Nitric Oxide Synthase Activity and Tumor Progression
Studies have shown that nitric oxide (NO) has both protumor and antitumor growth properties. Rabender and colleagues demonstrate that NO synthase (NOS) in tumor cells is uncoupled and instead of generating NO it synthesizes superoxide and peroxynitrite. Furthermore, recoupling NOS with the BH4 precursor, sepiapterin, is cytotoxic to tumor cells. These findings shed light on the conflicting results of NO signaling and reveal a critical switching mechanism for tumor progression. Synthetic BH4 is used to treat some phenylketonuria patients and diseases associated with endothelial dysfunction, suggesting a testable approach for correcting an abnormality of tumor metabolism and controlling tumor growth.
YAP/TAZ-Regulated Transcription in OSCC
Oral squamous cell carcinoma (OSCC) is a widespread form of cancer with poor survival rates. Progress in treatment strategies has been limited, and thus understanding dysregulated signals contributing to OSCC is required. Hiemer and colleagues show that the transcriptional regulators YAP and TAZ, downstream effectors of the Hippo pathway, drive protumorigenic signals in OSCC in vitro and in vivo. Further, comparing the YAP/TAZ-regulated gene expression changes with those identified in OSCC tissues by The Cancer Genome Atlas (TCGA) demonstrated a significant contribution of nuclear YAP/TAZ activity to OSCC onset and progression. This study reveals novel insight into the dysregulated signals contributing to this poorly understood cancer.
Canine Bladder Tumors Carry BRAFV600E Mutation
Canine invasive transitional cell carcinoma of the bladder (InvTCC) is a common, naturally occurring malignancy that shares histologic, biologic, and clinical characteristics with human invasive bladder cancers. Decker and colleagues observed that a large majority of tested canine InvTCC tumors are driven by a canonical activating BRAF (V600E) mutation. Administration of vemurafenib, a clinical-grade BRAF inhibitor, demonstrably reduced growth of canine bladder cancer cell lines, highlighting both the clinical and translational potential of this animal model for studies of human BRAF-dependent tumors. Finally, a urine-based diagnostic test was developed, based on the BRAF mutation, which is highly effective in dogs.
Targeting miR-21 in HCC
MicroRNA-21 (miR-21) is upregulated in many human malignancies and often correlates with poor clinical outcomes. Wagenaar and colleagues detected significant overexpression of miR-21 in two large independent cohorts of patients with hepatocellular carcinoma (HCC) and in HCC cell lines. Using potent anti–miR-21 compounds and genetic tools, they determined that miR-21 inhibition results in profound deregulation of multiple prosurvival pathways and leads to the suppression of HCC growth in vitro and in vivo. These results establish a critical role for miR-21 in maintaining tumorigenic phenotype in HCC and suggest that miR-21 represents an important target for pharmacologic inhibition in liver cancer.
- ©2015 American Association for Cancer Research.