Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

Laberge, Rémi-Martin; Awad, Pierre; Campisi, Judith; Desprez, Pierre-Yves

doi:10.1007/s12307-011-0069-4

Cited by 207 publications

(171 citation statements)

References 62 publications

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“…SASPcontaining CM from senescent fibroblasts stimulated 3.5-fold more invasion than CM from non-senescent fibroblasts, and apigenin reduced this stimulation to non-senescent levels. Consistent with this finding, apigenin suppressed the ability of the SASP to induce an epithelial-mesenchymal transition (EMT) and confer on epithelial cells their invasive and metastatic properties, which is an important step during cancer progression (Laberge et al 2012b). By immunofluorescence (Fig.…”

Section: Secretion Profile Of Apigenin-treated Senescent Cellssupporting

confidence: 72%

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

et al. 2017

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Apigenin (4′,5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cellsstressed cells that accumulate with age in mammalsdisplay a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin. Here, we confirm that apigenin suppresses the SASP in three human fibroblast strains induced to senesce by ionizing radiation, constitutive MAPK (mitogen-activated protein kinase) signaling, oncogenic RAS, or replicative exhaustion. Apigenin suppressed the SASP in part by suppressing IL-1α signaling through IRAK1 and IRAK4, p38-MAPK, and NF-κB. Apigenin was particularly potent at suppressing the expression and secretion of CXCL10 (IP10), a newly identified SASP factor. Further, apigenin-mediated suppression of the SASP substantially reduced the aggressive phenotype of human breast cancer cells, as determined by cell proliferation, extracellular matrix invasion, and epithelialmesenchymal transition. Our results support the idea that apigenin is a promising natural product for reducing the impact of senescent cells on age-related diseases such as cancer.

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Section: Secretion Profile Of Apigenin-treated Senescent Cellssupporting

confidence: 72%

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

et al. 2017

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“…We show here, for the first time, that pemetrexed treatment of mesothelioma cell lines and primary MPM cells readily induces a senescent phenotype with features of SASP (Coppe et al, 2010) (Figure 1). SASP consists of premature senescence and secretion of a complex mix of cytokines, chemokines and growth factors (Laberge et al, 2011). We show that treatment of naive MPM cells with CM derived from pemetrexed-treated MPM cells promotes the emergence of mesenchymal-like, chemoresistant cell subpopulations endowed with high levels of ALDH activity (ALDH bright cells).…”

Section: Discussionmentioning

confidence: 93%

“…In addition, genotoxic stress and oncogene expression promote a complex senescence leading to the secretion of cytokines and pro-mitogenic factors, named SASP (senescenceassociated secretory phenotype; Rodier et al, 2005;Young and Narita, 2009;Coppe et al, 2010;Laberge et al, 2011). SASP-induced chemokines are known to induce EMT (epithelial-to-mesenchymal)-like changes in neighboring cell populations, and this may be considered as a mechanism of tumor progression (Laberge et al, 2011). However, it is not entirely clear whether SASP signaling can impinge on the progression of the neoplastic disease by modulating chemoresistance and tumor-initiating-activity.…”

Section: Introductionmentioning

confidence: 99%

SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells

Canino¹,

Mori²,

et al. 2011

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Here we show that pemetrexed-treated mesothelioma cells undergo accelerated senescence. This is characterized by the secretion of proinflammatory and mitogenic cytokines, reminiscent of an SASP (senescence-associated secretory phenotype). Conditioned media from senescent MPM (malignant pleural mesothelioma) cells trigger the emergence of EMT (epithelial-to-mesenchymal)-like, clonogenic and chemoresistant cell subpopulations, expressing high levels of ALDH (aldehyde dehydrogenase) activity (ALDH bright cells). We show by fluorescence-activated cell sorting of purified ALDH bright and ALDH low cells, that both cell-autonomous and cell-non-autonomous mechanisms converge to maintain the SASP-induced, EMT-like cell subpopulations. Chemoresistant ALDH bright cells exist within primary MPM specimens and enrichment for ALDH bright cells correlates with an earlier tumor onset into NOD/SCID mice. We show that RAS v12 expression induces SASP-like changes in untransformed human mesothelial cells, and that p53 ablation increases the effect of RAS v12 expression. We identify STAT3 activation as a crucial event downstream to SASP signaling. In fact, small hairpin RNA-mediated ablation of STAT3 deeply attenuates the induction of EMT genes and the increase of ALDH bright cells induced by SASP-cytokines. This strongly affects the chemoresistance of MPM cells in vitro and leads to anticancer effects in vivo.

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“…Mechanistically, we speculate that DNA damage signaling from therapy-induced recurrent and/or persistent DNA lesions (e.g. from senescent cells 65 ) may promote the observed phenotypic switch via the ATM-induced cytokine network 66 including TGFb family members that can shape the phenotype of treated cancer cells toward EMT and stem cell enrichment in a paracrine manner. Finally, we suggest that such treatment resistance (see Supplementary Figure 7) could be overcome, and that the dependency on signaling cascades we report here reveal vulnerabilities potentially exploitable in cancer treatment.…”

Section: Discussionmentioning

confidence: 96%

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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Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

Cited by 207 publications

References 62 publications

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells

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

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