Nature can reset the clock in certain types of cancer and reverse many of the elements responsible for causing malignancy, reports a research team led by Whitehead Institute Member Rudolf Jaenisch, in collaboration with Lynda Chin from Dana Farber Cancer Institute. The team demonstrated this by successfully cloning mice from an advanced melanoma cell.
"This settles a principal biological question," says Jaenisch, who also is a professor of biology at MIT. "The epigenetic elements of cancer are reversible; the genetic elements, as expected, are not."
Researchers have known for decades that cancer begins when certain key genes in an otherwise healthy cell mutate, and tumor growth depends on continuing, multiple mutations. But only recently have scientists begun to understand the "epigenetic" components of cancer-that is, how other molecules in a cell affect genes without actually altering the sequence of DNA. Many of these epigenetic components, such as methylation, can determine if a gene is silent or active.
Konrad Hochedlinger and Robert Blelloch, postdoctoral researchers in the Jaenisch lab, studied whether any of these epigenetic influences can be reversed. First, they removed the nucleus from a melanoma cell and injected it into a de-nucleated egg cell (a process known as nuclear transfer). After the egg cell developed into a blastocyst, Hochedlinger and Blelloch harvested embryonic stem cells which they then incorporated into a group of healthy mouse blastocysts. Many of these blastocysts developed into normal adult mice. The work was reported in the August issue of the journal Genes and Development.
"It's important to note," says Blelloch, "that the stem cells from the cloned melanoma were incorporated into most, if not all, tissues of adult mice, showing that they can develop into normal, healthy cells," such as those for skin pigmentation, immunity, and connective tissue. But in spite of this, when certain cancer-related genes in these mice were activated, they developed malignant tumors at a much faster rate than the control mice.
According to Lynda Chin of Dana-Farber's oncology department, this research opens up the door to developing cancer animal models in which researchers could ask epigenetic questions. "Although studies are ongoing, these findings have provided initial clues of the relative contributions of the epigenetic versus genetic lesions in the development of cancer," she says. "Drugs that target the cancer epigenome may prove to be a key therapeutic opportunity for diverse cancers."
(c) 2004 - Whitehead Institute for Biomedical Research
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