[http://www.genomenewsnetwork.org/articles/03_03/stem_c.shtml]
The Real Problem in Breast Tumors: Cancer Stem Cells By Nancy
Touchette, March 7, 2003
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).
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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