One histologic subtype of ovarian carcinoma, ovarian endometrioid adenocarcinoma (OEA), frequently harbors mutations that constitutively activate Wnt/beta-catenin-dependent signaling. We now show that defects in the PI3K/Pten and Wnt/beta-catenin signaling pathways often occur together in a subset of human OEAs, suggesting their cooperation during OEA pathogenesis. Deregulation of these two pathways in the murine ovarian surface epithelium by conditional inactivation of the Pten and Apc tumor suppressor genes results in the formation of adenocarcinomas morphologically similar to human OEAs with 100% penetrance, short latency, and rapid progression to metastatic disease in upwards of 75% of mice. The biological behavior and gene expression patterns of the murine cancers resemble those of human OEAs with defects in the Wnt/beta-catenin and PI3K/Pten pathways.

MXenes, an emerging family of graphene-analogues two-dimensional (2D) materials, have attracted continuous and tremendous attention in many application fields because of their intrinsic physiochemical properties and high performance in versatile applications. In this work, we report on the construction of tantalum carbide (TaC) MXene-based composite nanosheets for multiple imaging-guided photothermal tumor ablation, which has been achieved by rational choice of the composition of MXenes and their surface functionalization. A redox reaction was activated on the surface of tantalum carbide (TaC) MXene for in situ growth of manganese oxide nanoparticles (MnO/TaC) based on the reducing surface of the nanosheets. The tantalum components of MnO/TaC acted as the high-performance contrast agents for contrast-enhanced computed tomography, and the integrated MnO component functionalized as the tumor microenvironment-responsive contrast agents for T-weighted magnetic resonance imaging. The photothermal-conversion performance of MnO/TaC composite nanosheets not only has achieved contrast-enhanced photoacoustic imaging, but also realized the significant tumor-growth suppression by photothermal hyperthermia. This work broadens the biomedical applications of MXenes, not only by the fabrication of family members of biocompatible MXenes, but also by the development of functionalization strategies of MXenes for cancer-theranostic applications.

Wnt signaling plays a key role in development and adult tissues via effects on cell proliferation, motility, and differentiation. The cellular response to Wnt ligands largely depends on their ability to stabilize B-catenin and the ability of B-catenin to bind and activate T-cell factor (TCF) transcription factors. Roughly 40% of ovarian endometrioid adenocarcinomas (OEA) have constitutive activation of Wnt signaling as a result of oncogenic mutations in the B-catenin protein or inactivating mutations in key negative regulators of B-catenin, such as the adenomatous polyposis coli and Axin tumor suppressor proteins. We used oligonucleotide microarrays to identify genes of which expression was activated in OEAs with B-catenin dysregulation compared with OEAs lacking Wnt/ B-catenin pathway defects. Using microarray and quantitative PCR-based approaches, we found that fibroblast growth factor (FGF9) expression was increased >6-fold in primary OEAs with Wnt/B-catenin pathway defects compared with OEAs lacking such defects. Evidence that B-catenin and TCFs regulate FGF9 expression in several epithelial cell lines was obtained. We found FGF9 was mitogenic for epithelial cells and fibroblasts and FGF9 could stimulate invasion of epithelial and endothelial cells through Matrigel in transwell assays. Furthermore, FGF9 could promote neoplastic transformation of the E1A-immortalized RK3E epithelial cell line, and short hairpin RNA-mediated inhibition of endogenous FGF9 expression in the OEA cell line TOV112D, which carries a B-catenin mutation, inhibited neoplastic growth properties of the cells. Our findings support the notion that FGF9 is a key factor contributing to the cancer phenotype of OEAs carrying Wnt/ B-catenin pathway defects. (Cancer Res 2006; 66(3): 1354-62)

The emerging of two-dimensional (2D) MXenes significantly broadens the family members and versatile applications of 2D materials, but the rational design of MXene-based composites and their specific applications in theranostic biomedicine are still challenging. In this work, we report, for the first time, on the elaborate design of the Ti3C2-based composite MXene (MnO x /Ti3C2) for highly efficient theranostic applications against cancer. These MnO x /Ti3C2 composite MXenes have been constructed by triggering a simple redox reaction to in situ grow small MnO x nanosheets on the surface of Ti3C2. These MnO x /Ti3C2 composite MXenes have been developed as multifunctional theranostic agents for efficient magnetic resonance (MR) and photoacoustic (PA) dual-modality imaging-guided photothermal therapy (PTT) against cancer. Especially, the decoration of the MnO x component onto MnO x /Ti3C2 realizes the unique tumor microenvironment-responsive T1-weighted MR imaging of tumors, and the high photothermal-conversion performance not only endows the MnO x /Ti3C2 with desirable contrast-enhanced PA-imaging property but also realizes the highly efficient tumor ablation and tumor-growth suppression. The in vivo biocompatibility of these MnO x /Ti3C2–SP composite nanosheets has also been systematically evaluated and revealed. This work not only paves a new way for the multifunctionalization of 2D MXenes simply by integrating other functional components but also broadens their versatile applications in theranostic nanomedicine.