Model shows melanoma's microenvironment critical

Chicago - Scientists need to develop melanoma therapies that target both tumor cells and their microenvironment, according to Mary Hendrix, Ph.D.

This hypothesis, an outgrowth of research presented in the November 2005 issue of Cancer Research, is one of several founded on a new laboratory model developed by Dr. Hendrix and colleagues at the Children's Memorial Research Center (CMRC) at Northwestern University Feinberg School of Medicine in Chicago.

In theory, the model is simple. Take a 3D collagen matrix. Insert aggressive human melanoma cells and leave them alone for three to four days. Remove the melanoma cells with ammonium hydroxide wash. Insert normal human melanocytes. Let everything sit for another three to four days. Finally, investigate possible changes in gene and protein expression.

This indicates that the message - cues for reprogramming cells and changing the phenotype - is embedded in the microenvironment of growth factors, matrix remodeling enzymes and extracellular matrix proteins.

As a result, Dr. Hendrix, who in addition to conducting research, serves as president and scientific director of CMRC, says, "This means we need to be more clever about treating melanoma, because after doctors remove tumor cells with surgery or drugs, the metastatic signals may remain. New therapies should target these signals in addition to tumor cells."

Melanoma modeling

Long gone is the hopeful theory that mutations within a single gene trigger melanoma. Instead, research now focuses on multiple genes and epigenetic pathways. Findings from the Hendrix lab could exponentially raise the degree of complexity by expanding the scope of research, and therefore therapy, to the microenvironment - a biochemical brew of enzymes, proteins and growth factors.

This news does, however, come with a silver lining: The experimental model developed by the Hendrix lab at Northwestern appears to be a major advance in studying these same complexities. That's because it provides scientists with the means to quickly test (in a period of one to two weeks) any given hypothesis - from candidate genes for therapeutic intervention to treatment strategy - before investing in animal or patient tissue studies.

Dr. Hendrix and researchers are now attempting to validate the model via these very studies.

She notes, "What's really exciting are the data generated with respect to genes. We're beginning to identify the genes turned on at the very earliest stages of melanoma. These may prove to be the new diagnostic markers, allowing physicians to characterize the disease more specifically and earlier than they have in the past."

Other findings

In looking at how to change the environment so as to retard the progression of melanoma cells, the Hendrix lab has conducted a number of experiments. Of significance, researchers have found that placing aggressive melanoma cells on a matrix preconditioned by melanocytes does not affect the melanoma cells, but placing them on a matrix preconditioned by human embryonic stem cells induces the melanoma cells to express melanocytic markers (antigens). This represents a regression of melanoma, since aggressive melanoma cells do not typically express these antigens.

Dr. Hendrix emphasizes, "We have found that the only native microenvironment that can change melanoma cells is that of human embryonic stem cells."

Another way to change the environment is, of course, with drugs. Earlier studies showed that a matrix preconditioned with aggressive melanoma cells could induce poorly aggressive melanoma cells to become more aggressive. This effect was prevented by treatment with a group of drugs called "chemically modified tetracyclines."