MMP8 AS A TUMOR SUPPRESOR?

Suppressor of Melanoma Tumor Growth Identified

April 3, 2009 — A gene that suppresses tumor growth in melanoma has been identified by researchers at the National Institutes of Health (NIH). The gene, known as matrix metalloproteinase-8 (MMP8), could pave the way for new individualized therapies for melanoma, write the authors of a new study that was published online March 29 in Nature Genetics.

The new finding also provides insight into why MMP inhibitors, once considered promising anticancer agents, disappointed clinically.

MMPs are enzymes that degrade components of cells, including the extracellular matrix, explain the study authors, led by Lavanya H. Palavalli, MD, from the National Human Genome Research Institute (NHGRI) at the NIH, in Bethesda, Maryland. The enzymes help the body break down and recycle proteins, and thus play a role in the process of remodeling skin after sunburns, cuts, or other injuries.

MMP8 is 1 of a family of 23 MMP genes. This family of genes has been associated with cancer metastasis, say the study authors.

MMP genes that mutate have been thought to be oncogenes, or promoters of cancer cell growth. Thus, the suppression of MMP activity with MMP inhibitors was the focus of oncologic research and drug development. There have been "decades of research on MMPs," note the authors, but it has proven fruitless. "Clinical trials using these inhibitors showed no effect and, occasionally, accelerated tumor growth," write the authors.

The new NIH research hints at why MMP inhibitors and MMP suppression were problematic and why MMP8 holds promise as a melanoma tumor suppressor.

Through a series of experiments, the NIH investigators discovered that the expression of wild-type, or normal, MMP8 — but not mutant MMP8 — in human melanoma cells inhibited those melanoma cells from growing. Thus, expression of some (the wild-type) MMP8 genes inhibit melanoma cell growth.

The finding is consistent with the molecular understanding of cancer, suggested 1 of the authors.

"We often talk about cancer as though it is 1 disease, and cancers do have many common denominators. But when we look at the DNA level, we see that different cancers have different genetic profiles, and so do different patients who have the same cancer," said the study's senior author, Yardena Samuels, PhD, in a statement. She is an investigator in the Cancer Genetics Branch of the NHGRI's Division of Intramural Research.

The new finding about MMP8 should spur research on the rest of this gene family, suggest the authors. "These findings emphasize the need to test the role of each MMP in an individual manner and to precisely define its functional role in cancer," they write.

Mutational Analysis Yields the Finding

The NIH undertook their new study in an effort to determine whether MMP genes are genetically altered in melanoma. There was good reason for the investigation.

As mentioned above, MMPs had been associated with cancer metastasis. However, in mouse models, there was the suggestion that MMPs had an antitumor effect, note the authors. "In particular, an increase in skin-tumor incidence was seen in MMP8-deficient mice," they write. The conflicting information about MMPs (agents of tumor growth vs producers of an antitumor effect) called for "an indepth analysis of the specific role of individual MMPs in particular cancer types," observe the authors.

Melanomas were chosen as the first cancer type. The study is the first systematic mutational analysis of the MMP family, say the authors.

To study the MMP genes, the researchers used a bank of tumor and blood samples collected from 79 patients with aggressive melanoma by coauthor Steven Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute.

After comparing the sequence of MMP genes in tumors and normal DNA from the same patients, the researchers identified 28 different mutations in 8 MMP genes (from a total of 23 genes) in the melanoma tumors.

These mutations were distributed in different frequencies and patterns among the tumor samples. Of the tumors analyzed, 23% had at least 1 MMP gene mutation. Notably, more than 6% of tumors had mutations in MMP8 and more than 7% had mutations in MMP27, making them the most frequently mutated genes in the samples.

In a series of subsequent in vitro and in vivo (mice) experiments that focused on MMP8, the researchers note that the expression of wild-type but not mutant MMP8 was associated with inhibition of melanoma cell growth.

For example, the researchers found that mice injected with cells expressing wild-type MMP8 did not develop skin ulcers, which are important measures of cancer aggressiveness in melanoma. However, mice injected with cells expressing mutated MMP8 developed ulcerations and metastases in their lungs.

A combination of genetic, biochemical, and cellular data suggests that MMP8 is a tumor suppressor in human melanoma, they summarize. Further research might eventually allow the "development of individualized therapy on the basis of the mutant MMP present in the specific tumors," the authors conclude.