Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream or lymph system. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissue. By degrading these proteins, cancer cells are able to breach the ECM and escape. When oral cancers metastasize, they commonly travel through the lymph system to the lymph nodes in the neck.
In studying oral cancer metastasis, scientists at the NIDCR-NCI Oral Cancer Research Center at the University of Alabama at Birmingham are focusing on matrix metalloproteinases (MMPs), a group of enzymes implicated in the metastatic process. Currently, they are looking at the MMP collagenase, an enzyme that can degrade collagen -- one of the ECM proteins. In healthy tissue, collagenase is activated only at appropriate times, and reacts with collagen to aid in wound healing, in fighting infection, and in the normal turnover of cells. In cancer, however, collagenase becomes active at the wrong time and enables cells to escape from the parent tumor.
Early data from the collagenase studies suggest that many oral tumor cells can produce the active form of the enzyme. In one of their experiments, the scientists used purified collagen in a tissue culture dish as an extracellular matrix model and then placed human oral tumor cells on top of the collagen. Upon removing the tumor cells, the scientists found a hole eaten through the collagen layer -- evidence, they say, that activated collagenase was present underneath the tumor cells. The researchers ultimately hope to prevent collagenase activation in tumor cells and pre-empt the metastatic process.
At the University of California, San Francisco, another NIDCR-NCI Oral Cancer Research Center, researchers are studying a viscous molecule called hyaluronic acid (HA), a building block of the "glue" that anchors cells to one another. The molecule is present on the surface of cancer cells as well, and allows them to become motile and to create space into which they can move, two requirements for metastasis. Saliva's HA-rich environment gives cancer cells further opportunity to fulfill these two requirements, and may be the reason oral cancers can be so aggressive, the scientists say. In some cancers, high levels of HA and its receptor, CD44 (in certain forms), have been correlated with advanced metastatic behavior. In these latest NIDCR studies, the scientists will evaluate whether HA and CD44 are predictors of oral cancer metastasis by documenting their levels in cell culture and in human biopsy specimens. The scientists say these potential biomarkers may be of enormous value in identifying patients at increased risk for developing malignancy, and also in predicting which lesions might be particularly aggressive. Additional studies are aimed at trying to determine whether hyaluronidase, an enzyme that breaks down HA, can inhibit oral cancer metastasis.
One compound that has already shown anti-metastatic activity is a non-antimicrobial
tetracycline analogue called CMT-3. Current research on this molecule evolved
from earlier NIDCR studies on periodontal disease that found tetracyclines
could inhibit collagenase activity independently of their antibiotic property.
In recent laboratory tests, NIDCR-funded researchers at the State University
of New York at Stony Brook found that CMT-3 inhibits cancer cells from degrading
and crossing synthetic basement membrane. The analogue also showed promise
in a rat model of prostate cancer in which it reduced tumor size in some
animals, caused tumor remission in others, and inhibited metastasis to the
lung. Additional safety and efficacy studies, now under way, are necessary
steps in moving toward the planned clinical testing of this compound. Further
anti-metastasis studies could lead to application of CMT-3 in treating many
cancers, including oral cancer.