Our Science – St. Croix Website
Brad St. Croix, Ph.D.
Inhibition of tumor angiogenesis has generated an enormous amount of excitement amongst cancer researchers and clinicians. The appeal of this approach can be attributed to several theoretical advantages of targeting the endothelial cells that line blood vessels, rather than the tumor cells themselves. First, endothelial cells are directly exposed to circulating blood, facilitating drug delivery and enabling the use of high molecular weight therapeutics. Second, a significant bystander effect can be expected because each vessel capillary supports hundreds of tumor cells. Third, endothelial cells are genetically stable and should, unlike tumor cells, be unable to develop resistance to therapy. Finally, this type of therapy should be applicable to a wide variety of tumor types.
To best exploit these theoretical advantages, a more detailed understanding of the molecular mechanisms underlying angiogenesis is required. Towards this goal, we recently conducted serial analysis of gene expression (SAGE) on endothelial cells isolated from normal human colonic tissue or from human colorectal cancers. This study led to the identification of 46 Tumor Endothelial Markers (TEMs), most of which were previously uncharacterized. As the sequences of the unknown TEMs were derived, four were found to encode novel cell surface proteins (TEMs 1, 5, 7, and 8). Although these surface TEMs have not yet been ascribed functions, TEM 5 is likely to have a signaling role as it appears to be a seven-pass transmembrane protein of the G-coupled protein receptor family, and TEM8 was recently identified as the Anthrax Toxin Receptor. Their accessibility on the cell surface and conservation in mice makes these genes attractive candidates for the development of better diagnostics and therapeutics for cancer.
Our laboratory is interested in determining the role of various TEMs, especially those on the cell surface, in angiogenesis. By disrupting TEM genes in mice, we hope to gain insight into the function of these genes and determine whether or not they are essential for angiogenesis. Knock-out mice could also prove valuable for drug screening. We are also continuing to conduct SAGE on various models of angiogenesis in an effort to identify the most tumor-specific endothelial markers. In addition, we are using monoclonal antibodies to analyze TEM expression at the protein level, and are focused on developing agents that are useful for imaging or therapeutically targeting TEMs. Our laboratory is also interested in identifying the interacting partners of TEMs, especially those that are involved in novel signaling pathways. The end goal of this research is to use new molecular information on tumor angiogenesis to develop clinically useful agents for improved diagnostics and therapeutics of cancer and other vascular diseases. Although it will likely be years before we can truly understand angiogenesis at a molecular level, the significance of this work for combating angiogenesis-dependent diseases such as cancer argue that the benefits will be worth the effort.
Our collaborators include: Bert Vogelstein, Ken Kinzler, and Victor Velculescu of Johns Hopkins University.
This page was last updated on 2/22/2013.