Researchers at the Johns Hopkins Oncology Center and Howard Hughes Medical Institute have uncovered important new biological information about how cancer cells grow and spread. Their findings are reported in the Aug. 18 issue of Science.
Their study focuses on the biochemistry of tumor angiogenesis, or the recruitment of new blood vessels by tumors, a process which tumors require for continued growth. Experts believe this process is an early and critical step to cancer growth and progression, but to date little is known about the basic molecular mechanisms that lead to tumor angiogenesis.
Suspecting that newly formed endothelial cells that line blood vessels in tumors may be different from those present in normal blood vessels, the investigators studied the endothelium isolated from both normal and tumor tissue of a colon cancer patient. The team used a panel of antibodies linked to beads to isolate endothelial cells from the tissues. They then used a sophisticated, partially computerized technology known as SAGE, for Serial Analysis of Gene Expression, to analyze 200,000 pieces of genetic material taken from the endothelial cells.
The team identified 46 genes that were overexpressed in tumor compared to normal endothelium, up to 10-fold, and 33 genes that were expressed at significantly lower levels, providing some of the first scientific evidence that tumor endothelium behaves differently than normal endothelium. The researchers believe that endothelial cells, though not malignant, create an environment that enables the tumor cells to thrive. As a result, they believe endothelial cells are promising therapeutic targets.
"Theoretically, if we can cut off the blood supply to tumors by going after endothelial cells, we can stop the tumor in its tracks," says Brad St. Croix, research fellow and lead author of the study. "Cancer kills primarily when tumors grow so large that they interfere with organ and tissue function. In the future, if we can halt the growth of cancer cells by interfering with their blood supply, then we may be able to save some patients' lives," he says. St. Croix likens tumor angiogenesis to grapes on a vine. Standard anti-cancer drugs attack the "grapes" or individual cancer cells. If the drug does not reach a particular cell, the cell survives and replicates. "If, on the other hand, you go after the "vine," which is the vasculature of a tumor, then the grapes can no longer grow," he says.
Kenneth Kinzler, professor of oncology and director of this research, cautions, however, that such therapies are not close at hand. "This early study uncovered a wealth of data, but before it will be useful to patients, we must pare it down to find the best diagnostic and therapeutic targets, and that could take years of additional research," he says.
The researchers focused on colon cancer in this study because of its high incidence and frequent resistance to treatment; however, they believe their findings may apply to a variety of cancers. Their future research will focus on developing better therapy and diagnostic tests for cancer patients. They hope to develop genetic screening tests that would pinpoint these changes and help detect cancer at an early stage. In addition, they will begin studying the effect of targeting endothelial cells as a form of cancer therapy.
The SAGE technology was developed at Johns Hopkins and has been widely used to speed the discovery of genes involved in a variety of diseases, including cancer. It is analogous to the bar coding system used to catalog and monitor merchandise in grocery stores. While accumulated bar code entries provide a picture of a store's sales, SAGE provides a picture of a cell's gene expression pattern.
In addition to Kinzler and St. Croix, other participants in this research included Carlo Rago, Howard Hughes Medical Institute; Victor Velculescu, Giovanni Traverso, Katharine E. Romans, Elizabeth Montgomery and Christoph Lengauer, from Johns Hopkins; Bert Vogelstein, Howard Hughes Medical Institute Investigator at Johns Hopkins; and Anita Lai and Gregory J. Riggins, from Duke University School of Medicine.
This research was funded by grants from the National Institutes of Heath.