March 15 Cancer Research Highlights

Selected Articles from the March 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 March 15 issue of Cancer Research.

Germ-Line CNV at 2p24.3 and Prostate Cancer Risk

Liu et al.

Page 2176

Although copy number variations (CNVs) are common in the human genome, their associations with risk of common diseases are not well understood. To explore the relationship between CNVs and the risk of prostate cancer, Liu and colleagues performed a two-stage genome-wide association study using three populations from Sweden and the United States. Among 4,314 cases and 2,176 controls, the authors found that the CNV at 2p24.3 was significantly associated with prostate cancer risk. More importantly, the association was stronger for aggressive prostate cancer than for nonaggressive prostate cancer. While the biological effect of this germ-line CNV is unknown, this result is important because it represents the first novel germ-line CNV identified via a genome-wide search for association with prostate cancer risk.

Engineered Knottin Peptides as In vivo Imaging Agents

Kimura et al.

Page 2435

Integrins are attractive targets for cancer therapeutic intervention and, thus, molecular imaging agents are needed to identify patients who will best respond to these targeted therapies and to monitor disease progression. Kimura and colleagues recently engineered small (~3 kDa), conformationally constrained knottin peptides that bind to α_vβ₃/α_vβ₅ or α_vβ₃/α_vβ₅/α₅β₁ integrins with low nmol/L affinity and evaluated their potential as in vivo imaging agents for optical and positron emission tomography imaging. The authors show that high-affinity integrin-binding knottin peptides exhibit significantly increased tumor uptake in mice compared with weaker binding peptides. These results, coupled with low nonspecific uptake in organs such as the liver, indicate that engineered knottin peptides have potential as clinical diagnostics for a variety of cancers.

Natural Killer Cells and Selectins in Tumor Suppression

Sobolev et al.

Page 2531

Natural killer (NK) cells play an important role in killing cancer cells in vitro and are believed to play diverse roles in suppression of cancer growth in vivo. While the mechanisms by which NK cells recognize and destroy cancer cells are becoming reasonably well established, how NK cells reach their sites of action in vivo is not well understood. Sobolev and colleagues demonstrate that selectins, a family of cell adhesion molecules important in leukocyte recruitment to sites of inflammation and infection, are necessary for NK cells to infiltrate and kill subcutaneous tumors. This study reveals a role for selectins in NK cell recruitment to tumors and in the regulation of tumor immunity.

HIF-1α and Carcinogenic Suppression

Scortegagna et al.

Page 2638

Scortegagna et al. HIF-1α is up-regulated in solid malignancies, functioning as a facilitator of tumor growth, invasion, and metastasis. However, the role of HIF-1 during multistage carcinogenesis is unknown. Scortegagna and colleagues tested HIF-1 gain of function during multistage murine skin chemical carcinogenesis in K14-HIF-1αDPM transgenic mice. The authors report that while papillomagenesis was facilitated, malignant conversion was inhibited and that inhibition was associated with up-regulation of the tumor suppressor NDRG1. Moreover, SELENBP1, previously identified as being lost in a spectrum of epithelial cancers, was discovered to be a novel HIF-1α target gene. These results suggest that different drug targeting of HIF-1 function may be required in cancer prevention compared with therapy of established malignancies.

Rapamycin Activates AKT through CDC25B

Chen et al.

Page 2663
Chen et al.

The anticancer effect of mTOR inhibitors, rapamycin and its derivatives, in the clinic has been limited and could be explained by recent observations of rapamycin-dependent induction of oncogenic cascades. Chen and colleagues investigated rapamycin-dependent phosphoproteomics and identified 250 phosphosites in 161 cellular proteins that are sensitive to rapamycin. A siRNA-dependent screening showed that AKT induction by rapamycin was attenuated by depletion of cellular CDC25B. Additional experiments demonstrated that CDC25B transduces rapamycin-induced oncogenic AKT activity. These data advance the global mechanistic understanding of rapamycin’s action in cancer and also suggest that CDC25B may serve as a drug target for improving mTOR-targeted cancer therapies.

Intratumoral Immune Reaction in Human Colorectal Cancer

Camus et al.

Page 2685
The impact of immune responses and tumor escape on patient prognosis is still poorly understood. Camus and colleagues investigated in situ immune responses in human colorectal cancer (CRC), according to metastatic lymph node or distant organ invasion (META− or META+ patients). META− patients presented significant correlations between cytotoxicity and effector memory T-cell subpopulations. These correlation profiles were absent in tumors with low T-cell infiltrates and were altered in META+ patients with high T-cell infiltrates. Overall investigation of the CRC primary tumor microenvironment uncovered four major intratumoral immune profiles. These results highlight optimal and altered immune correlation profiles to define patient outcome.

March 15 Cancer Research Highlights

Selected Articles from the March 15, 2009 Issue

Germ-Line CNV at 2p24.3 and Prostate Cancer Risk

Engineered Knottin Peptides as In vivo Imaging Agents

Natural Killer Cells and Selectins in Tumor Suppression

HIF-1α and Carcinogenic Suppression

Rapamycin Activates AKT through CDC25B

Intratumoral Immune Reaction in Human Colorectal Cancer

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