How do human cells become immortal? Despite the important implications for cancer development, the process is not well understood. Now, a research team based in the Berkeley Lab, US, have developed a new method to create and study immortal human mammary epithelial cells (IHMECs). It is already possible to do this but the oncogenic agents used to create the cells result in multiple genomic errors, meaning the cells are not accurate models of cancer etiology. The new method generates cells with normal, stable genomes, providing a more accurate model for studying the process in the same way it actually occurs in human cancers; while human cancer tissue may contain many genomic alterations, only a small number of these are thought to play a role in disease development.
This is the culmination of over 30 years of work for Berkeley researcher Martha Stampfer, lead author of the associated paper (1). “When I started this work, I was fascinated by the observation that rodent-derived cultures from both normal and tumor tissues could spontaneously immortalize in culture, but in humans, it only occurred in cells derived from tumors. I’ve been chasing the question ever since. Understanding the molecular mechanisms, along with a reproducible method, could facilitate identification of agents that might prevent this process, and thus halt malignant progression,” she says. It is believed that immortalization is mainly due to the upregulation of telomerase, the enzyme responsible for maintaining the telomeric ends of chromosomes, but very little is known about how human epithelial cells reactivate telomerase during cancer development in vivo. Creating the immortal cells involved overcoming two senescence barriers; using C-Myc to reactive the enzyme which maintains telomerase and allow division to continue, and using small hairpin RNA to silence the tumor suppressor p16 – a straightforward and reproducible method. Studying cells created in this manner could provide researchers with an invaluable tool for analyzing the underpinnings of immortality and potentially developing new approaches to cancer therapy. The Berkeley team intends to continue unravelling the mysteries of immortality, as Stampfer explains, “We are currently examining the molecular changes that occur during the process. Several molecules with observed changes in expression are now being studied, and will be tested for to see if they are necessary to attain or maintain immortality. The goal would be to identify therapeutics that could prevent immortalization in pre-malignant cells.”
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References
- J.C. Garbe et al., “Immortalization of Normal Human Mammary Epithelial Cells in Two Steps by Direct Targeting of Senescence Barriers Does Not Require Gross Genomic Alterations”, Cell Cycle, 13, [epub ahead of print] (2014).