In June, scientists at the Ross Eye Institute in Buffalo, New York, discovered that samples of tissue from the rare childhood cancer called retinoblastoma exhibit various markers and behaviors more characteristic of cells from an embryo. For example, these cells form tiny 'microspheres,' just as typical stem cells do.

Stem cells can be identified by certain characteristic markers on their surfaces. These markers are known as 'clusters of differentiation' or CDs. The Ross Eye Institute scientists demonstrated that CD133 was present on the surface of retinoblastoma cells, as were some other well-known stem cell markers.

Not surprisingly, lead author Gail Seigel and her colleagues concluded that there was a small, but critical, subpopulation of retinoblastoma cells that expressed human embryonic stem cell markers on their surfaces. These cells exhibited behavior that was entirely consistent with cancer stem cells. "These findings support the hypothesis that retinoblastoma is...comprised of subpopulations with stem cell-like properties," the researchers wrote (Seigel 2007; see also Seigel 2005).

Retinoblastoma is a very rare cancer of the eye that generally occurs in children four years and younger. It represents 2.8 percent of the 10,400 annual US pediatric cancer cases, and thus afflicts less than 300 individuals per year. But other, far more common cancers have also been traced back to cancer stem cells.

This finding in the case of retinoblastoma is only the latest in a string of exciting findings about the stem cell origin of cancer. In fact, it is no exaggeration to say that the biggest news in cancer research in recent years has been the discovery of the cancer stem cell (CSC) as pivotal to the initiation of the disease.

"I think this is one of the most interesting developments in cancer research in the last five years," Robert Weinberg, a cancer geneticist at the Whitehead Institute in Cambridge, Mass, told the New York Times last year (Feb. 21, 2006). "I think more and more people are accepting it and evidence is accumulating that cancer stem cells exist in a variety of tumors."

These rare cancer stem cells constitute a tiny side population within the tumor itself. Generally speaking, it is only the cancer stem cell that perpetuates itself indefinitely and is capable of forming new tumors or metastases.

The saga of the cancer stem cell began in 1994, when John E. Dick of the University of Toronto identified such a cell type in acute myeloid leukemia (AML). He showed that most AML cells have only a limited capacity to proliferate. He suggested therefore that the leukemic clone was maintained by a "rare population of stem cells." Dick physically isolated an AML-initiating cell that could be transplanted into mice. Once transplanted, this primitive cell homed in on the bone marrow and there proliferated extensively. The result was an experimental disease whose patterns of dissemination and morphology were similar to those seen in the original human patients (Lapidot 1994).

Among the most surprising findings was that these leukemia-initiating cells were exceedingly rare in the circulating blood of AML patients. The authors could isolate just one 'engraftment unit' in every 250,000 cells. To do so, they separated the various AML-associated cells on the basis of their CD profile. They found that these rare leukemia-initiating cells could all be classified as positive for CD34 while being negative for CD38. All subsequent cancer stem cells have similarly been classified by the presence, or absence, of antigens of the CD series.

The first solid tumor to be definitively ascribed to cancer stem cells was breast cancer (Al-Hajj 2003). Again, only a small minority of breast cancer cells - the cancer stem cells - displayed the capacity to form new tumors. Mohammad Al-Hajj, working in the laboratory of Michael Clarke at the University of Michigan, was able to distinguish tumorigenic - or cancer-forming - from non-tumorigenic cancer cells based on cell surface marker expression. The tumorigenic cells were positive for CD44 while negative (or low) for CD24. The few cells with this cell surface (antigenic) profile could form new tumors, whereas tens of thousands of cells with other phenotypes were unable to do so.

Since then, the field has opened up in a remarkable way. In the last few years, scientists have identified CSCs in tumors of the brain and central nervous system, multiple myeloma, bone, lung, prostate, colon, pancreas, and head and neck.

Many questions remain about the cancer stem cells. For me, the most intriguing is: Where do they come from? I have yet to see a clear explanation of the path that these stem cells follow from the fertilized egg to the formation of a tumor. But I am hopeful that such an explanation will emerge in the years to come.

The retinoblastoma finding in Buffalo is a harbinger of things on the horizon. One can expect to hear about many more such discoveries in the future. The payoff may eventually be agents to specifically target cancer stem cells while leaving normal cells untouched. This could eventually open up a field of cancer therapeutics to leave current chemotherapy in the dust.

DEPARTMENT OF CORRECTIONS

In a recent newsletter concerning the work of Dr. Dennis Slamon of UCLA, I remarked that with the exception of the Annie Appleseed Project, no one appeared to have noticed the article by Robert Bazell, NBC's chief science correspondent, in which he commented on the statement by Dr. Slamon that only 8 percent of women with breast cancer stand to benefit from Adriamycin-based chemotherapy.

I was wrong. Annie Appleseed Project was not alone in picking up Bazell's article on Dr. Slamon's work. In fact, the National Breast Cancer Coalition also reviewed this important work, and has an extremely helpful position paper on the subject at the NBCC Web site:

http://www.stopbreastcancer.org/bin/index.asp?strid=944&depid=20

I apologize to NBCC for this omission.

--Ralph W. Moss, Ph.D.

References:

Al Hajj M, Wicha MS, Benito-Hernandez MA, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983-8.

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645-8.

Seigel GM, Campbell LM, Narayan M, Gonzalez-Fernandez F. Cancer stem cell characteristics in retinoblastoma. Mol Vis. 2005;11:729-737.

Seigel GM, Hackam AS, Ganguly A, Mandell LM, Gonzalez-Fernandez F. Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis. 2007 Jun 8;13:823-32.