Clues To Molecular Cancer Switches Probed

December 14, 1998

HANOVER, NH-A genetic variation in human cells could facilitate cancer invasion and spread by boosting production of agents that dissolve the framework that holds the body together, report Dartmouth Medical School researchers. Their findings offer clues to molecular switches that control cancer progression and provide tools for cancer detection and treatment.

The study, headed by Dr. Constance Brinckerhoff, Nathan Smith Professor of Medicine and of Biochemistry, was reported in the Dec. 1 issue of Cancer Research.

The work builds on Brinckerhoff's studies of the enzymes called collagenases that break down collagen, the body's most abundant protein. The rigid collagen molecule gives the body shape and structure.

A family of at least 15 enzymes have essential roles in the modeling of connective tissues-the network of skin, bones, and blood vessels that mold the body. These enzymes are active in normal physiological processes such as wound healing and in diseases such as arthritis. Several have the unique ability to degrade collagens in the connective tissue matrix outside cells.

The team studied two different versions of a particular collagenase in normal skin cells and in cells from melanoma, the most serious form of skin cancer and one of the fastest growing cancers, according to Brinckerhoff, with more than 40,000 new cases a year.

Both the normal and cancer cells with one particular version had high levels of the collagenase, while those with the other version did not. Collagenase destroys tissue and its increased production could be a factor in the ability of tumor cells to invade other tissues and migrate.

The enzymes require metals and are also known as matrix metalloproteinases. The most ubiquitous of these is matrix metalloproteinase-1 (MMP-1), also called collagenase-1. Too much of the emzyme is associated with irreversible cartilage damage in arthritis. Cancer patients whose tumors produce MMP-1 have an overall poorer prognosis than those with non enzyme-producing tumors, studies have found.

Genomic differences are powerful tools for identifying disease genes, the researchers note. Most such alterations, known as a polymorphisms, involve the region of genes that code the information to make proteins and enzymes. The polymorphism the DMS team documents is in the promoter or control region that turns the enzyme on and off.

Brinckerhoff and her colleagues compared versions of MMP-1 whose genetic sequence varies by a single nucleotide building block. The polymorphism entails the presence or absence of the chemical guanine (G), one of the four DNA bases for genetic blueprints. The precise order of these units is unique for each gene.

The version with the extra "G" significantly augments production of the MMP-1 gene in both normal and malignant cells, the team found. It's as if the switch for the enzyme is always in the on position. Additional analysis determined that the difference was an inherited structural variation found in the general population rather than an abnormal mutation of these cancer cells.

"It is well established that MMP-1 has a critical role in collagen degradation. Therefore, the discovery of a structural alteration in the MMP-1 gene that influences its level of expression is important to our understanding of how this enzyme modulates extracellular matrix metabolism, " said Brinckerhoff. The continuous production of the enzyme, she adds, could be a factor in tumor invasion and metastasis.

Other team members included DMS researchers Teresa Mitchell and Jennifer Meyers (biochemistry) and Joni Rutter (pharmacology and toxicology) as well as Laurie Ozelius and James Gusella of Harvard Medical School and Giovanna Butticè of the Institute de Biologie, Lille, France.

The Geisel School of Medicine at Dartmouth

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