Stem Cell researcher sounds cautionary note

It remains one of the great hopes of modern biomedicine: the prospect of using a patient’s own cells to renew and rejuvenate virtually any diseased tissue in the body. Such hopes rest in part on the success of a relatively new class of stem cells that could one day give doctors the ability to grow healthy new body cells — perhaps even entire organs — as if from scratch.

First developed in 2007, these so-called induced pluripotent stem cells (iPSCs) have given researchers a new window into the critical processes governing cell development as well as a new tool for studying disease. Like embryonic stem cells, iPSCs are undifferentiated, capable of specializing into any kind of tissue; unlike embryonic stem cells, they are taken not from a developing embryo but from normal muscle or skin cells and genetically reprogrammed to revert to an embryonic, or pluripotent, state.

Their importance was highlighted last month by the 2012 Nobel Prize for Medicine or Physiology, awarded to two scientists who were instrumental in the discovery and development of iPSCs. But despite the promise they hold for treating ailments such as diabetes, heart disease and organ failure, it is unclear how long it will be before the clinical use of iPSCs can herald a new age of regenerative medicine.

A recent study from UC Davis has underscored one part of the challenge by pointing to the apparent similarity between the process used in the production of iPSCs and the process used to make specific types of cancer cells grown for laboratory studies. In other words, says UC Davis Medical Center researcher Paul Knoepfler, iPSCs and cancer cells are “close enough to be called siblings,” which he says may contribute to the potential for iPSCs to become cancerous.

Knoepfler and his team published their results in September, after conducting the first-ever direct comparison of gene expression between the two types of cells.

“We really feel that there are a lot of positives that could come out of this,” Knoepfler said. “It could really be helpful in making better, safer iPS cells. It’s definitely a case where the more you know, the better.”

The team began by producing iPSCs and cancer cells from a common parent cell taken from mouse tissue. They then analyzed each type of cell’s transcriptome, the array of RNA molecules that indicate which parts of the genome are turned on or off in any given cell. The comparison revealed similar patterns of expressed and repressed genes in each of the two cell types, which Knoepfler and his colleagues believe reflects the similarity underlying pluripotency and cancer formation.

The idea that there might be some kind of relationship between the two processes is not new. In fact, one controversial theory proposes that cancerous tumors are caused by small populations of adult stem cells, though studies on the subject have been inconclusive.

Gerhard Bauer of the UC Davis Institute for Regenerative Cures said the fact that similar transcription factors were found in iPSCs and cancer cells doesn’t surprise him, given the methods used to create the cells in the laboratory. But he says that this in itself doesn’t prove that stem cells would be prone to cause cancer if used in treatment, since it is out-of-control growth that distinguishes cancer cells from other cell types, including iPSCs.

“It is very good that people look into iPSCs, but I would caution anybody against using hype to compare iPSCs to cancer cells,” Bauer said.

Knoepfler says that while the “functional meaning of the connection” between iPSCs and cancer cells remains to be elucidated, the specific connections his team reported have important implications for furthering stem cell research. The results not only potentially suggest new ways to “tweak the biotechnology” currently used to produce iPSCs, he said, but could also point to improvements in cancer treatment. For example, the team was able to reprogram some of the cancer cells to become less cancer-like and more stem cell-like. This suggests that future patient-specific treatments could involve cellular reprogramming as an alternative to cancer cell eradication, which often involves debilitating side effects such as nausea and weakness.

“Some of the things we found may be inconvenient, but if on the other hand this helps make better versions of cells, then I think it’s important to really explore,” Knoepfler said.

UC Davis molecular and cellular biology professor Frederic Chedin said that one of the challenges in such work is translating conclusions from a laboratory to a clinical context, given that cells behave in different ways depending on their environment. For example, regenerative therapy would not involve injecting the stem cells directly into the body, but rather growing iPSCs into differentiated cells before transplantation. These iPSCs could be taken directly from the patient, or, more likely, from a common “bank” of iPSCs.

“The more we understand about pluripotency processes and cancer formation — both their similarities and differences — the better, and in that sense this is a useful study,” Chedin said. “The study does not show that stem cells are cancerous. What they’ve done is something you’d only do in a lab, while what we do in therapy is very, very different.”

Though he advocates greater caution in moving ahead, Knoepfler said he hopes to see iPSCs eventually used in clinical trials on humans, once further research is done to clarify the potential risks involved. Japanese researchers have reportedly already sought permission to carry out such trials as early as next year.

“One of my labs’ area of focus is to better understand how stem cells sometimes do things we don’t want them to do, and we want to figure that out,” Knoepfler said. “I think [stem cells] are great. But in science, and particularly in medical applications, you have to be realistic.”

OYANG TENG can be reached at science@theaggie.org.

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