Suppression of ovarian cancer by low-intensity ultrasound through depletion of IL-6/STAT3 inflammatory pathway-maintained cancer stemness

Gong, Ting; Zhang, Penghua; Jia, Liping; Pan, Yanyan

doi:10.1016/j.bbrc.2020.03.136

Cited by 12 publications

(12 citation statements)

References 24 publications

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“…Apart from its role in inflammation, Stat3 signaling has also been linked to a cancer stem cell phenotype in the context of another syndecan member, syndecan-1, and to a cancer stem cell phenotype and resistance to chemotherapy in ovarian cancer [ 39 , 42 , 43 , 44 , 45 ]. Therefore, reduced Stat3 signaling in SDC3-depleted cells may be linked to the reduction in both cell lines’ 3D spheroid growth as a readout of putative stem cell function.…”

Section: Discussionmentioning

confidence: 99%

The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis

Hillemeyer

Espinoza-Sánchez

Greve

et al. 2022

IJMS

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Syndecans are transmembrane heparan sulfate proteoglycans that integrate signaling at the cell surface. By interacting with cytokines, signaling receptors, proteases, and extracellular matrix proteins, syndecans regulate cell proliferation, metastasis, angiogenesis, and inflammation. We analyzed public gene expression datasets to evaluate the dysregulation and potential prognostic impact of Syndecan-3 in ovarian cancer. Moreover, we performed functional in vitro analysis in syndecan-3-siRNA-treated SKOV3 and CAOV3 ovarian cancer cells. In silico analysis of public gene array datasets revealed that syndecan-3 mRNA expression was significantly increased 5.8-fold in ovarian cancer tissues (n = 744) and 3.4-fold in metastases (n = 44) compared with control tissue (n = 46), as independently confirmed in an RNAseq dataset on ovarian serous cystadenocarcinoma tissue (n = 374, controls: n = 133, 3.5-fold increase tumor vs. normal). Syndecan-3 siRNA knockdown impaired 3D spheroid growth and colony formation as stemness-related readouts in SKOV3 and CAOV3 cells. In SKOV3, but not in CAOV3 cells, syndecan-3 depletion reduced cell viability both under basal conditions and under chemotherapy with cisplatin, or cisplatin and paclitaxel. While analysis of the SIOVDB database did not reveal differences in Syndecan-3 expression between patients, sensitive, resistant or refractory to chemotherapy, KM Plotter analysis of 1435 ovarian cancer patients revealed that high syndecan-3 expression was associated with reduced survival in patients treated with taxol and platin. At the molecular level, a reduction in Stat3 activation and changes in the expression of Wnt and notch signaling constituents were observed. Our study suggests that up-regulation of syndecan-3 promotes the pathogenesis of ovarian cancer by modulating stemness-associated pathways.

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Section: Discussionmentioning

confidence: 99%

The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis

Hillemeyer

Espinoza-Sánchez

Greve

et al. 2022

IJMS

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“…The pro-inflammatory cytokine IL-6 plays a role in the pathogenesis of EOC. It has been shown to be associated with worse prognosis, and to promote chemoresistance and stemness ( 14 – 16 ). IL-1 is another pro-inflammatory cytokine released during ovulatory inflammation.…”

Section: Microenvironment At the Site Of Originmentioning

confidence: 99%

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

Ritch

Telleria

2022

Front. Endocrinol.

