 publications

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

Accelerated Senescence of Cancer Stem Cells: A Failure to Thrive or a Route to Survival?

Chemically-Induced DNA Damage, Mutagenesis, and Cancer

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