Hypoxia Activates β-catenin and Promotes HCC Metastasis
Aberrant activation of β-catenin contributes to the malignant phenotype of hepatocelluar carcinoma (HCC), but its role in hypoxia remains unclear. Liu and colleagues demonstrate that β-catenin becomes activated in HCC cells in response to hypoxia, regardless of β-catenin mutational status. Activation of β-catenin due to hypoxia had no effect on cell proliferation, but contributed to hypoxia-induced metastatic potential of HCC cells by eliciting epithelial-mesenchymal transition. Further, depletion of β-catenin abrogated the enhanced aggressiveness of HCC caused by hypoxia. These results support using the combination of a β-catenin inhibitor and hypoxia-related therapy for the treatment of HCC.
Mechanism of the Hsp90 Inhibitor KW-2478
Multiple myeloma (MM) is a B-cell malignancy commonly characterized by chromosomal translocations. In this study, Nakashima and colleagues evaluated KW-2478, a heat shock protein 90 (Hsp90) inhibitor, in MM. By treating MM cells with KW-2478, they found that FGFR3 is a new Hsp90 client protein. They also found that two other Hsp90 client proteins, Cdk9 and phosphorylated 4E-BP1, were depleted following treatment with KW-2478, demonstrating that KW-2478 affects both transcriptional and translational pathways. Studies using an orthotopic mouse model of MM further suggested that KW-2478 could be a promising strategy for the treatment of MM.
Near-Infrared Cyanine Dyes for Cancer Imaging
Near-infrared fluorescence imaging can be used for noninvasive in vivo imaging of tumors. Yang and colleagues demonstrate that a group of heptamethine cyanine dyes have special uptake and retention properties in cancer but not normal cells, mediated by organic anion transporter peptides. They found that these dyes accumulated in human cancer cells, human tumor xenografts, and mouse tumors in transgenic animals without the need for chemical conjugation. The differential accumulation of these dyes in cancer but not normal cells could have clinical utility, including the detection of circulating cancer cells in the blood and of tumor cells in pathologic specimens.
Immune Monitoring in a Presurgical Anti–CTLA-4 Trial
Many immunotherapy trials are conducted in the metastatic setting and rely on monitoring of peripheral blood. However, systemic immune responses may not reflect changes within tumors. Here, Carthon and colleagues conducted a preoperative trial with anti–CTLA-4, in which they identified an increased frequency of ICOShi T cells in tumors and blood following treatment. Additional studies in a separate cohort of patients with metastatic disease correlated a sustained increase in frequency of ICOShi T cells with clinical benefit. These results suggest that the preoperative model is a powerful investigational platform that can be used to efficiently guide immune monitoring in the metastatic setting.