metastasis research on "cell adhesion"

[john]

Initial Award Abstract

Lung cancer is a particularly aggressive form of cancer: It is the leading cause of cancer death in the United States, and the majority of patients present with advanced disease for which surgery is not an option. Metastasis, the process whereby tumor cells spread to distant organs via the bloodstream, contributes a large part of the morbidity and mortality of lung cancer. Metastasis is also associated with the vast majority of lung cancer treatment allures, and drugs aimed at inhibiting this process have great potential in both halting disease progression and modifying response to current therapy.

This project targets important steps in lung cancer metastasis. There are certain adhesion molecules (those that contain sugar, a.k.a. "glycosides") which assist metastatic cells in binding to blood vessels of distant organs, once they are free from the primary tumor. A class of adhesion molecules which may serve a vital role in this process is known as selectins. Their presence on the inner lining of blood vessels throughout the body may facilitate lung tumor cells (bearing the corresponding "ligand" molecules, much like a "lock and key") in attaching to blood vessels in the brain, liver, bones, or to other parts of the lungs – common organs to which lung cancer spreads. Research has also shown that platelets, which are normal clotting elements of blood, may facilitate this process by using the same molecules to mediate platelet-tumor cell adhesion. In distant blood vessels, such tumor cell-bound platelets may assist in tumor cell attachment and eventual uptake.

The proposed research is aimed at the above tumor ligand molecules, and specifically at disrupting their sugar-molecule structure by treating tumor cells with a new class of drugs that impair the cell's sugar-making machinery. Tumor cells treated with such compounds lack the ability to bind platelets or blood vessel inner-lining cells; and thus these inhibitors have potential as anti-metastatic drugs. To date, no studies have examined lung cancer cells treated with such agents. We are initially examining if these agents affect the ability of lung tumor cells to bind donated human platelets and to cultured blood vessel-lining cells. Subsequent animal studies will include simulated metastasis models under humane treatment conditions; and as pharmacology develops, techniques to examine tumor growth /metastasis in inhibitor-treated mice are planned. Ultimately, such agents have potential as anti-metastatic agents in human lung cancer.