December 15 Cancer Research Highlights

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Selected Articles from the December 15, 2005 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 December 15 issue of Cancer Research.

Targeting TRAIL-R1 Essential for Triggering Apoptosis in Lymphoid Malignancies

TRAIL and its agonistic antibodies, currently in clinical trials for various malignancies, induce apoptosis through triggering of TRAIL-R1 or -R2. MacFarlane et al. have synthesized TRAIL mutants specific for TRAIL-R1 or TRAIL-R2 and demonstrated that primary chronic lymphocytic leukemia (CLL) cells signal apoptosis almost exclusively through TRAIL-R1. Their data suggest that very limited therapeutic benefit can be anticipated from treating CLL patients with either HGS-ETR2 or Apo2L/TRAIL, as these agents signal almost exclusively through TRAIL-R2. Their data also highlight the necessity to ascertain, prior to initiating therapy, whether primary tumor cells signal via TRAIL-R1 or -R2.

Fusion Gene Prompts Mesenchymal Progenitor Cells to Initiate Ewing’s Pathogenesis

The EWS-FLI-1 fusion gene is associated with 85% of Ewing’s family tumors (EFT). To explore its role in EFT pathogenesis, Riggi et al. expressed EWS-FLI-1 in primary bone marrow-derived mesenchymal progenitor cells (MPCs). MPCs expressing EWS-FLI-1 underwent transformation and developed tumors with histological features of EFT. The tumor cells displayed induction and repression of several key EWS-FLI-1 target genes and, similar to primary EFT cells, were highly sensitive to IGF-1R inhibition. These observations provide evidence that MPCs may be a candidate cell type from which EFTs originate and that EWS-FLI-1 expression in the appropriate cellular environment is sufficient to initiate EFT pathogenesis.

ErbB Family Bolsters Lung Adenocarcinoma Resistance to EGFR Inhibition

Somatic mutations in the kinase domain of epidermal growth factor receptor (EGFR) predict response to treatment with EGFR kinase inhibitors (TKIs) in some patients with lung adenocarcinoma, but additional predictive markers are needed. Fujimoto et al. examined three models of lung adenocarcinoma that are sensitive to TKIs (Kras^LA1 mice, lung cancer patients, and cell lines) and found high intratumoral expression of ErbB family members, their ligands, or both. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and over-expression of EGFR dimeric partners and their ligands. Analysis of the expression of these molecules may complement EGFR mutational analysis as a predictive marker of sensitivity to TKIs.

DMP1 Bridges Matrix, MMP-9 to Facilitate Tumor Invasion

Both MMP-9 and dentin matrix protein 1 (DMP1) are up-regulated in many tumors. Furthermore, DMP1 has been shown to bind and activate proMMP-9 and keep MMP-9 active in the presence of equimolar TIMP1. Karadag et al. investigated the dose-dependent DMP1 invasion enhancement of MMP-9–expressing colon cancer cell line, SW480, in a modified Boyden chamber assay. FACS analysis showed that DMP1 could use either RGD-dependent integrins or CD44 to bridge MMP-9 to the cell surface. These data and immunohistological results showing the expression of all components in tumor sections suggest that DMP1 may aid tumor cell invasion in vivo.

Shed Nr-CAM Ectodomain Stimulates Proliferation, Motility, Transformation

Nr-CAM, a cell-cell adhesion transmembrane receptor, known for its function in neuronal guidance, was recently identified as a β-catenin target gene in human melanoma and colon carcinoma. Nr-CAM expression in fibroblasts induces tumorigenesis. Conacci-Sorrell et al. investigated the mechanisms by which Nr-CAM confers oncogenesis and found that it constitutively activates growth promoting and antiapoptotic signaling. They detected metalloprotease-mediated shedding of the Nr- CAM ectodomain whose expression induces motility and tumorigenesis, while suppression of Nr-CAM by siRNA inhibited the adhesive and neoplastic capacities of melanoma. Cell-surface–associated and shed Nr-CAM therefore provides a novel target for diagnosis and cancer therapy.