Targeted therapeutics capable of preventing or limiting the metastasis of skin cancer

An international team of scientists has identified an important molecular link involved in the spread – or metastasis – of melanoma to other organs such as the lungs.

By introducing a synthetic peptide that mimics one component of this link, the researchers blocked this cellular interaction, significantly deterring the migration of cancer cells beyond the original tumor site. Blocking this protein linkage also was shown to inhibit angiogenesis--the creation of blood vessels that nourish new, secondary tumors--and spur cell death or apoptosis.

The results, published in the July issue of the journal Cancer Research, open the door to the prospect of targeted therapeutics capable of preventing or limiting the metastasis of skin cancer.

"The ability of these synthetic peptides to reduce tumor cell metastasis and angiogenesis and increase apoptosis may be important in the development of therapeutics for malignancy," said Hynda Kleinman, Ph.D., chief, cell biology section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Md.

As described in their study, the spread of melanoma cancer cells requires the interaction of two proteins, one located on the cell's surface called CD44, and an extracellular matrix protein known as laminin á5.

CD44 is considered a proteogylcan, which is a protein that has lengthy chains of carbohydrates that extend outward from its protein core, giving it a structure similar to a bottle brush. Carbohydrate side chains, called glycosaminoglycans (GAGs), can interact with other molecules outside of the cell wall membrane. CD44 is produced by cells and positioned on their cell surface membrane. It is often overexpressed in cancer cells. Dr. Kleinman and her associates determined that the GAG near one end of the CD44 protein backbone binds to a specific sequence of amino acid residues in laminin á5.

The laminin á5 molecule is an extracellular matrix protein that occupies areas between cells in the body and gives definition and structural identity to organs and tissue.

The research team, which includes scientists from Tokyo Metropolitan Komagome Hospital and Hokkaido University in Japan, tested a library of 113 synthetic peptides for their ability to attach to melanoma cells and for their effect on the colonization of melanoma cells in the lung. Those peptides were constructed to match sequences along the laminin á5 globular domain. The scientists observed that the peptideA5G27 competed with laminin á5 in binding to the CD44 receptor at the site of the specific CD44 GAG side chain. A5G27 consists of 13 amino acid residues that are consistent with the laminin á5 sequence extending between residues 2893 and 2904.

Kleinman's colleagues documented the ability of A5G27 to inhibit metastasis of skin cancer cells to the lungs of mice. Furthermore, when melanoma cells were placed under the skin of mice treated with A5G27 synthetic peptides, the cells formed a tumor that was smaller in size and lacking in ample growth of novel blood vessels, compared to the tumors that developed in mice that received no synthetic peptide treatment.

By identifying the peptide that inhibits the laminin á5–CD44 interaction from propelling cancer cell migration, invasion and angiogenesis, the research team uncovered a potentially key target for molecular therapy.

More than one million cases of basal cell or squamous cell skin cancers occur annually; melanoma and other non-epithelial skin cancers will cause an estimated 10,250 deaths in 2004.