September 15 Cancer Research Highlights

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

EPHB4 Regulates Colorectal Tumorigenesis

The family of receptor tyrosine kinases EPH and their Ephrin ligands regulate cell proliferation, migration, and attachment. Davalos et al. identified EPHB4 as a powerful new marker of prognosis in colorectal cancer using immunohistochemical assessment of EPHB4 levels. The authors provide mechanistic evidence showing that methylation of EPHB4 is common in colorectal tumors and that this epigenetic mechanism is capable of downregulating EPHB4 expression. Moreover, functional evidence is provided showing that modulation of EPHB4 levels has a profound impact on the long-term clonogeneic potential of colorectal cancer cells. These results help to establish EPHB4 as a novel candidate tumor suppressor gene in colorectal cancer, and strengthen the emerging view of EPH/EFN family members as important regulators of colorectal tumorigenesis.

New Model Developed for BRCA1-Associated Ovarian Cancer

Little is known about the mechanisms that underlie Brca1-associated ovarian tumorigenesis, mainly due to the lack of an appropriate experimental model. Xing and Orsulic demonstrated that myc cooperates with the loss of p53 and Brca1 in transforming mouse ovarian surface epithelial cells (OSE). The Brca1-deficient cells are highly sensitive to cisplatin, suggesting that this model will be useful for the evaluation of other therapies that target the DNA repair pathways. Unlike cell lines isolated from human tumors, the mouse OSE are genetically defined and form serous papillary carcinomas in immunocompetent mice, thus providing an experimental model to study targeted therapies that may interfere with the immune system.

Tumor SDF-1 Recruits Vascular Progenitors

Mechanisms underlying tumor vasculogenesis, the homing and engraftment of bone marrow-derived vascular progenitors, remain undefined. Aghi et al. hypothesized that tumor cell-secreted factors regulate vasculogenesis, and studied vasculogenic and nonvasculogenic intracranial murine gliomas. The authors identified stromal derived factor-1 (SDF-1) as a factor secreted by tumor cells that mediates the recruitment of these progenitor cells to the tumor vasculature; demonstrated that the significance of vasculogenesis lies in the fact that the endothelium generated from bone marrow–derived progenitors has a higher mitotic index; and demonstrated that factors in the tumor microenvironment, one of which we found to be hypoxia, can expand the range of differentiated vascular progenitor phenotypes to include endothelium and pericytes.

Heterotrimeric G-proteins Targeted by Inhibitor

A large number of guanine-binding protein-coupled receptors (GPCR) play a major role in cancer. GPCR agonist activity is classically inhibited by a specific receptor antagonist. However, the therapeutic benefit of such strategy appears limited when tumor growth is simultaneously driven by several agonists. Instead of targeting each cancer involved GPCRs, Prévost et al. targeted the heterotrimeric G-protein complex, a downstream effector common to all GPCRs. BIM-46174 represents the first inhibitor for such a target, inhibiting growth of tumor cells in vitro and in vivo. Targeting heterotrimeric G-protein functions may represent a new strategy against cancer.

Melanoma Risk and MC1R Link Questioned

Natural variation in the coding region of the melanocortin-1 receptor gene (MC1R) is associated with constitutive pigmentation phenotypes and development of melanoma and nonmelanoma skin cancers. Kanetsky et al. investigated the impact of MC1R variants upon melanoma using a large, international population-based study design with complete determination of all MC1R coding region variants. Effects were similar across geographic regions and categories of pigmentation characteristics or number of moles. Our results confirm that MC1R is a low penetrance susceptibility locus for melanoma, demonstrate that pigmentation characteristics may not modify the relationship of MC1R variants and melanoma risk, and suggest that associations may be smaller than previously reported, in part due to the study design.