January 15 Cancer Research Highlights

Selected Articles from the January 15, 2009 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 15 issue of Cancer Research.

Brain Tumor Initiation by Plasmid DNA

Wiesner et al.

Page 431

Spontaneous animal models have long been praised as being more reflective of human cancer than their transplanted xenograft counterparts. Nevertheless, the considerable time and expense involved in creating and maintaining such models has limited their widespread use. Wiesner and colleagues describe a novel method to induce spontaneous malignant gliomas in three separate mouse strains using plasmid DNA cotransfection. Remarkably, up to five different transgenes can be simultaneously expressed in these tumors, including reporter genes to measure tumor burden. This method could be used to generate “humanized” tumors expressing human oncogenes as molecular targets for preclinical trials with unprecedented speed and flexibility.

FAK in Mammary Cancer Stem Cells and Breast Cancer

Luo et al.

Page 466

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase implicat-ed in cancer initiation and progression, although the mechanisms by which FAK promotes mammary tumorigenesis in vivo are not well un-derstood. Recent studies identified several integrins, upstream activa-tors of FAK, as markers for breast cancer stem cells. Luo and colleagues generated and analyzed mammary-specific deletion of FAK in a well-characterized breast cancer mouse model. The authors showed that ablation of FAK significantly suppressed mammary tumor initiation and progression by depleting a subset of bipotent cells in the tumors. Further analysis indicated a significant decrease in breast cancer stem cells in FAK-null tumors as determined by established markers in vitro as well as limiting dilution transplantation in vivo. These results are the first demonstration of a function for FAK in the regulation of malignant mammary stem/progenitor cells and provide a novel mechanism by which FAK may promote breast cancer development and progression.

Nuclear Export Inhibitors with Anticancer Activity

Mutka et al.

Page 510

CRM1 is required for the nuclear export of a wide variety of cancer-related “cargo” proteins including p53, c-Abl, and FOXO-3A. Leptomycin B (LMB) is a highly specific inhibitor of CRM1 with significant in vitro potency, but limited in vivo efficacy due to toxicity. Mutka and colleagues now report a series of semisynthetic LMB derivatives showing substantially improved therapeu-tic windows. Exposure of cancer cells to these compounds leads to a rapid, prolonged block of nuclear export and apoptosis. These new nuclear export inhibitors show significant efficacy in multiple mouse xenograft models, demonstrating the potential of CRM1 inhibitors as novel and potent anticancer agents.

MAGE-11 Inhibits PHD2 Activity

Aprelikova et al.

Page 616

Aprelikova et al. Growing tumors usually suffer from a lack of oxygen and nutrients. To survive, they engage hypoxia-inducible factors (HIFs) that activate genes controlling angiogen-esis, glucose consumption, and energy metabolism. Normal cells keep HIF factors at low levels through the mechanism that involves HIF-α prolyl hydroxylation, fol-lowed by ubiquitination by von Hippel- Lindau tumor suppressor protein and proteasomal degradation. Apreliko-va and colleagues report that the cancer-testis antigen MAGE-A11 inhib-its prolyl hydroxylase and stabilizes the HIF-1α subunit. MAGE-A family members are not expressed in normal tissues with the exception of testis, but are aberrantly expressed in tumors. When overexpressed, MAGE-11 may trigger a prosurvival program through HIF stabilization at the very early stages of tumor development, even in the presence of oxygen.

ADI in Autophagy and Caspase-Independent Apoptosis

Kim et al.

Page 700
Kim and colleagues report on a new treatment option for prostate cancer based on metabolic stress, which complements conventional treat-ments based on genotoxic stress. Accordingly, arginine deprivation with pegylated arginine deiminase (ADI-PEG20) has proven effective in other cancers. For reasons still unclear, prostate cancers preferentially lack expression of argininosuccinate synthetase (ASS), becoming particularly sensitive to arginine deprivation. CWR22Rv1 prostate cancer cells do not express ASS and undergo caspase-independent apoptosis with ADI-PEG20 treatment. ADI-PEG20 synergizes with docetaxel to greatly reduce tumor growth in CWR22Rv1 mouse xenografts. Significantly, autophagy is induced by ADI-PEG20 as a protective response. The inhibition of autophagy therefore enhances ADI-PEG20-induced cell death, pointing to an interrelationship among ASS deficiency, autophagy, and apoptosis. Finally, a tissue microarray of prostate tissues demonstrated a complete lack of ASS in prostate cancer specimens, indicating that ADI-PEG20 is a potential novel therapy for prostate cancer, especially in combination with docetaxel and the autophagy modulator choloroquine.

January 15 Cancer Research Highlights

Selected Articles from the January 15, 2009 Issue

Brain Tumor Initiation by Plasmid DNA

FAK in Mammary Cancer Stem Cells and Breast Cancer

Nuclear Export Inhibitors with Anticancer Activity

MAGE-11 Inhibits PHD2 Activity

ADI in Autophagy and Caspase-Independent Apoptosis

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