The transcription factor Forkhead box E1 (FOXE1) is a key player in thyroid development and function and has been identified by genome-wide association studies as a susceptibility gene for papillary thyroid cancer. Several cancer-associated polymorphisms fall into gene regulatory regions and are likely to affect FOXE1 expression levels. However, the possibility that changes in FOXE1 expression modulate thyroid cancer development has not been investigated. Here, we describe the effects of FOXE1 gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for FOXE1 null allele (FOXE1+/−) were crossed with a BRAFV600E-inducible cancer model to develop thyroid cancer in either a FOXE1+/+ or FOXE1+/− genetic background. In FOXE1+/+ mice, cancer histological features are quite similar to that of human high-grade papillary thyroid carcinomas, while cancers developed with reduced FOXE1 gene dosage maintain morphological features resembling less malignant thyroid cancers, showing reduced proliferation index and increased apoptosis as well. Such cancers, however, appear severely undifferentiated, indicating that FOXE1 levels affect thyroid differentiation during neoplastic transformation. These results show that FOXE1 dosage exerts pleiotropic effects on thyroid cancer phenotype by affecting histology and regulating key markers of tumor differentiation and progression, thus suggesting the possibility that FOXE1 could behave as lineage-specific oncogene in follicular cell-derived thyroid cancer.
Cell plasticity is the ability that cells have to modify their phenotype, adapting to the environment. Cancer progression is under the strict control of the the tumor microenvironment that strongly determines its success by regulating the behavioral changes of tumor cells. The cross-talk between cancer and stromal cells and the interactions with the extracellular matrix, hypoxia and acidosis contribute to trigger a new tumor cell identity and to enhance tumor heterogeneity and metastatic spread. In highly aggressive triple-negative breast cancer, tumor cells show a significant capability to change their phenotype under the pressure of the hypoxic microenvironment. In this study, we investigated whether targeting the hypoxia-induced protein carbonic anhydrase IX (CA IX) could reduce triple-negative breast cancer (TNBC) cell phenotypic switching involved in processes associated with poor prognosis such as vascular mimicry (VM) and cancer stem cells (CSCs). The treatment of two TNBC cell lines (BT-549 and MDA-MB-231) with a specific CA IX siRNA or with a novel inhibitor of carbonic anhydrases (RC44) severely impaired their ability to form a vascular-like network and mammospheres and reduced their metastatic potential. In addition, the RC44 inhibitor was able to hamper the signal pathways involved in triggering VM and CSC formation. These results demonstrate that targeting hypoxia-induced cell plasticity through CA IX inhibition could be a new opportunity to selectively reduce VM and CSCs, thus improving the efficiency of existing therapies in TNBC.
Triple negative breast cancer (TNBC) is a heterogeneous disease, and even though it occurs in only 15-20% of all patients with breast cancer, it is characterized by an extremely high rate of mortality due to metastatic and drug-resistance recurrent disease. Chemotherapy is the primary established systemic treatment for TNBC patients in both the early and advanced-stages. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumors. Many evidences highlight the crucial role played by stromal cells in the hypoxic tumor microenvironment in promoting tumor growth, metastasis and chemoresistance. In this study, we aimed to investigate tumor-educated mesenchymal stem cells (TE-MSCs) function in supporting TNBC aggressive behavior through hypoxic-induced protein carbonic anhydrase IX (CAIX). First, we analyzed CAIX expression in a public data-set of 198 TNBC samples and in two TNBC cell lines (MDA-MB-231 and BT-549). All experiments were performed by growing the TNBC cells in normoxic (21% O2) and hypoxic conditions (1% O2) in presence of TE-MSCs or their conditioned medium (CM-MSC). CAIX expression was down-regulated using a specific siRNA. Cell migration and invasion assays were carried out using Boyden chamber uncoated and coated with matrigel, respectively. TNBC cell capability to form vascular-like tubular networks and mammospheres with stemness features were analyzed growing cells on Matrigel and Vitrogel-RGD, respectively. Furthermore, the ability of a novel molecule targeting CAIX (RC44) to hamper metastatic potential of TNBC cells as well as to sensitize them to cisplatin treatment was investigated. In addition, important signaling pathways underlying these mechanisms such as epithelial-mesenchymal-transition (EMT) markers (N-cadherin, β-catenin, slug) were analyzed by western blotting. TNBC cells grown in hypoxia in presence of TE-MSCs showed an increase of HIF-1α and CAIX levels as well as a strong enhancement of their ability to migrate, invade the extracellular matrix, form vascular channels and mammospheres. Furthermore, the effect of cisplatin on cell viability was reduced when TNBC cells were grown in these conditions thus demonstrating the protective effect of TE-MSCs against anti-cancer therapy. All these events were prevented when CAIX expression was inhibited by specific siRNA or its activity blocked by RC44. Furthermore, EMT program was hampered after CAIX inhibition. In conclusion, our findings suggest that targeting CAIX it is possible to hinder some malignant features of TNBC drastically modulated by mesenchymal stem cells in hypoxic microenvironment. Citation Format: Annachiara Sarnella, Giuliana D'Avino, Billy Hill, Vincenzo Alterio, Jean Yves Winum, Giuseppina De Simone, Laura Cerchia, Antonella Zannetti. Blocking mesenchymal stem cell-induced CAIX hampers metastatic potential and chemoresistance in TNBC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5088.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.