Gutierrez-Uzquiza et al. Page 1336

The bone is a preferred site for metastatic dissemination and homing for many cancers. In this study, Gutierrez-Uzquiza and colleagues identified PKCϵ, a protein kinase C isoform that is highly expressed in prostate cancer, as a novel player in skeletal metastasis. Silencing PKCϵ in PC3-ML cells, an androgen-independent cell model system with high bone tropism, severely impaired the formation of bone metastatic foci in mice. Furthermore, PKCϵ is required for prostate cancer cell invasiveness and transendothelial cell migration (TEM). This study provides experimental evidence for targeting PKCϵ for the treatment of bone metastatic disease.

Ye et al. Page 1274

Expression and function of the vascular endothelial growth factor receptor 1 (VEGFR1) in epithelial tumor cells has been well documented. In the current article, Ye and colleagues identified pseudogene FLT1P1 transcripts that are highly homologous to VEGFR1 mRNA expressed in colorectal cancer cells. Mechanistic studies showed that FLT1P1 noncoding transcripts play a vital role in translational regulation of cognate gene VEGFR1 expression, as well as modulation of noncognate gene expression through interaction with microRNAs. Finally, inhibiting FLT1P1 significantly impacted cell and tumor growth. These findings provide a putative target for non-coding RNA intervention in colorectal cancer.

Hensel et al. Page 1306

Tantamount to the identification of genetic mutations in patient tumors is the need to identify those mutations that drive tumor growth. From known bladder cancer mutations, Hensel and colleagues bioinformatically predicted which mutations promote loss of function. Then a screen was designed to mirror loss of function by introducing a shRNA library into cells and injecting the cells into mice. Genomic sequencing of the tumors revealed a number of dominate shRNAs and subsequent validation studies confirmed that loss of IQGAP1 leads to a dramatic increase in tumorigenic properties in vitro and in vivo. Importantly, reduced expression of IQGAP1 correlates with decreased bladder cancer patient survival indicating that this directed screen uncovered a novel tumor growth suppressor with biomarker potential in bladder cancer.

Hunter et al. Page 1325

Cancers bearing KRAS mutations are common, providing ample numbers of cases to suggest that specific mutant KRAS isoforms have distinct biological behaviors; the KRAS G13D mutation in colon cancer is a noteworthy example. Biochemical and structural analyses show that KRAS G13D rapidly exchanges its bound nucleotide, relative to other isoforms, due to a destabilizing interaction between the codon 13 aspartate side-chain and the phosphate portion of the ligand. These crystallographic insights from G13D and other KRAS mutants combined with the biochemical properties such as rates of intrinsic or GAP-stimulated GTP hydrolysis and the strength of protein-protein interactions between mutant KRAS isoforms and their effectors provides a framework for subclassifying KRAS driven cancers for better clinical decision making.