Mechanistic insight into immortal cells could speed clinical use

February 25, 2015

WASHINGTON -- The mechanistic understanding of the relatively new technique for growing cells in culture indefinitely - known as conditional reprogramming - has been deciphered and reported in the February 25th issue of PLOS ONE. Researchers at Georgetown Lombardi Comprehensive Cancer Center say identifying the mechanisms of immortalization lays the groundwork for future clinical use of these cells.

Investigators discovered the signaling pathways associated with the two primary components of the "conditional reprogramming" technique developed at Georgetown University -- feeder cells derived from mouse fibroblasts and a Rho kinase inhibitor -- work in parallel to immortalize the cells. Both the inhibitor and feeder cells suppress terminal differentiation of cells allowing them to keep multiplying. The feeder cells achieve this by secreting a specific set of proteins.

"A lot more work remains before we can provide a complete formulation, which can replace the feeder cells utilized by researchers to generate patient-specific cells for gene correction or regenerative therapies," says the study's senior investigator, Geeta Upadhyay, PhD, research assistant professor of oncology at Georgetown Lombardi.

The ability to generate conditionally reprogrammed cells, which was first described in 2012 in the American Journal of Pathology by Richard Schlegel, MD, PhD, of Georgetown Lombardi, and colleagues, holds the promise of significantly advancing personalized medicine, Upadhyay says. The method can keep both normal and diseased cells alive indefinitely -- which previously had not been possible. When the two components are withdrawn, normal cells begin to differentiate.

Schlegel published a demonstration of the technique's power in 2012 in the New England Journal of Medicine, when the method was used to grow cells in the lab from a man with a lung tumor that contained HPV and for which there was no known therapy. Using both normal and tumor cells from the patient, the investigators screened several drugs and identified a therapy which was effective clinically.

Upadhyay has identified the precise cell pathways that the two key components used to immortalize cells, and also found that the feeder cells secrete 14 different proteins to do their work. Both discoveries will likely speed clinical application, she says, because mouse feeder cells would not be needed if the 14 proteins they secrete could be used in isolated and purified form.

"There has been much global interest in conditionally reprogrammed cells, but not all laboratories have the capacity to irradiate the feeder cells, which pushes them to secrete the factors. With a cocktail of purified proteins, we can reduce the possibility of contamination of human cells by mouse feeder cells."
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Co-authors of the PLOS ONE study include Segni Ligaba, Anikita Khurana, MS, Garrett Graham, Ewa Krawczyk, PhD, Sandra Jablonski, PhD, and Robert I. Glazer, PhD, from Georgetown Lombardi, and Emanuel Petricoin, PhD, at George Mason University.

The research was funded by the Georgetown's Department of Pathology, Georgetown-Howard Universities Center for Clinical and Translational Sciences and the National Cancer Institute (R21CA175862-01A1).

Georgetown has created the Center for Cell Reprogramming to promote research on conditionally reprogrammed cells (a patented technology that has been licensed by the university to an outside company for commercialization), and their relevant biological and medical applications.

About Georgetown Lombardi Comprehensive Cancer Center


Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Georgetown Lombardi is one of only 41 comprehensive cancer centers in the nation, as designated by the National Cancer Institute (grant #P30 CA051008), and the only one in the Washington, DC area. For more information, go to http://lombardi.georgetown.edu.

About Georgetown University Medical Center


Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health.

Georgetown University Medical Center

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