Disabling partners in crime: Gold nanoparticles disrupt multicellular communications within the tumor microenvironment to inhibit ovarian tumor aggressiveness

[Display omitted] •Cocultured EC and CAF promote CC proliferation.•20 nm GNP inhibit the growth of CC cocultured with EC and CAF.•Supernatant of CC, EC & CAF coculture treated with GNP reduce CC aggressiveness.•GNP downregulate cytokines initiating MAPK and PI3-AKT pathways and EMT.•Co-inoculate...

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Published in:Materials today (Kidlington, England) England), 2022-06, Vol.56, p.79-95
Main Authors: Zhang, Yushan, Elechalawar, Chandra Kumar, Yang, Wen, Frickenstein, Alex N., Asfa, Sima, Fung, Kar-Ming, Murphy, Brennah N., Dwivedi, Shailendra K, Rao, Geeta, Dey, Anindya, Wilhelm, Stefan, Bhattacharya, Resham, Mukherjee, Priyabrata
Format: Article
Language:English
Subjects:
Cancer-associated fibroblast (CAF)
Epithelial ovarian cancer (EOC)
Epithelial-mesenchymal transition (EMT)
Gold nanoparticle (GNP, AuNP)
Tumor microenvironment (TME)
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Summary:[Display omitted] •Cocultured EC and CAF promote CC proliferation.•20 nm GNP inhibit the growth of CC cocultured with EC and CAF.•Supernatant of CC, EC & CAF coculture treated with GNP reduce CC aggressiveness.•GNP downregulate cytokines initiating MAPK and PI3-AKT pathways and EMT.•Co-inoculated EC and CAF promote tumor growth in vivo and GNP inhibit the process. The tumor microenvironment (TME) plays a key role in the poor prognosis of many cancers. However, there is a knowledge gap concerning how multicellular communication among the critical players within the TME contributes to such poor outcomes. Using epithelial ovarian cancer (EOC) as a model, we show how crosstalk among cancer cells (CC), cancer associated fibroblasts (CAF), and endothelial cells (EC) promotes EOC growth. We demonstrate here that co-culturing CC with CAF and EC promotes CC proliferation, migration, and invasion in vitro and that co-implantation of the three cell types facilitates tumor growthin vivo. We further demonstrate that disruption of this multicellular crosstalk using gold nanoparticles (GNP) inhibits these pro-tumorigenic phenotypesin vitroas well as tumor growthin vivo. Mechanistically, GNP treatment reduces expression of several tumor-promoting cytokines and growth factors, resulting in inhibition of MAPK and PI3K-AKT activation and epithelial-mesenchymal transition - three key oncogenic signaling pathways responsible for the aggressiveness of EOC.The current work highlights the importance of multicellular crosstalk within the TME and its role for the aggressive nature of EOC, and demonstrates the disruption of these multicellular communications by self-therapeutic GNP, thus providing new avenues to interrogate the crosstalk and identify key perpetrators responsible for poor prognosis of this intractable malignancy.
ISSN:1369-7021
1873-4103
DOI:10.1016/j.mattod.2022.01.025