"I'm a developmental biologist by training," Mary Hendrix told BioWorld Today. "And so I think about studying cancer a little bit differently than most researchers." To Hendrix, who is president and scientific director of the Children's Memorial Research Center at the Northwestern University's Feinberg School of Medicine, "aggressive cancer cells look a lot like embryonic stem cells that have lost their regulators."
In the March 4, 2008, issue of the Proceedings of the National Academy of Sciences, senior author Hendrix and her colleagues report the fruits of looking at stem cells through that unusual lens. Their studies of the embryonic stem cell microenvironment have identified a factor, called Lefty, that is secreted into the stem cell microenvironment by embryonic - and only embryonic - stem cells, but can bring metastatic breast cancer and melanoma cells back to the straight and narrow when they are exposed to it.
Hendrix said that cells expressing Nodal "might represent a cancer stem cell subpopulation." That possibility also is the case for those cells expressing another protein, Cripto, which is part of the Nodal receptor and is expressed in embryonic stem cells and some of the cancer cell lines she and her colleagues used in their study.
The team is investigating the cancer cells to see whether they meet the criteria for being cancer stem cells. For the time being, Hendrix and her colleagues avoid calling the cells they work with cancer stem cells, characterizing them instead as aggressive metastatic cells.
In embryonic stem cells, Lefty works to inhibit another protein, Nodal, in a negative feedback loop. In previous work, Hendrix and her colleagues had shown that the Nodal pathway is active in both embryonic stem cells and aggressive cancer stem cells. In their current paper, they show that Lefty is not. They could not detect the protein in metastatic melanoma or breast cancer cells, suggesting that Nodal can fuel cell division unchecked in those cells.
When the authors exposed the cancer cells to an embryonic stem cell-conditioned environment, which included Lefty protein as well as other signals that embryonic stem cells secrete, the cancer cells decreased their expression of Nodal, leading to reduced tumor cell growth and invasiveness and an increase in apoptosis.
Some politicians tend to use every bit of promising research news about adult stem cells, or induced pluripotent cells as proof that embryonic stem cell research is not necessary.
Many scientists - even those who work on such cells - have taken pains to contradict that opinion. At a press conference last November describing the generation of induced pluripotent cells - reprogrammed adult cells that act much like embryonic stem cells - iPS cell co-discoverer James Thomson stressed that embryonic stem cells continue to be the "gold standard" against which other cells' capabilities are measured for the time being.
The work now reported in PNAS showed a striking example of a factor that appears to be specific to embryonic stem cells. Hendrix and her colleagues also searched for Lefty in stem cells from adult bone marrow, amniotic fluid and cord blood, as well as placental cells - to no avail.
Perhaps even more striking, to date at least Lefty has to be the real thing to do its job: When Hendrix and her team tried using recombinant Lefty to stop tumor cells from dividing, the necessary concentration was 50 times that of the protein that is secreted by embryonic stem cells - a dose that is much too high to use on cancer patients, Hendrix said.
Hendrix's group currently is investigating whether recombinant Lefty has differences in either folding or glycosylation that could explain the difference. Whatever the reason, Hendrix does not intend to let it thwart the obvious therapeutic potential that Lefty has. She said that "we would like to work with a pharmaceutical or biotech company to develop a super-active Lefty" that could be tested in the clinic.