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Researchers use embryonic model to reprogram malignant melanoma

01.03.2006

Scientists at Northwestern University and the Stowers Institute for Medical Research have reprogrammed malignant melanoma cells to become normal melanocytes, or pigment cells, a development that may hold promise in treating of one of the deadliest forms of cancer.

A report describing the group’s research was published in the Feb. 27 online edition of the Proceedings of the National Academy of Sciences that will appear in the March 7 issue of the journal.

The experiments were conducted as a collaboration involving the laboratories of Mary J. C. Hendrix, president and scientific director of the Children’s Memorial Research Center, Northwestern University Feinberg School of Medicine, and Paul M. Kulesa, director of Imaging at the Stowers Institute for Medical Research in Kansas City, Mo.

Hendrix is professor of pediatrics at the Feinberg School and a member of the executive committees of The Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The study demonstrated the ability of malignant melanoma cells to respond to embryonic environmental cues in a chick model -- in a manner similar to neural crest cells, the cell type from which melanocytes originate -- inducing malignant cells express genes associated with a normal melanocyte.

The researchers also showed that the malignant melanoma cells lost their tumor-causing ability as they became reprogrammed by the embryonic microenvironment to assume a more normal melanocyte-like cell type.

"Using this innovative approach, further investigation of the cellular and molecular interactions within the tumor cell embryonic chick microenviroment should allow us to identify and test potential candidate molecules to control and reprogram metastatic melanoma cells," Hendrix said.

Neural crest cells give rise to pigment cells as well as bone and cartilage, neurons and other cells of the nervous system. During embryonic development, neural crest cells display "invasive" behavior, similar to metastatic cancer cells, migrating from the neural tube (which becomes the brain and spinal cord) to form tissues along specific pathways.

Kulesa’s laboratory transplanted adult human metastatic melanoma cells, isolated and characterized by the Hendrix laboratory group, into the neural tube of chick embryos.

The transplanted melanoma cells did not form tumors.

Rather, like neural crest cells, the melanoma cells invaded surrounding chick tissues in a programmed manner, distributing along the neural-crest-cell migratory pathways throughout the chick embryo.

The investigators found that a subpopulation of the invading melanoma cells produced markers indicative of skin cells and neurons that had not been present at the time of transplantation.

Taken together, results of this study suggest that human metastatic melanoma cells respond to and are influenced by the chick embryonic neural-crest-rich microenvironment, which may hold promise for the development of new therapeutic strategies, the researchers said.

"This idea was pioneered 30 years ago by scientists who thought that the complex signals within an embryonic field may reprogram an adult metastatic cancer cell introduced into such an environment and cause it to contribute in a positive way to an embryonic structure," Kulesa said.

"Today, we have advanced imaging and molecular techniques that allow us to pose the same questions within an intact chick embryo and directly study the molecular signals involved in the reprogramming. The ancestral relationship between melanoma and the neural crest provides a wonderful bridge between developmental and cancer biology," Kulesa said.

One of the hallmarks of aggressive cancer cells, including malignant melanoma, is their unspecified, plastic nature, which is similar to that of embryonic stem cells.

The Hendrix lab has shown that the unspecified or poorly differentiated cell type serves as an advantage to cancer cells by enhancing their ability to migrate, invade and metastasize virtually undetected by the immune system.

Also collaborating on this research were Jennifer C. Kasemeier and Jessica Teddy, Stowers Institute; and Naira V. Margaryan; Elisabeth A. Seftor; and Richard E. B. Seftor, Children’s Memorial Research Center.