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October 15 Cancer Research Highlights

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Selected Articles from the October 15, 2007 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 October 15 issue of Cancer Research.

Small Molecule Inhibitor of STAT3 Pathway Reverses Immune Tolerance

Hussain et al.

Page 9630

Hussain et al. Many cancer patients have profound immunosuppression, which impedes efficacious immunotherapy. Hussain and colleagues have shown that a novel small molecule inhibitor of STAT3 can reverse tolerance in immune cells that are refractory to conventional immune activators by inducing the expression of costimulatory molecules, stimulating the production of the immune-stimulatory cytokines, and inducing proliferation of effector T cells. The mechanism of immune activation was by phosphorylation of Syk (Tyr352) in monocytes and ZAP-70 (Tyr319) in T cells, which bypasses the impaired immune activation pathways in cancer patients. This novel small molecule STAT3 inhibitor has great potential as a potent immune adjuvant in immunosuppressed cancer patients. 

RAD51 Up-regulation Bypasses BRCA1 Function

Martin et al.

Page 9658

While BRCA1 is known to be required for genome stability and survival of DNA damage, the mechanism of tumor suppression remains elusive. One of the difficulties in answering this fundamental question is the plethora of functional assignments reported for the protein. Martin and coauthors have provided genetic and cellular evidence that homologous recombination is the critical BRCA1-dependent effector pathway for cell growth and DNA damage repair by showing that the damage sensitivity of a BRCA1 null mutant can be rescued by overexpression of the homologous recombinase RAD51. The mechanism of suppression involves the bypass of BRCA1’s role in recruitment of RAD51 to sites of DNA damage.

CKIP-1 Down-regulates PI3K/Akt Signaling

Tokuda et al.

Page 9666

Akt plays an important role in cancer cell survival and proliferation. Using an E.  coli–based two-hybrid screening system, Tokuda and colleagues identified casein kinase 2–interacting protein-1 (CKIP-1) as a novel Akt plekstrin homology domain-binding protein. Dimerization of CKIP-1 via its leucine zipper motif is associated with Akt inactivation and attenuation of downstream Akt signaling. Forced expression of CKIP-1 suppressed tumor growth in vitro and in vivo. Because expression level of CKIP-1 is down-regulated in some tumors, CKIP-1 may be a tumor suppressor with an Akt-inhibitory function.

Bcl-2 Orchestrates Cellular Cross-talk

Kaneko et al.

Page 9685

While the effect of tumor cell–secreted factors on angiogenesis is well established, little is known about the impact of factors secreted by endothelial cells on tumor cell gene expression and progression. Kaneko and colleagues demonstrated that bcl-2 gene expression is significantly higher in the tumor-associated endothelial cells of patients with head and neck squamous cell carcinomas (HNSCC), as compared to endothelial cells from the normal oral mucosa. Their results demonstrate that Bcl-2 is the orchestrator of a cross-talk between neovascular endothelial cells and tumor cells, which has a direct impact on tumor growth.

Listeria Monocytogenes Treats Hepatic Metastases

Yoshimura et al.

Page 10058

Kaneko et al.The liver represents a major and frequently sole site of metastases for many types of cancer, particularly gastrointestinal cancers. Yoshimura and colleagues demonstrated that administration of multiple doses of an engineered hepatic-targeting Listeria monocytogenes (LM) generates therapeutic responses against hepatic metastases. LM treatment of mice bearing hepatic metastases induced tumor-specific CD8+ T-cell responses that were enhanced by depletion of regulatory T cells either by anti-CD25 or cyclophosphamide treatment. Antitumor activity of LM was dependent on the presence of natural killer (NK) cells but was inhibited by the presence of NK T cells. LM treatment provided a significant survival advantage, which was greatly enhanced by depletion of CD25+ regulatory T cells.

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