August 1 Cancer Research Highlights

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Selected Articles from the August 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 August 1 issue of Cancer Research.

17β-Estradiol Mobilizes Bone Marrow–Derived Endothelial Progenitor Cells to Tumors

Neovascularization is critical for tumor growth and development and requires assistance from bone marrow–derived endothelial progenitor cells (BM-EPCs). Estradiol (E₂) has been shown to act as a potent agent of BM-EPC proliferation and mobilization of these cells to tumors, but its effect on neovascularization of estrogen-responsive breast cancer has not been explored. Using the Tie2/GFP mouse model in which GFP expression is under the control of the endothelial cell–specific receptor tyrosine kinase Tek promoter, BMC-EPCs were found to initiate neovascularization in response to Tg1 mammary cells implanted into the inguinal mammary glands of these animals. Furthermore, E₂ was found to enhance neovascularization through the stimulation of BM-EPC–secreted paracrine factors. These results show that E₂ orchestrates an interplay between BM-EPCs and tumor cells leading to the overexpression of angiogenic cytokines culminating in enhanced tumor homing and tumor vasculature. 

Reduced Tamoxifen Sensitivity and Increased Metastastic Potential Linked to VEGF-Induced Desmoplasia

Inhibition of Metastatic Outgrowth by Targeting the Cytoskeleton

The emergence of metastatic disease arising from dormant tumor cells is poorly understood. Barkan and colleagues describe a three-dimensional culture system in which the behavior of cancer cells in vitro correlates with dormant behavior in vivo. Using this system, they demonstrate that the switch from dormancy to proliferation can be regulated by the extracellular matrix through activation of integrin β1 signaling and actin stress fiber formation. Inhibition of cytoskeletal reorganization prevents the dormant-to-proliferative switch. Thus, modifying interactions between metastatic cells and the  microenvironment, or targeting the cytoskeleton may inhibit the emergence of metastatic disease from dormant cells.

Extending their recent observation that bone marrow–derived dendritic cells (DCs) from aged mice are less effective than those from their younger counterparts in inducing the regression of B16-ovalbumin (OVA) melanomas, Grolleau-Julius and colleagues examined the effect of aging on DC tumor antigen presentation and migration and on their ability to stimulate T cells. Experiments in mice showed defective trafficking of aged DCs to draining lymph nodes, impaired activation of OVA-specific CD8⁺ T cells, and decreased influx of intratumor CD8⁺ T cells. Although defective migration could be restored by increasing the number of old DCs injected, the aging defect in DC tumor surveillance and OVA-specific CD8⁺ T-cell induction remained, suggesting that defective T-cell stimulation contributes to the observed impaired DC tumor immunotherapeutic response in aging. 

Antitumor Activity of Immunotoxins with T-Cell Receptor–like Specificity