September 1 Cancer Research Highlights

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

A Stochastic Model for Cancer Stem Cell Origin in Metastatic Colon Cancer

Odoux et al.

Page 6932

While evidence for a hierarchical model in colon cancer with the presence of cancer-initiating cells has been reported, limited support has surfaced for a possible role of tissue-derived stem cells in colon cancer initiation and its metastatic process. Odoux and colleagues demonstrate that stem-like tumor cells, having both self-renewal and multipotency properties, are present at the clonal level in metastatic colon cancer. However, the occurrence of chromosomal instability in these same stem-like tumor cells supports a stochastic model for colon cancer with the existence of a genetically heterogeneous population of cancer stem cells. Thus, this new model for cancer origin and metastatic progression includes features of both the hierarchical model for cancerous stem cells and the stochastic model, driven by the observation of chromosomal instability.

CTLA-4 Polymorphism and Cancer Susceptibility

Sun et al.

Page 7025

Antitumor T lymphocytes play a pivotal role in immunosurveillance of malignancy. The cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation and proliferation and recent research suggests it plays an important role in cancer development and progression. Polymorphisms in CTLA-4 are associated with autoimmune diseases but little is known about the relationships between genetic polymorphisms in CTLA-4 and cancer susceptibility. Sun and colleagues hypothesized that polymorphisms in CTLA-4 might be a genetic susceptibility factor for common human cancers and investigated their hypothesis in two Chinese populations. The authors found that the 49G>A polymorphism in the CTLA-4 leading sequence is associated with increased susceptibility to multiple cancers, including lung, breast, esophageal, and gastric cancers. Furthermore, T cells carrying the 49AA genotype had significantly lower activation and proliferation rates compared with T cells carrying the 49GG genotype upon stimulation. These results indicate that genetic polymorphisms influencing T-cell activation modify cancer susceptibility.

Ultrasound Imaging of Tumor Vessel Maturity

Palmowski et al.

Page 7042

Flow-sensitive high-frequency volumetric Power Doppler ultrasound (HF-VPDU) and contrast-enhanced HP-VPDU are two related methods that can be used to assess antiangiogenic therapy effects. Palmowski and colleagues investigated whether these two methods could assess different blood vessel fractions and their early response to antiangiogenic therapy in mice. The authors find that contrast-sensitive HF-VPDU is more sensitive for small immature vessels while flow-sensitive HF-VPDU mostly captures large vessels at the tumor periphery and that the combination of both methods can provide evidence of vascular maturity in tumors before changes in tumor size become apparent.

Tumor Targeting with isoDGR Peptides

Curnis et al.

Page 7073

Curnis et al. Angiogenesis is now recognized as an important process in tumor development, and identification of strategies to inhibit this process is an active area of research. Curnis and colleagues have recently shown that the isoaspartate-glycine-arginine (isoDGR) motif can interact with αvβ3, an integrin critically involved in angiogenesis. Using a cyclic isoDGR peptide (CisoDGRC) fused to tumor necrosis factor α, the authors now show that 1–10 pg doses were sufficient to induce antitumor effects when administered alone or in combination with chemotherapy to tumor-bearing mice. These results suggest that isoDGR is a novel tumor vasculature–targeting motif and that peptides containing isoDGR could be exploited as ligands for targeted delivery of drugs, imaging agents, or other compounds to tumor vasculature.

Genetic Evidence for Nitric Oxide in Inflammation-Accelerated Tumorigenesis

Hussain et al.

Page 7130
Hussain et al.

Nitric oxide (NO^·) is an important component of inflammatory response and has recently been shown to be involved in tumorigenesis. The quantity of NO^· is dependent on the NO^· synthase (NOS) family of enzymes, of which the NOS2 member is regulated by a variety of stress conditions including inflammation. Hussain and colleagues show that a high level of NO^·, produced during inflammation due to the enhanced expression of NOS2, accelerated spontaneous tumor development in p53-deficient mice, an animal model of the cancer-prone Li-Fraumeni syndrome. However, inflammation did not affect spontaneous tumor incidence in mice lacking NOS2. Spontaneous tumor development is correlated with decreased apoptosis, increased proliferation, and modulation of the immune profile. These results reveal a protumorigenic function for high NO^· levels produced during inflammation.