January 1 Cancer Research Highlights

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Selected Articles from the January 1, 2006 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 January 1 issue of Cancer Research.

Imprinted Modifiers Exert Epistatic Regulation on Nstr1, Nstr2

Neurofibromatosis type 1 (NF1) is a common genetic disease exhibiting a high degree of variable expressivity and increased cancer risk. To determine the genetic and epigenetic modifiers underlying cancer susceptibility, Reilly et al. have used the Nf1-/+;Trp53-/+cis mouse to identify the first mapped modifier loci for NF1. This study demonstrates that susceptibility to peripheral nerve sheath tumors is controlled by an imprinted modifier on mouse chromosome 11 and polymorphic modifiers on mouse chromosomes 19 (Nstr1) and 15 (Nstr2). The imprinted modifier epistatically interacts with Nstr1 and Nstr2, demonstrating the complex interactions in the genome that determine cancer susceptibility.

Meta-Analysis Defines Gastric Cancer Wnt Regulation of PLA2G2A

Gastric cancer is a major cause of global cancer mortality. By combining microarray data from four independent patient cohorts, Aggarwal et al. have assembled a gene co-expression meta-network of gastric cancer to establish a systems-level map of this disease. The resulting scale-free meta-network possesses numerous deeply embedded modules associated with distinct functional and topological properties. They identify a novel interaction between the prognostic marker PLA2G2A and the EphB2 receptor, and show that Wnt signaling may regulate PLA2G2A. These results advance our understanding of gastric cancer and demonstrate how meta-analytical approaches can be applied to genome-wide data to accelerate biological discovery.

Mist1 Conveys Permissive Compartment for Kras-Induced Tumorigenesis

Exocrine pancreatic cancer is an extremely lethal neoplasm due to the lack of early detection methods and the poor responsiveness to therapies. Therefore, a thorough understanding of the molecular and cellular events that mediate pancreatic tumorigenesis is warranted. To investigate potential cellular compartments, Tuveson et al. targeted the expression of the Kras^G12D oncogene to the Mist1 promoter, and found that mutant mice developed mixed lineage pancreatic cancer and hepatocellular carcinomas. The heterogeneous histological features of pancreatic tumors in Mist1-Kras^G12D mice suggest that Mist1-expressing cells may assume alternative cellular fates, identifying these cells as a potentially important lineage in pancreatic cancer genesis.

β₁ Integrins Regulate IGF-II Levels and Signaling in the Microenvironment

Insulin-like growth factors (IGFs) mediate autocrine and paracrine pathways that are deregulated in prostate cancer progression. Using gene expression analysis, Goel et al. discovered that β₁ integrin adhesion receptors regulate IGF-II expression, and that IGF-II increases cell adhesion to basement membrane proteins in an autocrine manner. This effect depends on the expression of specific β₁ integrin variants. The mechanism underlying IGF-mediated effects is selectively regulated by the β₁ integrin cytoplasmic domain via activation of the Gab1/Shp2/PI3-kinase signaling pathway. Whether it is released from a tumor cell or from the tumor microenvironment, IGF-II will ultimately stimulate a response that is selectively regulated by expression of specific integrins. Thus, concurrent deregulation of β₁ integrin variants and of their basement membrane ligands may contribute to prostate cancer progression by regulating IGF-II levels and the ability of a neoplastic cell to respond to changes in the microenvironment.

Novel IKKβ Inhibitor Suppresses Cell Cycle Breast Cancer Progression

Constitutive NF-κB activity plays a crucial role on development and progression of breast cancers. Tanaka et al. clearly demonstrate that a new IKKβ inhibitor, IMD-0354, suppresses the growth of human breast cancer cells by arresting cell cycle and inducing apoptosis. Addition of IMD-0354 suppresses expression of both D-type cyclins and Bcl-family proteins, but up-regulated a cyclin-dependent kinase inhibitor p27Kip1. Daily administration with IMD-0354 inhibited tumor expansion in mice transplanted with MDA-MB-231 cells. Since great contribution of NF-κB to development of breast cancers is obvious, inhibition of NF-κB activity may be a clinically relevant strategy in treatment of human breast cancers.