Copyright 1996 Scientific American, Inc. tulate their “area code” hypothesis, that a cell has on its surface an address system—written in one set of molecules and readable by molecules on other cells—that identifies where the cell should be. It seemed to me at the time that if a molecular address system existed, something had to be wrong with it in cancer, because cancer cells did not stay put. I decided to try to find such molecules. As the work of many laboratories eventually showed, area code molecules do exist. They mediate cell adhesion, the anchoring of cells to adjacent structures. In normal tissues, cells adhere both to one another and to an insoluble meshwork of protein filling the space between them, known as extracellular matrix.(This arrangement is particularly descriptive of the epithelia, which are the cell layers that form the outer surface of the skin and the lining of the gut, lungs and some other organs, and from which most cancer originates.) The two kinds of adhesion play different critical roles during tissue invasion and metastasis. Cell-cell adhesion molecules appear to help keep cells in place; these molecules seem to be missing or compromised in cancer cells. For example, various kinds of cancers lose some or all of an intercellular adhesion molecule called E-cadherin. By manipulating this molecule in cultured cancer cells, one can change the cells’ ability to invade tissues and form tumors. Walter Birchmeier, now at the Max Delbrück Center in Berlin, first showed that blocking the function of E-cadherin can turn a cultured lineage of cells from noninvasive to invasive. Conversely, restoring E-cadherin to cancer cells that lack it can negate their ability to form tumors when they are injected into mice. Thus, loosening of the adhesive restraint between cells is likely to be an important early step in cancer invasion.