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The Real Problem in Breast Tumors: Cancer Stem Cells
By Nancy Touchette

Featured Article.

The quest for a cancer cure seems like the ending to a Kafka novel: so close, yet so far away. Decades of research and billions of dollars in funding have revealed much about the molecular events that lead to cancer. But overall, today's cancer cure rates are not much better than they were 30 years ago.

Part of the problem, a new study suggests, is that current cancer therapies may be targeting the wrong cells. The real issue may be a small population of cells in tumors that resemble adult stem cells, the self-replicating cells that give rise to specialized cells in tissues.

A cluster of breast tumor cells.

Michael F. Clarke and Max S. Wicha and their colleagues at the University of Michigan in Ann Arbor have identified a small population of cells in breast tumors that can seed the growth of new cancers. These cancer-causing cells, which make up a tiny fraction of cells within tumors, have properties similar to those of stem cells.

"This study creates a whole new conceptual paradigm of how tumors form," says Robert A. Weinberg, of the Whitehead Institute for Biomedical Research, an early pioneer in the study of cancer-causing genes. "It changes our thinking."

Researchers have traditionally thought of cancer as a collection of cells, all growing exponentially. "This paper demonstrates convincingly that the model is wrong," says Weinberg. "Only a few cells are endowed with the ability to replicate. It has profound implications for how we think tumors evolve and how we treat tumors."

Conventional cancer therapies do an effective job killing the majority of cells within the tumor, but they may miss cancer stem cells, according to the new research, published in Proceedings of the National Academy of Sciences. As a result, cancers often recur.

This is the first time that cells with stem-cell-like properties have been found in solid tumors. However, researchers had previously found similar cells in leukemia.

"This is a landmark study," says Irving L. Weissman of Stanford University in California, who discovered leukemia stem cells. "It is significant because all of the useful cancer drugs that we have are those that shrink the main body of the tumor. This study reveals that this may not be enough."

Both non-tumorigenic and tumorigenic cells exist within breast tumors.

"Shrinking the tumor is fine, but if it doesn't get rid of the cancer stem cells, the cancer will grow back," according to Weissman.

Stem cells are immature cells that can replicate, or renew themselves, and are able to differentiate, or mature, into all the cells that an organism or particular organ system need.

Three years ago, Weissman discovered that mutations and rearrangements of the genomes of stem cells that give rise to all the cells of the blood can lead to some forms of leukemia. Weissman proposed that these changes could underlie the development of cancers in many tissues.

"Ideas are cheap," says Weinberg. "Without evidence, we could only treat Weissman's idea as speculation. Now it seems that he was right on the mark."

In the present study, the Michigan researchers examined cells from nine human breast tumors and tumor metastases. They looked for "markers"—proteins attached to the outside of only some cells—to distinguish cells. Using three different markers, the researchers grouped the tumor cells into two different classes.

The difference between the two cell types became evident when they transplanted them into mice. When as few as 200 of one cell type were injected into mice, tumors developed. But when they implanted as many as 10,000 cells of the second type, no tumors developed.

"This is the classic definition of a stem cell," says Weissman. "Take a small subset of cells and put it in the organism and see if it regenerates the original tissue. This is just what happens when they implant the tumor stem cells. All the cells of the original tumor are generated."

The key to developing new cancer therapies may be to focus on these cancer stem cells. But this is likely to be difficult.

"Stem cells are more difficult to kill," says Wicha. "Because they are so important throughout a person's lifetime, they have developed mechanisms that protect themselves."

For example, tumor stem cells are able to resist toxic substances, such as cancer drugs. More mature cells are easier to kill than stem cells, because these mechanisms are not always active.

Normal Stem Cells vs. Cancer Stem Cells

The stem cells in tumors discovered by researchers at the University of Michigan are not the same type of stem cells being explored as potential therapies to treat degenerative diseases. Both normal embryonic and adult stem cells are being actively studied for their ability to proliferate and replace damaged cells in diseases such as diabetes, Parkinson's disease, and heart disease.

But stem cells in tumors develop because of mutations that accumulate over years and often decades. The mutations are thought to promote the tumor stem cells' ability to proliferate, eventually leading to cancer.

The next step is to figure out what makes the cancer stem cells different from the other cells in the tumor. The researchers are currently using DNA microarrays, or "gene chips" to identify genes that are active in the cancer-causing cells compared to benign tumor cells. Some of these genes might control the cell's ability to replicate and metastasize.

Identifying these genes may suggest new drug targets that could selectively kill the cancer cells.

"The only cells within an organism that live long enough to accumulate the mutations that lead to cancer are the stem cells," says Wicha. "When the cancer cell differentiates, it produces other cells that have lost the ability to self-renew."

If the researchers can find normal adult breast stem cells, they may understand how breast cancers develop. "A key question is what is the difference between a normal stem cell and a tumor stem cell," says Wicha.

"A normal breast stem cell can make copies of itself, but then shuts itself off. Cancer stem cells make too many copies of themselves." Wicha thinks that a primary event in cancer development occurs when the normal stem cell loses the ability to regulate its own growth. But many other mutations must occur to turn a normal stem cell into cancer stem cell.

Weissman suspects that most cancers develop from mutations in the genomes of stem cells in various tissues throughout the body. "I suspect that a lot of researchers studying different types of cancers are going to be looking for stem cells in their tumors now," says Weissman.

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Al-Hajj, M., et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA Published online February 24, 2003.
Reya, T. et al. Stem cells, cancer, and cancer stem cells. Nature 414, 105-111 (2001).
Miyamoto, T. et al. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci USA 97, 7521-7526 (2000).

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