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Epithelial ovarian cancer (EOC) is considered the deadliest gynecological disease and is normally diagnosed at late stages, at which point metastasis has already occurred. Throughout disease progression, EOC will encounter various ecosystems and the communication between cancer cells and these microenvironments will promote the survival and dissemination of EOC. The primary tumor is thought to develop within the ovaries or the fallopian tubes, both of which provide a microenvironment with high risk of causing DNA damage and enhanced proliferation. EOC disseminates by direct extension from the primary tumors, as single cells or multicellular aggregates. Under the influence of cellular and non-cellular factors, EOC spheroids use the natural flow of peritoneal fluid to reach distant organs within the peritoneal cavity. These cells can then implant and seed distant organs or tissues, which develop rapidly into secondary tumor nodules. The peritoneal tissue and the omentum are two common sites of EOC metastasis, providing a microenvironment that supports EOC invasion and survival. Current treatment for EOC involves debulking surgery followed by platinum-taxane combination chemotherapy; however, most patients will relapse with a chemoresistant disease with tumors developed within the peritoneum. Therefore, understanding the role of the unique microenvironments that promote EOC transcoelomic dissemination is important in improving patient outcomes from this disease. In this review article, we address the process of ovarian cancer cellular fate at the site of its origin in the secretory cells of the fallopian tube or in the ovarian surface epithelial cells, their detachment process, how the cells survive in the peritoneal fluid avoiding cell death triggers, and how cancer- associated cells help them in the process. Finally, we report the mechanisms used by the ovarian cancer cells to adhere and migrate through the mesothelial monolayer lining the peritoneum. We also discuss the involvement of the transcoelomic ecosystem on the development of chemoresistance of EOC.

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“…As we know, JAK-STAT3 activation promotes cell stemness and favours the generation of CSCs. 36,37 Several preclinical studies have also demonstrated that blocking STAT3 signalling with stattic (STAT3 inhibitor) may reduce the stemness of BC cells. 38,39 To regulate stemness, we used stattic to block STAT3 activation in MCF-7/R cells.…”

Section: The Elevated Stemness Is Responsible For Palbociclib Resista...mentioning

confidence: 99%

PFKFB4 facilitates palbociclib resistance in oestrogen receptor‐positive breast cancer by enhancing stemness

et al. 2022

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Background ER+ breast cancer (ER+ BC) is the most common subtype of BC. Recently, CDK4/6 inhibitors combined with aromatase inhibitors have been approved by FDA as the first‐line therapy for patients with ER+ BC, and showed promising therapeutic efficacy in clinical treatment. However, resistance to CDK4/6 inhibitors is frequently observed. A better understanding of the drug resistance mechanism is beneficial to improving therapeutic strategies by identifying optimal combinational treatments. Methods Western blotting, qPCR, flow cytometry and a series of cell experiments were performed to evaluate the phenotype of MCF‐7/R cells. RNA sequencing, non‐targeted metabolomics, shRNA knockdown and tumour cell‐bearing mouse models were used to clarify the drug resistance mechanism. Results Here, we found that ER+ BC cells have shown an adaptive resistance to palbociclib‐induced cell cycle arrest by activating an alternative signal pathway, independent of the CDK4/6‐RB signal transduction. Continuing treatment of palbociclib evoked cellular senescence of ER+ BC cells. Subsequently, the senescence‐like phenotype promoted stemness of ER+ BC cells, accompanied by increased chemoresistance and tumour‐initiating potential. Based on transcriptome analysis, we found that PFKFB4 played an important role in stemness transformation and drug resistance. A close correlation was determined between PFKFB4 expression by ER+ BC cells and cell senescence and stemness. Mechanistically, metabolomic profiling revealed that PFKFB4 reprogramed glucose metabolism and promoted cell stemness by enhancing glycolysis. Strikingly, diminishing PFKFB4 levels improved drug sensitivity and overcame chemoresistance during palbociclib treatment in ER+ BC. Conclusions These findings not only demonstrated the novel mechanism underlying which ER+ BC cells resisted to palbociclib, but also provided a possible therapeutic strategy in the intervention of ER+ BC to overcome drug resistance.

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Suppression of ovarian cancer by low-intensity ultrasound through depletion of IL-6/STAT3 inflammatory pathway-maintained cancer stemness

Cited by 12 publications

References 24 publications

The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis

The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

PFKFB4 facilitates palbociclib resistance in oestrogen receptor‐positive breast cancer by enhancing stemness

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