CMRC Children's Memorial Research Center
Lefty

Newly Discovered "Lefty" Protein Inhibits Malignant Tumor Cells

InTouch Spring 2008 (Volume 5: Issue 1)

A protein that governs development of human embryonic stem cells (hESCs) also inhibits the growth and spread of the deadliest skin cancer, Mary J.C. Hendrix, PhD, and colleagues have discovered. Malignant melanoma has a death rate of more than 80 percent and a median survival of less than 7.5 months. The scientists found that the protein, called Lefty, also prevents aggressive breast cancer cells from metastasizing. Death from metastatic breast cancer exceeded 40,000 in 2007, with over 180,000 new cases diagnosed in the United States. Importantly, Lefty is secreted only in hESCs, and not in any other stem cell type tested. Results of the study, described in the March 18 issue of The Proceedings of the National Academy of Sciences, build on an elegant body of research by the Hendrix lab to identify genes and cellular pathways involved in cancer metastasis.
 
Lynne-Marie Postovit, PhD, who was first author on the study and a postdoctoral trainee in the Hendrix lab, is currently an assistant professor at the University of Western Ontario, Canada.
 
Embryonic stem cells are pluripotent, meaning they can become any cell type in the adult body, depending on the signals they receive from their microenvironment (surrounding cells, tissues and vasculature). During cancer progression, malignant cells receive and release signals that promote tumor growth and metastasis. Hendrix and colleagues are elucidating how, by becoming more like unspecialized stem cells, aggressive melanoma cells gain abilities to migrate, invade and metastasize while remaining virtually undetected by the immune system.
 
The lab previously demonstrated that a three-dimensional matrix conditioned by hESCs induced metastatic melanoma cells to revert to normal, with the ability to form colonies in a manner similar to hESCs. “This observation allowed us to appreciate the powerful influence of the hESC microenvironment on the reprogramming of metastatic melanoma cells,” Hendrix said. In subsequent experiments, Hendrix, Postovit and co-researchers found that aggressive melanoma and breast cancer produce a protein called Nodal that is essential for hESC pluripotency. Other researchers have found that Nodal also is present in testicular cancer. “Thus, Nodal may serve as a prognostic marker of aggressive behavior in human cancers,” Hendrix said.
 
As described in the PNAS study, Lefty inhibits production of Nodal and therefore plays a major role in embryonic cell differentiation and development under normal circumstances. The lab discovered that metastatic tumor cells do not express Lefty, allowing them to overproduce Nodal in an unregulated manner. However, when exposed to the microenvironment of hESCs containing Lefty, the cells showed dramatically reduced Nodal expression, decreased tumor cell growth and invasiveness, and an increase in apoptosis, or programmed cell death.
 
Both the metastatic melanoma and breast cancer cells underwent apoptosis following exposure to the hESC microenvironment. “The remarkable similarity of the responses is likely attributable to the commonality of plasticity (for example, the aberrant and unregulated expression of Nodal) that unifies highly aggressive cancer cells, regardless of their origin,” Hendrix said. “Further, the tumor suppressive effects of the hESCs’ microenvironment, by neutralizing the expression of Nodal, provide previously unexplored therapeutic modalities for cancer treatment,” she added.

Contributing authors on the study include N. Margaryan; E. Seftor; D. Kirschmann; D. Abbott; W. Wheaton; A. Lipavsky; and R. Seftor. This study was supported by grants from the Illinois Regenerative Medicine Institute; the National Institutes of Health; the Charlotte Geyer Foundation (to Hendrix); and a Canadian Institutes of Health Research Postdoctoral Fellowship (to Postovit).

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