its tasks on behalf of the whole. With the exception of white blood cells, which patrol the body for microbial invaders and tissue damage, normal cells stay in the tissue of which they are part. Cancer
cells, however, are rogues that trespass aggressively into other tissues. Metastasis, the spread of cancer to distant sites in the body, is in fact what makes cancer so lethal. A
surgeon can
remove a primary tumor relatively easily, but a cancer that has metastasized usually reaches so many places that cure by surgery alone becomes impossible. For that reason, metastasis and the invasion
of normal tissue by cancer cells are the hallmarks of malignancy. In countries where health care is primitive, one sometimes sees people who live with tumors as big as a soccer ball; the cells that make up these so-called benign tumors obviously overproliferate, but unlike malignant
cancer cells, they do not invade or metastasize. Acquiring the capabilities needed to emigrate to another tissue is therefore a key event in the development of a cancer. To metastasize successfully, cancer cells have to detach from their original location, invade a blood or lymphatic vessel, travel in the circulation to a distant site and establish a new cellular colony. At every one of these steps, they must escape many controls that, in effect, keep normal cells in place. A fruitful way of understanding how tumor cells evade these controls has consequently been to study the signals that normally direct cells to their place in the body and keep them there during adulthood.
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 th cells’ ability to invade tissues and form
tumors.
The Need for Adhesion Adhesion to extracellular matrix, on the other hand, allows cells to survive
and proliferate. As researchers have known for many years, cultured cells cannot reproduce until they attach to a surface, a phenomenon called anchorage dependence. This attachment is mediated by cell-surface molecules known as integrins that bind to the extracellular matrix. As Steven Frisch of the Burnham Institute in La Jolla, Calif., Martin A. Schwartz of the Scripps Research Institute,
also in La Jolla, Calif., and Mina J. Bissell of the University of California at Berkeley have shown, only attachments involving integrins can satisfy the requirements of anchorage dependence.
My laboratory at the Burnham Institute, together with Tony Hunter of the Salk Institute for Biological Studies in San Diego, Calif., has recently shown that unattached cells stop growing because one of the nuclear proteins (known as the cyclin E–CDK2 complex) that regulates the growth and division of cells becomes less active. Inhibitory substances in the nuclei of these cells seem to shut
down this protein. As Frisch, Schwartz and Bissell also discovered, when many types of cells are
denied anchorage, they not only stop proliferating but commit suicide. That is, they spontaneously undergo specific changes that lead to their own death. This kind of cell death, in which the cell
is an active participant, has been termed apoptosis. My group has demonstrated that for cells to survive, the extracellular matrix to which they adhere must bear the right
“area code,” one that is probably found only in the extracellular matrix of select tissues. Moreover, they have to use the appropriate integrin to attach to the ma-trix. As all these results show, a molecula explanation for anchorage dependence is beginning to take shape, although
much more critical detail still needs to be filled in. Cellular suicide from lack of anchorage or from inappropriate anchorage is likely to be one of the safeguards that maintain the integrity of tissues. Cells usually cannot just float away from their tissue and establish themselves somewhere
else, because they will die on the way. Yet cancer cells get around this requirement;
they are anchorage independent. The cyclin E–CDK2 complex in such cells stays active whether the cells are attached or not. How cancer cells accomplish this trick is not fully understood, but it seems that oncogenes can be blamed.
as various experiments have shown, proteins made by these oncogenes convey a false message to the nucleus that the cell is properly attached when it is not, thereby stopping the cell from arresting
its own growth and dying through apoptosis. Anchorage dependence is only one of
the constraints that a cancer cell must overcome to roam around the body. Epithelial cells, the most common sources of cancers, are separated from the rest of the body by a basement membrane,
a thin layer of specialized extracellular matrix. Basement membranes form a barrier that most normal cells cannot breach,
by giving cells in a test tube an opportunity to invade through a natural or reconstructed basement membrane: cancer cells will penetrate it; normal ones will not. Furthermore, in this experiment, cells from metastatic cancers generally invade faster than those from nonmetastatic tumors. White blood
cells, in keeping with their role as security patrol, are an exception to the rule that normal cells do not invade—they, too, are adept at penetrating tissues, including basement membranes.
Cancer
cells and white blood cells do so by releasing enzymes, called metalloproteinases,
that dissolve basement membranes and other extracellular matrices. Other cells have less of these enzymes and more enzyme inhibitors. After a cancer cell has passed through the basement membrane separating it from the rest of the tissue at its original site, it soon encounters another basement
membrane, one surrounding a small
lood vessel.
Fundamental Understandings
MELANOMA
CELL
RGD
MELANOMA METASTASIZES NO METASTASIS
RGD
TRIPEPTIDE
FIBRONECTIN
TUMOR
CELL INHIBITING METASTASIS by interfering with cancer cell adhesion may someday be
a therapeutic option. In mouse experiments, injections of RGD, a fragment of the protein
fibronectin, discouraged melanoma cells from spreading to the lungs. Presumably,
the RGD molecules blocked receptors that wandering cancer cells needed for binding
to fibronectin in the extracellular matrix of tissues.tients. Great strides have been made in
CELLULAR ADHESION is a vital brake on the migration of normal cells. Two types
apply to most body cells: cell-cell adhesion and adhesion to the extracellular matrix
(top). If a cell cannot adhere to other cells, it may become more invasive and migrate
through the matrix (middle). If a cell lacks adhesion to the extracellular matrix, it can
detach from its native tissue (bottom).
