Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model

Touboul, Cyril; Lis, Raphaël; Farsi, Halema Al; Raynaud, Christophe M.; Warfa, Mohamed; Al-Thawadi, Hamda; Mery-Lamarche, Eliane; Mirshahi, Massoud; Rafii, Arash

doi:10.1186/1479-5876-11-28

Cited by 71 publications

(64 citation statements)

References 39 publications

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“…Cancer-associated adipocytes can also promote radio-resistance by secreting IL-6 [158], whilst IL-6 and IL-8 secreted by mesenchymal stem cells activate macrophages in the microenvironment of human colorectal and ovarian cancers, causing chemoresistance [159,160]. Besides causing resistance to chemo-and radiotherapy, autocrine secretion of IL-6 (induced by therapy) also confers resistance to some targeted therapies; for example, aflibercept (anti-VEGF, inhibitor)-resistant epidermoid carcinoma cells and herceptin (trastuzumab, anti-HER2)-resistant breast cancer cells secrete a large amount of IL-6 and show hyperactivation of STAT-3 signalling, causing resistance to therapy [161,162].…”

Section: Il-6 Induces Therapeutic Resistance In Cancermentioning

confidence: 99%

Role of interleukin-6 in cancer progression and therapeutic resistance

et al. 2016

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In the last several decades, the number of people dying from cancer-related deaths has not reduced significantly despite phenomenal advances in the technologies related to diagnosis and therapeutic modalities. The principal cause behind limitations in the curability of this disease is the reducing sensitivity of the cancer cells towards conventional anticancer therapeutic modalities, particularly in advance stages of the disease. Amongst several reasons, certain secretory factors released by the tumour cells into the microenvironment have been found to confer resistance towards chemo- and radiotherapy, besides promoting growth. Interleukin-6 (IL-6), one of the major cytokines in the tumour microenvironment, is an important factor which is found at high concentrations and known to be deregulated in cancer. Its overexpression has been reported in almost all types of tumours. The strong association between inflammation and cancer is reflected by the high IL-6 levels in the tumour microenvironment, where it promotes tumorigenesis by regulating all hallmarks of cancer and multiple signalling pathways, including apoptosis, survival, proliferation, angiogenesis, invasiveness and metastasis, and, most importantly, the metabolism. Moreover, IL-6 protects the cancer cells from therapy-induced DNA damage, oxidative stress and apoptosis by facilitating the repair and induction of countersignalling (antioxidant and anti-apoptotic/pro-survival) pathways. Therefore, blocking IL-6 or inhibiting its associated signalling independently or in combination with conventional anticancer therapies could be a potential therapeutic strategy for the treatment of cancers with IL-6-dominated signalling.

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Section: Il-6 Induces Therapeutic Resistance In Cancermentioning

confidence: 99%

Role of interleukin-6 in cancer progression and therapeutic resistance

et al. 2016

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“…Verification of the modified screening assay A known antagonist, ab47215, was used to assess the reliability of the modified assay [31,32] . Different concentrations of ab47215 were added to the rhIL-6 reactions and incubated together with membrane IL-6R for 1 h at 37 °C.…”

Section: Determination Of the Z′-factormentioning

confidence: 99%

Establishment of a novel cell-based assay for screening small molecule antagonists of human interleukin-6 receptor

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: Blockade of interleukin-6 (IL-6) or its receptor (IL-6R) is effective in preventing the progression of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In the present study, we established a novel cell-based assay for identifying small molecule IL-6R antagonists. Methods: HEK293A cells were transfected with recombinant plasmids pTaglite-SNAP-IL6R and pABhFc-IL6 to obtain membranebound IL-6R and recombinant human IL-6 coupled with human Fc fragment (rhIL-6), respectively. A novel screening assay based on the interaction between IL-6R and rhIL-6 was established, optimized and validated. The stability of the assay was also assessed by calculating the Z′-factor. Results: RhIL-6 dose-dependently bound to IL-6R expressed at HEK293A cell surface. The IC 50 value of the known antagonist ab47215 was 0.38±0.08 μg/mL, which was consistent with that obtained using the traditional method (0.36±0.14 μg/mL). The value of Z′-factor was 0.68, suggesting that the novel assay was stable for high throughput screening. A total of 474 compounds were screened using the novel screening assay, and 3 compounds exhibited antagonistic activities (IC 50 =8.73±0.28, 32.32±9.08, 57.83±4.24 μg/mL). Furthermore, the active compounds dose-dependently inhibited IL-6-induced proliferation of 7TD1 cells, and reduced IL-6-induced STAT3 phosphorylation in U937 cells. Conclusion: A novel cell-based screening assay for identifying small molecule IL-6R antagonists was established, which simplifies the procedures in traditional cellular ELISA screening and profiling and reduces the costs.

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“…Although survival has increased slightly over the past 25 years, 5-year survival remains below 50% (Corney et al, 2010). In recent years, biotherapies for ovarian cancer, including molecular targeted therapy, immunotherapy and gene therapy, have attracted more and more attention (Zhao et al, 2011;Touboul et al, 2013). Therefore, developing biological methods for ovarian cancer treatment are important for improving the outcome and prognosis of ovarian cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Inhibitor of signal transducer and activator of transcription 3 (STAT3) suppresses ovarian cancer growth, migration and invasion and enhances the effect of cisplatin in vitro

Tang¹,

Sun²,

Wu³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of the present study was to investigate the antiovarian cancer effect of the inhibitor of signal transducer and activator of transcription 3 (STAT3), WP1066. Western blot was used to detect the phosphorylation of STAT3 in ovarian cancer cell line SKOV3 and cisplatin-resistant ovarian cancer cell line SKOV3/DDP. MTT and colony-forming assays were performed to evaluate the viability and growth of ovarian cancer cells. The apoptosis of ovarian cancer cells was determined by flow cytometry. The wound healing assay and Transwell assay were performed to examine the migration and invasion of ovarian cancer cells. WP1066 significantly inhibited the phosphorylation of STAT3 in SKOV3 and SKOV3/DDP cells. WP1066 treatment inhibited the proliferation and clonogenicity of both SKOV3 and SKOV3/DDP cells. After WP1066 treatment for 24 h, the apoptosis rates of SKOV3 and SKOV3/DDP cells were significantly increased compared with the control cells. After treatment with WP1066, the reduction of the wound gaps was significantly less in both SKOV3 and Anti-ovarian cancer effect of WP1066 SKOV3/DDP cells. WP1066 also significantly inhibited the invasion capacity of SKOV3 and SKOV3/DDP cells compared with the control group. Treatment with WP1066 combined with cisplatin significantly increased proliferation inhibition and apoptosis in SKOV3 and SKOV3/ DDP cells compared with treatment with cisplatin alone. A synergistic action between WP1066 and cisplatin on the proliferation and apoptosis of ovarian cancer cells was determined. In conclusion, inhibition of STAT3 may suppress the proliferation, migration and invasion, induce apoptosis and enhance the chemosensitivity of ovarian cancer cells, indicating that STAT3 is a new therapeutic target of ovarian cancer.

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Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model

Cited by 71 publications

References 39 publications

Role of interleukin-6 in cancer progression and therapeutic resistance

Role of interleukin-6 in cancer progression and therapeutic resistance

Establishment of a novel cell-based assay for screening small molecule antagonists of human interleukin-6 receptor

Inhibitor of signal transducer and activator of transcription 3 (STAT3) suppresses ovarian cancer growth, migration and invasion and enhances the effect of cisplatin in vitro

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