Constitutive proteasomal degradation of TWIST-1 in epithelial–ovarian cancer stem cells impacts differentiation and metastatic potential

Abstract

Epithelial-mesenchymal transition (EMT) is a critical process for embryogenesis but is abnormally activated during cancer metastasis and recurrence. This process enables epithelial cancer cells to acquire mobility and traits associated with stemness. It is unknown whether epithelial stem cells or epithelial cancer stem cells are able to undergo EMT, and what molecular mechanism regulates this process in these specific cell types. We found that Epithelial Ovarian Cancer Stem cells (EOC stem cells) are the source of metastatic progenitor cells through a differentiation process involving EMT and Mesenchymal-Epithelial Transition (MET). We demonstrate both in vivo and in vitro the differentiation of EOC stem cells into mesenchymal spheroid-forming cells (MSFCs) and their capacity to initiate an active carcinomatosis. Furthermore, we demonstrate that human EOC stem cells injected i.p in mice are able to form ovarian tumors, suggesting that the EOC stem cells have the ability to “home” to the ovaries and establish tumors. Most interestingly, we found that TWIST1 is constitutively degraded in EOC stem cells, and that the acquisition of TWIST1 requires additional signals that will trigger the differentiation process. These findings are relevant for understanding the differentiation and metastasis process in EOC stem cells.

High Frequency of Putative Ovarian Cancer Stem Cells With CD44/CK19 Coexpression Is Associated With Decreased Progression-Free Intervals In Patients With Recurrent Epithelial Ovarian Cancer

“…18 We have shown recently that ovarian cancer cells expressing CD44 are highly tumorigenic, have capabilities of self-renewal, and recapitulate the heterogeneous phenotype of the tumor. 8,10,38 In addition, CD44þ cells are resistant to chemotherapy and are able to survive treatment with conventional drugs such as carboplatin and paclitaxel. 39 The findings described in this study are in support of the hypothesis that the CSCs are significant players in chemoresistance.…”

TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

“…These patient samples were obtained from patients at Yale New Haven Hospital (New Haven, CT) who were diagnosed with stage III/IV serous ovarian cancer and propagated as described previously (9,10,14,(28)(29)(30)(31)(32)(33) …”

“…More importantly, it allows us to test the efficacy of treatment against the mesenchymal cancer subtype. We previously showed that spheroid formation is a function of OCSCs and that this correlates with the acquisition of a mesenchymal phenotype, augmented migratory capacity, and enhanced chemoresistance (32). Thus, we tested the ability of TRX-E-002-1 to induce cell death in 3D spheroid cultures of OCSC2 by monitoring spheroid integrity using kinetic imaging.…”

MicroRNA expression signatures of stage, grade, and progression in clear cell RCC

“…Our analysis implicated several miRNAs as dysregulated in ccRCC for the first time including upregulation of miR-494 reported to target PTEN, 40 142-3p implicated in angiogenesis 20 as discussed above, 22-3p involved in the regulation of differentiation of mesenchymal stem cells 41 and also known to be a repressor of PTEN 42 as well as other miRNAs such as miR-1225-5p and 342-3p of which little or nothing is known of targets and functional role. We also identified downregulation of the let-7 family involved in the inhibition of cell growth and proliferation, 17 miR-200a-3p and 429 which are both members of the miR-200 family that target the ZEB1 and ZEB2 transcriptional repressors of E-cadherin and so are implicated in EMT and tumor invasion, 17 199a-5p involved in the regulation of the IKKβ/ NFκB and PTEN/AKT pathways 43 and other miRNAs such as miR-30c-5p of unknown function. Analysis by DIANA mirpath on a set of the 20 most upregulated and 30 most downregulated miRNAs identified the PI3K-Akt, MAPK, Wnt, TGF-β, p53, mTOR, Hedgehog, and VEGF signaling pathways, various pathways of metabolism, EMT, apoptosis, pathways in cancer, renal cell carcinoma, and other cancers as over-represented (P < 0.05) (Sup.…”