This, in turn, could lead to uncontrolled cellular proliferation, and tumorigenesis. These mechanisms, present both in lower organisms as well as in mammals, have always been thought to be separated and independent.

The work, which appears on the cover this week in the June issue of the prestigious journal Cancer Cell, carried out by researchers of the Differentiation and Cancer Programme, at the Centre for Genomic Regulation (CRG), in Barcelona (Spain), demonstrates the cross-talk between these two gene silencing mechanisms in patients suffering from acute leukemia. The work, led by the ICREA researcher Luciano Di Croce, head of the group Epigenetics and Cancer, at the CRG, performed in collaboration with Kristian Helin ™s group, at the Biotech Research and Innovation Centre in Copenhagen (Denmark), and Dr. Nomdedeu ™s group, at the Santa Creu and Sant Pau Hospital, in Barcelona, will have important consequences in the development of new anti-tumor therapies. On the one hand, the study shows a better understanding of the basic mechanisms of gene regulation and, on the other hand, identifies a possible new pathway to reactivate erroneously switched off genes in tumors. In 2002, in a study published in Science, Di Croce showed that uncontrolled DNA methylation contributed to tumor progression in its first stages. Less than a year ago, Di Croce ™s group described, in another study published in Nature, the biochemical connection between the Polycomb protein complex and the enzymes methylating the DNA (DNA methyltransferases).

In this new study, Di Croce has shown that the two mechanisms are not only interconnected in leukemic cells, but also that one reinforces the other and, more importantly, that one needs the other. Therefore - and this is one of the most interesting aspects of the investigation - if one of these mechanisms is blocked by specific drugs, the other will also be affected. The results achieved will allow, in the future, identifying new chemical compounds able to block both mechanisms simultaneously and exclusively, without altering other cellular mechanisms. For these reasons, this is one of the new investigations lines recently adopted by the group led by Di Croce.

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The researchers systematically examined gene expression patterns in the endothelial cells that line blood vessels derived from normal resting tissues, regenerating tissues, and tumors. A comparison of the normal vessels revealed several organ-specific endothelial genes that could potentially aid in the delivery of molecular medicine to specific anatomical sites. The study also revealed 13 genes that are selectively overexpressed in tumor blood vessels. Although the function of most of the newly identified genes in tumor blood vessels is unclear, many of the genes encode cell surface proteins, making them appealing targets for the development of new therapeutic agents.

One of the cell surface proteins identified, called CD276, was found to be frequently overexpressed in the blood vessels of a variety of human cancers. The researchers also report that in many of the tumors examined CD276 was also overexpressed by the tumor cells, making this protein a particularly attractive target because a suitable inhibitory molecule might be able to deliver a double blow: one to the tumor cells themselves and the other to the blood vessels that feed it. "These studies reveal that tumor vessels contain a unique molecular fingerprint that can be used to distinguish them from normal proliferating vessels," explained Dr. St. Croix; they also provide new targets that could help guide the development of safer vascular-targeted therapies with potentially fewer side effects."

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