Northwestern University researchers have demonstrated how the microenvironments of two human embryonic stem cell (hESC) lines (federally approved) induced metastatic melanoma cells to revert to a normal, skin cell-like type with the ability to form colonies similar to hESCs. The researchers also showed that these melanoma cells were less invasive following culture on the microenvironments of hESCs.
"Our observations highlight the potential utility of isolating the factors within the hESC microenvironment responsible for influencing tumor cell fate and reversing the cancerous properties of metastatic tumor cells, such as melanoma," said Mary J. C. Hendrix, in whose laboratories at Children's Memorial Research Center the experiments were conducted.
An article describing the findings by Hendrix and her laboratory group was published in the Nov. 17 online issue of the journal Stem Cells. Hendrix is president and scientific director of the Children's Memorial Research Center at Northwestern University Feinberg School of Medicine and a member of the executive committees of The Robert H. Lurie Comprehensive Cancer Center and the Center for Genetic Medicine at Northwestern University. The Northwestern researchers used a unique, three-dimensional model to test whether the microenvironment supporting human embryonic stem cells (hESCs) would influence the behavior of human metastatic melanoma cells -- since hESCs have the ability to develop into a variety of normal cell types -- to assume a more normal melanocyte-like cell, the skin cell type of origin for melanoma.
The model, which was developed in Hendrix's laboratories, consists of a three-dimensional collagen matrix preconditioned by hESCs, followed by their removal and subsequent application, or seeding, of metastatic melanoma cells onto the embryonic microenvironment, which was followed by molecular and functional analyses.
The team applied two different hESC lines, independently, onto three-dimensional collagen matrices and allowed the cells to form colonies and precondition their microenvironments for several days. The hESCs were removed and the matrix microenvironments were left intact. Then, human metastatic melanoma cells were seeded onto the hESC-preconditioned matrix microenvironment and were allowed to remain for several days. After this period, the metastatic melanoma cells exposed to the hECS microenvironment were reprogrammed to express a melanocyte-associated protein, called Melan-A, and form colonies similar to the hESC colonies. The melanoma cells reprogrammed by the hESC microenvironment were also less invasive than the tumor cells that had not been exposed to the embryonic matrices.
"These findings offer a new approach to investigating the possible effects of identifying the microenvironmental factors produced by hESCs on reversing the metastatic properties of tumor cells," Hendrix said.
The study was led by Lynne-Marie Postovit, postdoctoral scholar, and Elisabeth A. Seftor, research scientist, in the Hendrix laboratory. Hendrix's co-researcher on the study was Richard E.B. Seftor from Northwestern University.
This research was supported in part by a grant from the National Institutes of Health/National Cancer Institute (CA59702), the Michael Sweig Foundation, and the Medical Research Institute Council.
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