Converting Human Cells to Cancerous Cells

For this article, Leslie Pray interviewed William C. Hahn, postdoctoral fellow at the Whitehead Institute for Biomedical Research in Cambridge, Mass., and an oncologist at the Dana-Farber Cancer Institute in Boston. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. W.C. Hahn, C.M. Counter, A.S. Lundberg, R.L. Beijersbergen, M.W. Brooks, R.A. Weinberg, "Creation of human tumour cells with defined genetic elements," Nature, 400:464-8, July 29, 1999. (Cited in 177 papers) Courtesy of Justin KnightWilliam C. Hahn For nearly two decades, scientists have been generating cancer cells in the lab using specific combinations of oncogenes. But, up until two years ago, they could only do this with rodent cells. Generating human tumor cells required other methods, such as irradiation and chemical treatment. However, these methods produced mutations not necessarily related to tumorigenesis, thus making it difficult to pinpoint which specific genetic changes were essential to the tumorigenesis process. A breakthrough came in July 1999, when William C. Hahn and his colleagues at the Whitehead Institute for Biomedical Research in Cambridge, Mass. reported in this paper that they had successfully converted normal human cells into cancer cells by introducing a specific set of genes that interfered with telomerase growth. The genes were hTERT, a telomerase expression regulator, and a combination of two oncogenes: the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras. By disrupting the intracellular pathways regulated by these genes, Hahn and his colleagues directly converted normal human epithelial and fibroblast cells into cancer cells. The study shows how "using these sets of genes, you can turn a normal human cell into a cancer cell in one step," Hahn says. Because hTERT plays such a key role, it follows that telomere maintenance is also critical in forming tumors by allowing pre-cancerous cells to continue replicating longer than normal, according to Hahn. In normal human cells, hTERT is not usually found and the telomeres progressively shorten with each round of cell division, until they reach the point where they stop replicating. In contrast, telomerase is turned on in most human tumors. In fact, the difference in telomerase expression between normal human cells and human cancer cells was an important clue in guiding the lab's efforts. "We are beginning to understand which intracellular pathways are disrupted during the conversion of a normal cell into a cancer cell," Hahn says. An understanding of these pathways will ultimately guide development of cancer therapies. Indeed, in a follow-up study, Hahn and his colleagues demonstrated that disruption of hTERT inhibits telomerase activity, reduces telomere length, and causes tumor cell death, providing important evidence that telomerase activity inhibition is a potentially new anti-cancer strategy.1 But before these pathways can be targeted, says Hahn, "the question is how close are these models to real cancer cells?" His lab extended its work to breast tissue and used the same three genes to see if they could convert human mammary epithelial cells into tumor cells.2 Their success showed that indeed, "the human cell model behaved in many similar ways to cells derived from patients," Hahn says. "We want to make better models of cancer cells," he notes, models that will provide more precise information about the complex process of human tumor development. Biological differences between rodent and human cells, such as those derived from telomere expression, might ultimately mean revisiting much of what is already known about tumorigenesis within the framework of these new human cell models. Since publication of their findings, Hahn and colleagues have focused on two major areas of study. "We want to create a whole cadre of model systems," Hahn says, for breast, lung, prostate, ovarian, and other cancers, so they can compare tumorigenesis among different tissue types. They are also trying to better understand exactly what hTERT and the other genes mentioned in this paper do. Leslie Pray can be contacted at lpray@nasw.org. References 1. W. C. Hahn et al., "Inhibition of telomerase limits the growth of human cancer cells," Nature Medicine, 5:1164-70, 1999. 2. B. Elenbaas et al., "Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells," Genes & Development, 15:50-65, January 2001.

Converting Human Cells to Cancerous Cells

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