Journal Watch

Vanderbilt-Ingram Cancer Center is committed to conducting innovative, high-impact basic, translational and clinical research with the greatest potential for making a difference for cancer patients, today and in the future. Here’s a sampling of recent work published in peer-reviewed journals by center investigators:

Cancer drug allergy clues
Cancer patients in the Southeast are far more likely to suffer severe allergic reactions to the drug cetuximab (Erbitux) – a monoclonal antibody approved for use in colon cancer and squamous-cell head and neck cancer – than patients in other regions of the country. In the New England Journal of Medicine, Christine Chung, M.D., and colleagues report that a pre-existing antibody – that reacts to sugar molecules added to the drug during its production – triggers the life-threatening allergic reaction. Based on the findings, a commercial assay to test patients for the troubling antibody before drug treatment is being developed. Chung and colleagues are continuing to search for the antigen that triggers the formation of these antibodies in Southerners.

Rigid surrounds spawn aggressive cancers
Alissa Weaver, M.D., Ph.D., and colleagues have found a cellular explanation for why denser breast tissue is correlated with more aggressive tumors and a poorer prognosis. In Current Biology, they report that dense, rigid surroundings cause cancer cells to build more drilling structures – called invadopodia – with which to bore into the matrix around them. Breast cancer cells cultured on a denser, more rigid matrix had a greater number of active invadopodia than breast cancer cells cultured on a less dense matrix, they found. Two signaling proteins – FAK and p130Cas – were present in an activated state in the invadopodia, suggesting that they are important players in this response and possible targets for anti-invasive therapies.

Good, bad sides of anti-cancer agents
Compounds known as “HDAC inhibitors” are currently being tested as anti-cancer agents in clinical trials, but how they execute their cancer-killing effects is unclear. In Molecular Cell, Scott Hiebert, Ph.D., and colleagues report that cells from mice lacking the HDAC3 enzyme die because they can't repair the DNA damage that occurs naturally when cells copy their DNA during cell division. This explains why HDAC inhibitors specifically kill rapidly dividing tumor cells while sparing healthy cells. Therefore, giving an HDAC inhibitor before chemotherapy or radiation may keep tumor cells from repairing the DNA damage inflicted by those treatments, they suggest. In a second study in the EMBO Journal, the researchers reported that mice lacking HDAC3 in the liver only developed extensive liver damage, developed grossly enlarged and fatty livers, and had major metabolic abnormalities. The studies provide a potential mechanism by which HDAC inhibitors specifically damage cancer cells and offer clues about possible adverse effects of these compounds.

Halting cancer’s wandering ways
It might be possible to stop metastasis by making cancer cells “stick” to the primary tumor. In Cancer Cell, Andries Zijlstra, Ph.D., and colleagues report that an antibody targeted to the CD151 protein prevents cancer cells from leaving the original tumor and blocks metastasis. CD151 associates with integrins – cell surface proteins responsible for adhesion to the matrix – and is expressed in a variety of human tumors. Using intravital imaging, the researchers found that tumor cells in antibody-treated chick embryos could move around a fixed point, but could not detach from that point and move away from the tumor. The antibody treatment prevented metastasis of two types of aggressive human cancer cells, epidermoid carcinoma and fibrosarcoma, suggesting that the immobilizing machinery may be common to different cancers.

Security team for the genome
Genome “surveillance systems” prevent and repair DNA damage to maintain the genome’s stability and protect against cancer-causing mutations. One such system in human cells includes a pair of proteins, ATR and ATRIP. In Genes & Development, David Cortez, Ph.D., and colleagues provide insight into how ATR-ATRIP complexes are activated by DNA damage. They found that another protein, TopBP1, activates ATR by interacting with surfaces on both ATR and ATRIP proteins. These interactions are required for cell survival and for restarting DNA synthesis after slowed or stalled DNA replication. The investigators also determined that related genome-maintaining enzymes share this mechanism of ATR regulation. The results provide a starting point for designing agents to disrupt genome surveillance systems and sensitize cancer cells to many chemotherapy drugs.

Too many chromosomes spark tumors
Polyploidy – having extra sets of chromosomes – may to contribute to cancer development by promoting genomic instability, but it is unclear whether this instability drives tumorigenesis or is a consequence of it. Meejeon Roh, Ph.D., Sarki Abdulkadir, M.D., Ph.D., and colleagues report in PLoS ONE that polyploidy causes genomic instability and has a direct role in tumor development in human cells. They expressed Pim-1, an oncogene implicated in the development of various tumors, in human prostate and breast epithelial cells. Pim-1 expression caused the gradual emergence of polyploidy, allowing the investigators to sort the cells into diploid (normal chromosomal content) and polyploid populations. The polyploid cells were tumorigenic in vitro and in vivo and showed chromosomal abnormalities. The findings suggest that polyploid cells in human tumors may be attractive targets for novel therapeutics.

More info about our research at www.vicc.org/research