April 1 Cancer Research Highlights

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Selected Articles from the April 1, 2007 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the April 1 issue of Cancer Research.

Angiogenesis Achieved in Zebrafish Tumor Xenografts

The zebrafish (Danio rerio) represents a powerful alternative model system in cancer research. Nicoli et al. designed a novel mammalian tumor xenograft model in zebrafish to investigate tumor angiogenesis, a pivotal step in cancer progression and target for antitumor therapies. Injection of proangiogenic mammalian tumor cells into the perivitelline space of zebrafish embryos induced the formation of a new vasculature infiltrating the xenograft. The neovascular response was inhibited by systemic exposure to prototypic antiangiogenic compounds or by antisense morpholino oligonucleotide–targeted gene inactivation. The zebrafish/tumor xenograft model represents a novel tool for drug discovery and gene targeting in tumor angiogenesis.

Nanodelivery System for siRNA Targets Tumors

An effective, systemic, tumor cell–specific delivery system is necessary for siRNA to become a viable therapeutic modality. Pirollo et al. described a nano-sized tumor-specific immunoliposome complex for siRNA delivery that, when intravenously administered, specifically targets primary tumors and metastatic disease. This efficient delivery of the anti–HER-2 siRNA payload silences the target gene in vivo, affects the components of the downstream pathway in the tumor, and sensitizes tumor cells to conventional chemotherapeutics resulting in significant inhibition of tumor growth. Thus, the use of this nanocomplex delivery system can be utilized to exploit the enormous potential of siRNA for cancer treatment.

MDS1/EVI1 Levels Associated with Increased Ovarian Cancer Survival

Although advances in surgery and chemotherapy have improved the five-year survival rate for ovarian cancer to over 50%, the cure rate has not improved significantly. Both genetic and biomarkers are needed. Nanjundan et al. found that EVI1 and MDS1/EVI1 gene copy number and transcript levels are associated with increased survival duration in ovarian cancer patients. The MDS1/EVI1 fusion protein, historically associated with leukemias, may represent a novel target for immunotherapy or for early diagnosis in solid tumors. These results may apply broadly to epithelial tumors where the 3q26.2 aberration is present (ovary, breast, head and neck, cervix, lung), as well as in leukemias.

Mutant Thermostable Firefly Luciferase Improves Detection In vivo

Multimodality imaging using several reporter genes and imaging technologies has become an increasingly important tool in determining the location(s), magnitude, and time variation of reporter gene expression in small animals. Ray et al. created a mutant (mtfl) of a thermostable firefly luciferase (tfl) bearing the peroxisome localization signal to have greater cytoplasmic localization and improved access for its substrate, D-luciferin. Comparison between the three luciferases [mtfl, tfl and firefly luciferase (fl)] both in cell culture and in living mice revealed that mtfl possessed six- to ten-fold (in vitro) and two-fold (in vivo) higher activity than fl. This improved triple fusion reporter vector will enable high sensitivity detection of lower numbers of cells from living animals using combined bioluminescence, fluorescence, and microPET imaging techniques.

p18 Collaborates with Men1 to Suppress Lung Tumors

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18^Ink4c and p27^Kip1 develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18^Ink4c and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN, Pei et al. characterized p18-Men1 and p27-Men1 compound mutant mice and demonstrate that p18, but not p27, functionally collaborates with Men1 in suppressing lung tumorigenesis. These results reveal a previously unrecognized function of p18 in lung tumor suppression through collaboration with Men1 and implicate both in the control of lung stem cell proliferation.