April 15 Highlights: CR

September 15, 2008 Cancer Research Highlights

Selected Articles from the September 15, 2008 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 September 15 issue of Cancer Research.

Mutant Muc2 and Apc Interaction in Intestinal Tumorigenesis

Yang et al.

Page 7313

Intestinal tumorigenesis is frequently initiated by mutations in the adenomatous polyposis coli (APC) gene, a component of the Wnt/β-catenin signaling pathway. A common characteristic of such tumors is a reduction in the number of goblet cells that produce the mucin MUC2, the protein component of mucus that protects the intestinal epithelium against mechanical and chemical insults. Muc2-deficient mice display spontaneous tumors along the entire gastrointestinal tract, independent of deregulated Wnt signaling. Yang and colleagues show that introduction of the mutant Muc2 allele into two mouse models of APC-initiated intestinal cancer increased transformation induced by the Apc mutation and significantly shifted tumor development toward the colon, a phenotype similar to those observed in these mice when challenged to mount an inflammatory response. Gene expression profiles suggest that Muc2 deficiency is associated with low levels of subclinical chronic inflammation, leading the authors to hypothesize that Muc2^−/− tumors develop through an inflammation-related pathway that is distinct from and can complement tumorigenesis.

CYR61 and αVβ5 Cooperate to Promote Metastasis

Monnier et al.

Page 7323

Tumors locally recurring after radiotherapy are highly invasive and metastatic, a condition referred to as the tumor bed effect. Currently, no effective treatment exists. Monnier and colleagues report that tumors growing within preirradiated areas are selected for stable metastatic escape variants though hypoxia-dependent, HIF-independent mechanisms. The authors found that the matricellular protein CYR61 and αVβ5 integrin cooperate to mediate these effects and that the αV integrin inhibitor was able to suppress invasion and metastasis in this model. This study represents a conceptual advance to the understanding of the tumor bed effect, and identifies αVβ5 as a potential therapeutic target for patients at risk for postradiation recurrences.

Molecular Profile of Resistance in Breast Cancer

Creighton et al.

Page 7493

The effectiveness of therapies targeting specific pathways in breast cancer such as the estrogen receptor (ER) or HER2 is limited because many tumors manifest either de novo or acquired resistance. Creighton and colleagues profiled the expression of more than 50,000 RNA transcripts in xenograft tumors after various targeted therapy regimens against ER and HER2 and compared these gene signatures with those derived from clinical breast cancers. The authors found that acquired resistance to various ER-targeted therapies transformed the associated molecular profile from that of an estrogen-dependent, ER⁺ tumor to that of an ER⁻/HER2⁺ tumor. These results lend support to a cancer treatment paradigm that targets not only the tumor in its pretreatment state but also that tumor as it might manifest itself during progression and acquired therapeutic resistance.

HDAC6 and Oncogenic Transformation

Lee et al.

Page 7561

HDACs are a family of enzymes that were initially characterized as histone deacetylases. HDAC inhibitors (HDACIs) display potent antitumor activity and many are at various stages of clinical trials despite a lack of understanding of how these inhibitors achieve their antitumor effects. Lee and colleagues show that one member of this family, HDAC6, a cytoplasmic-localized and cytoskeleton-associated deacetylase, is required for efficient oncogenic transformation and tumor formation. Inactivation of HDAC6 in several cancer cell lines reduced anchorage-independent growth and the ability to form tumors in mice, mediated at least partially through the AKT pathway. The authors also show that HDAC6 null mice are resistant to chemical carcinogen–induced skin tumors. These results provide the first experimental evidence that a specific HDAC member is required for efficient oncogenic transformation and that HDAC6, specifically, is an important component underlying the antitumor effects of HDACIs.

MRI of Angiogenesis with cNGR-labeled Quantum Dots

Oostendorp et al.

Page 7676
Oostendorp et al.

In vivo detection and quantification of tumor angiogenesis provides valuable information on tumor status and treatment response. Oostendorp and colleagues have developed novel paramagnetic quantum dots labeled with the cyclic tripeptide Asn-Gly-Arg (cNGR) for the bimodal detection of angiogenic activity using molecular and fluorescence microscopy. In vivo quantitative MRI of colorectal tumor–bearing mice demonstrated specific binding of the cNGR-particles at the tumor rim, but not in tumor core or muscle tissue. Ex vivo microscopy at subcellular resolution demonstrated that the cNGR-particles were primarily located on the surface of tumor endothelial cells. These results support the potential of molecular MRI to quantitate tumor angiogenic activity in the clinic.

September 15, 2008 Cancer Research Highlights

Selected Articles from the September 15, 2008 Issue

Mutant Muc2 and Apc Interaction in Intestinal Tumorigenesis

CYR61 and αVβ5 Cooperate to Promote Metastasis

Molecular Profile of Resistance in Breast Cancer

HDAC6 and Oncogenic Transformation

MRI of Angiogenesis with cNGR-labeled Quantum Dots

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