E-Cadherin loss associated with EMT promotes radioresistance in human tumor cells

Theys, Jan; Jutten, Barry; Habets, R.; Paesmans, Kim; Groot, Arjan J.; Lambin, Philippe; Wouters, Bradly G.; Lammering, Guido; Vooijs, Marc

doi:10.1016/j.radonc.2011.05.044

Cited by 195 publications

(164 citation statements)

References 35 publications

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“…Although the former corroborates with a previous study that showed that autophagy contributes to radioresistance of GSCs, 36 the latter, although generally hypothesized in cancer stem cells, has not been demonstrated yet in glioma. 32,37,38 Taken together, the implication is that Wnt is one of many important pathways involved in GBM radioresistance, and future studies that link these pathways (Wnt, Notch, c-Met, DNA checkpoint, autophagy, and epithelial-mesenchymal transition) are warranted. Our results presented here implicate Wnt inhibition as one possible radiosensitizing agent ( Figure 5), and we speculate that a combination therapy that inhibit some or all of the other mentioned pathways will likely translate to successful treatment in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Wnt activation is implicated in glioblastoma radioresistance

Kim

Lee

et al. 2012

Laboratory Investigation

139

105

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Glioblastoma (GBM) patients have dismal median survival even with the most rigorous treatments currently available. Radiotherapy is the most effective non-surgical therapy for GBM patients; however, patients succumb due to tumor recurrence within a year. To develop a curative therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance in GBM. Towards this goal, we developed an in vivo orthotopic GBM model system that mimics the radiation response of human GBM, using both established-GBM cell line and patient-derived freshly dissociated GBM specimen. In-vivo ionizing radiation (IR) treatment prolonged the survival of mice with intracranical tumor derived from U373MG, but failed to prevent tumor recurrence. U373MG and GBM578 cells isolated after in-vivo IR (U373-IR and 578-IR) were more clonogenic and enriched with stem cell-like characteristics, compared with mock-treated control tumor cells. Transcriptomic analyses and quantitative real-time reverse-transcription PCR analyses using these matched GBM cells before and after radiation treatment revealed that Wnt pathways were preferentially activated in post-IR GBM cells. U373-IR cells and 578-IR were enriched with cells positive for both active b-catenin (ABC) and Sox2 population, and this subpopulation was further increased after additional in-vitro radiation treatment, suggesting that radiation resistance of GBM is mediated due, in part, to the activation of stem cell-associated pathways including Wnt. Finally, pharmacological and siRNA inhibition of Wnt pathway significantly decreased the survival and clonogenicity of GBM cells and reduced their ABC þ /Sox2 þ population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Wnt activation is implicated in glioblastoma radioresistance

Kim

Lee

et al. 2012

Laboratory Investigation

139

105

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“…17 Several studies have also reported a relationship between EMT and radioresistance. 18,28 Our results indicate that the combination of miR-200c nanoparticles and ionizing radiation increases expression of E-cadherin, an important epithelial marker, and could reverse the EMT process. Our experiments further confirmed that two main properties of CSCs, ie, invasiveness and resistance to apoptosis, and two main mechanisms involved in CSC radioresistance, ie, reactive oxygen species generation and DNA double strand break repair, were impaired by the miR-200c nanoparticles, suggesting that radiosensitization of miR-200c nanoparticles is dependent on its ability to inhibit CSCs.…”

Section: Discussionmentioning

confidence: 75%

“…Furthermore, there is evidence showing that EMT may directly induce radioresistance. 18 Generation of CSCs and the EMT process may be two coalitional and overlapping factors affecting progression of cancer and therapeutic failure. 19 Because of these functions, miR-200c has the potential to promote radiosensitivity in cancer cells by inhibiting CSClike properties and repressing EMT.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of radiotherapy efficacy by miR-200c-loaded gelatinase-stimuli PEG-Pep-PCL nanoparticles in gastric cancer cells

