June 1 Cancer Research Highlights

Selected Articles from the June 1, 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 June 1 issue of Cancer Research.

Laforin and Resistance to Energy Deprivation–Induced Apoptosis

Wang et al.

Page 4039

A poorly understood observation in cancer therapy is the heterogeneity in cancer susceptibility to therapies targeting abnormalities in energy metabolism. Laforin, a dual-specific phosphatase, regulates glycogen synthase kinase 3β, which is known to play a role in cellular response to energy deprivation. Wang and colleagues show that the hexose kinase inhibitor 2-deoxyglucose (2-dG) preferentially kills cancer cells with defective laforin expression and significantly increases the survival of mice with aggressive lymphoma due to a genetic defect of the laforin-encoding Epm2a gene. Normal cells from Epm2a^–/^– mice also had greatly increased susceptibility to 2-dG. Thus, laforin is a novel regulator for cellular response to energy deprivation, and its defects in cancer cells may be targeted for cancer therapy.

SDHB Silencing and the Tumor Phenotype

Cervera et al.

Page 4058

The tricarboxylic acid (TCA) cycle has recently gained attention in the field of tumor biology and, although the mechanism(s) by which disruption of mitochondrial metabolism leads to neoplasia are largely unknown, increasing evidence points to an activation of pseudohypoxia. In order to better understand this link, Cervera and colleagues show that silencing of one of the TCA cycle enzymes, succinate dehydrogenase (SDHB), results in impaired cellular proliferation and respiration as well as a corresponding shift to glycolysis in Hep3B hepatocellular carcinoma cells. The hypoxia-inducible transcription factors HIF-1α and HIF-2α, as well as the stress-signaling proteins c-Jun amino-terminal kinase and p38 kinase, appear to play a role but there are no changes in levels of reactive oxygen species. Microarray analysis identified > 400 genes involved in proliferation, adhesion, and the hypoxia pathway influenced by SDHB silencing, illustrating the complexity of the links between the TCA cycle and cancer.

CAF-like Differentiation of hMSCs

Mishra et al.

Page 4331

Carcinoma-associated fibroblasts (CAFs) have recently been implicated in important aspects of tumor biology such as neoplastic progression, tumor growth, angiogenesis, and metastasis. However, neither the source of CAFs nor the differences between CAFs and fibroblasts from nonneoplastic tissue have been well defined. Mishra and colleagues demonstrate that human bone marrow–derived mesenchymal stem cells (hMSCs) exposed to tumor-conditioned medium (TCM) assume a CAF-like myofibroblastic phenotype and are able to promote tumor cell growth both in vitro and in an in vivo coimplantation model. Gene expression profiling revealed similarities between TCM-exposed hMSCs and CAFs. These data suggest that hMSCs are a source of CAFs and can be used in the modeling of tumor-stroma interactions.

Combined Inhibition of mTOR, VEGF/VEGFR-2 in Melanoma

Molhoek et al.

Page 4392

Vascular endothelial growth factor (VEGF) is produced in human melanomas. The VEGF receptor 2 (VEGFR-2) is also expressed by most advanced stage melanomas, suggesting the possibility of an autocrine loop. Molhoek and colleagues show that the anti-VEGF antibody bevacizumab inhibits proliferation of melanoma cells and that the combination of bevacizumab and rapamycin, a drug that inhibits mammalian target of rapamycin (mTOR), causes a net loss in cell number. Both of these effects are dependent on the presence of VEGFR-2. The effects of bevacizumab alone and in combination with rapamycin are eliminated by VEGFR-2 knockdown with siRNA. These results identify an autocrine growth loop active in VEGFR-2⁺ melanoma and a possible therapeutic role for a combination of inhibitors of mTOR plus VEGF in selected melanomas.

Intratumoral Androgens in Metastatic Prostate Cancer

Montgomery et al.

Page 4447
Montgomery et al.

Testosterone suppression remains the most effective therapy for metastatic prostate cancer; however, nearly all patients develop castration-resistant disease. Intracrine androgen production may play a role in castration-resistant growth. Montgomery and colleagues report that metastases from castration-resistant prostate cancers exhibit significantly elevated testosterone levels as well as significant increases in the expression of several key enzymes required for testosterone synthesis and metabolism. They also show that castration-resistant tumor xenografts maintain similar intratumoral androgen levels in castrate, compared with eugonadal, animals. These results suggest that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens and identify intracrine steroidogenic pathways within the prostate tumor microenvironment as novel therapeutic targets.

June 1 Cancer Research Highlights

Selected Articles from the June 1, 2008 Issue

Laforin and Resistance to Energy Deprivation–Induced Apoptosis

SDHB Silencing and the Tumor Phenotype

CAF-like Differentiation of hMSCs

Combined Inhibition of mTOR, VEGF/VEGFR-2 in Melanoma

Intratumoral Androgens in Metastatic Prostate Cancer

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