Cui¹,

Liu²,

Li³

et al. 2014

IJN

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Radiotherapy is the main locoregional control modality for many types of unresectable tumors, including gastric cancer. However, many patients fail radiotherapy due to intrinsic radioresistance of cancer cells, which has been found to be strongly associated with cancer stem cell (CSC)-like properties. In this study, we developed a nanoparticle formulation to deliver miR-200c, which is reported to inhibit CSC-like properties, and then evaluated its potential activity as a radiosensitizer. miR-200c nanoparticles significantly augmented radiosensitivity in three gastric cancer cell lines (sensitization enhancement ratio 1.13–1.25), but only slightly in GES-1 cells (1.06). In addition to radioenhancement, miR-200c nanoparticles reduced the expression of CD44, a putative CSC marker, and the percentage of CD44 + BGC823 cells. Meanwhile, other CSC-like properties, including invasiveness and resistance to apoptosis, could be suppressed by miR-200c nanoparticles. CSC-associated radioresistance mechanisms, involving reactive oxygen species levels and DNA repair capacity, were also attenuated. We have demonstrated that miR-200c nanoparticles are an effective radiosensitizer in gastric cancer cells and induce little radiosensitization in normal cells, which suggests that they are as a promising candidate for further preclinical and clinical evaluation.

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“…Abnormal activation of TGF-b leads to trans-differentiation of quiescent fibroblasts into myofibroblasts, and excessive production of fibrillar collagens [1,22,23] as observed in IPF patients [24]. Additionally, increased elevation of TGF-b1 under hypoxic conditions can lead to rapid and pronounced EMT [25].…”

Section: Discussionmentioning

confidence: 99%

Epithelial–mesenchymal transition of A549 cells is enhanced by co-cultured with THP-1 macrophages under hypoxic conditions

Sueki

Matsuda

Iwashita

et al. 2014

Biochemical and Biophysical Research Communications

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a b s t r a c tEpithelial-mesenchymal transition (EMT) is associated with pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF). In this study, we investigated EMT of human pulmonary epithelial-derived cells (A549). A549 cells was either cultured by itself or co-cultured with THP-1 macrophages under normoxic (21% O 2 ) and hypoxic (2% O 2 ) conditions. We evaluated the presence of EMT by determining the expression of EMT markers, E-cadherin, vimentin, and fibronectin. To determine the role of TGF-b1 and IL-1b in EMT of the A549 cells, we analyzed the effects of blocking their activity with TGF-b1 inhibitor or IL-1b neutralizing antibody respectively. The A549 cells presented EMT when they were co-cultured with THP-1 macrophages. The EMT of the A549 cells co-cultured with THP-1 macrophages was exacerbated under hypoxia. In addition, the EMT were prevented by the addition of TGF-b1 type I receptor kinase inhibitor. The hypoxic condition increased the mRNA levels of TGF-b1 in A549 cells and THP-1 macrophages and that of IL-1b in THP-1 macrophages when each cells were co-cultured. Anti-IL-1b neutralizing antibody attenuated TGF-b1 secretion in co-culture media under hypoxic conditions. Thus, the IL-1b from THP-1 macrophages up-regulated the TGF-b1 from A549 cells and THP-1 macrophages, and then the TGF-b1 from both cells induced and promoted the EMT of A549 cells when they were co-cultured under hypoxia. Together, these results demonstrate that the interaction between type II pneumocytes and macrophages under hypoxia is necessary for the development of pulmonary fibrosis.

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E-Cadherin loss associated with EMT promotes radioresistance in human tumor cells

Cited by 195 publications

References 35 publications

Wnt activation is implicated in glioblastoma radioresistance

Wnt activation is implicated in glioblastoma radioresistance

Enhancement of radiotherapy efficacy by miR-200c-loaded gelatinase-stimuli PEG-Pep-PCL nanoparticles in gastric cancer cells

Epithelial–mesenchymal transition of A549 cells is enhanced by co-cultured with THP-1 macrophages under hypoxic conditions

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