Stem Cells May Be at Root of Cancer

Are most current cancer treatments -- as
well as many in development -- aimed at eradicating the wrong cancer cells?

That's the position of some leading researchers, who say that cancer is,
fundamentally, a stem cell problem -- and that therapy should be targeted at
so-called cancer stem cells.

"The models we currently use to develop cancer treatments are
fundamentally flawed," says Max Wicha, MD, director of the University of
Michigan Comprehensive Cancer Center in Ann Arbor.

B "Most approaches up to now are targeting the wrong population of
cancer cells," which explains why so many fail to produce a cure, he tells
WebMD.

At the annual meeting of the American Association for Cancer Research here
this week, Wicha moderated a session during which researchers discussed new
discoveries suggesting that stem cells in leukemia, breast, and colon cancer
are at the root of many tumors.

A Primer on Cancer Stem Cells

All stem cells -- regardless of their source -- share some general
properties: They can reproduce and make exact copies of themselves, they live
longer than ordinary cells, and they can give rise to other cells in our
bodies.

Embryonic stem cells are a hot, if controversial, area of research. They are
at such an early stage of development that they have potential to become many
different types of cells, including those of the heart or brain, for
example.

Adult stem cells, on the other hand, are generally limited to
differentiating into cell types of their tissue of origin. Under typical
conditions, for example, adult stem cells in liver tissue can only form liver
cells, Wicha explains.

In labs worldwide, scientists are working furiously to figure out how to use
both embryonic and adult stem cells to produce virtually unlimited quantities
of healthy cells to replace the damaged ones in patients suffering from
disorders ranging from Alzheimer's to Parkinson's disease.

Cancer stem calls are a perversion of other adult stem cells. "They are
cells that have the ability to reproduce themselves and develop into cancer
cells," Wicha says.

A New Model for Cancer

Wicha says that the current model of what causes cancer assumes that cells
become malignant after a series of mutations disables their genetic control
system.

"In this theory, any cell that gets the right series of mutations can
become cancer," he says.

In the stem cell hypothesis, cancer is driven by specific cells that contain
stem cell properties, Wicha says. These cells then reproduce and replenish
malignant tumors.

Currently, most treatments target cancer cells, but not necessarily cancer
stem cells, he says. While the treatment may shrink the tumor and keep it in
check for a while, eventually, the untreated cancer stem cells proliferate into
cancer cells, leading to a return of the tumor and death, he says.

If the treatments targeted the cancer stem cells, however, the tumor would
lose the ability to generate new cancer cells, eventually resulting in a cure,
Wicha says.

Think dandelions, says researcher Peter Chu, PhD, of Biogen Idec in San
Diego. "If you cut a weed and don't get the root, it will grow back,"
he tells WebMD. "So if you don't [kill off] cancer stem cells, you're not
going to see better long-term survival."

Wicha notes that the concept that stem cells cause cancer is not new. But
recent advances in molecular biology -- such as the development of tests that
allow researchers to locate and measure the cancer stem cells -- are giving it
new credibility, he says.

Stem Cells Drive Aggressive Breast Tumors

Experiments in Wicha's lab show that two genes, PTEN and HER2/neu, that are
associated with aggressive breast cancers have stem cell properties. Defects in
either gene are tied to faster-growing tumors that are more likely to
return.

The researchers studied thre types of genetically altered breast cancer
cells: One had the PTEN defect, one had the HER2/neu defect, and one had both
genetic alterations.

Results showed that that either defect increases the stem cell population by
two to five times. Furthermore, there was an approximately tenfold increase in
the stem cell population when they created a cell line with both PTEN and
HER2/neu defects.

Then, the researchers injected the three types of genetically altered cells
into mice. Cells with either defect induced the growth of tumors that were
fourB to six times more aggressive than normal. Injection of the cells with
both alterations caused tumors that were 10 times more aggressive.

Wicha believes the experiments may help explain why Herceptin, the biologic
therapy that targets the HER2 protein on cancer cells, works so well.

"We believe that knocking out the tumor-causing cancer stem cells
explains why Herceptin reduces that chance of cancer coming back by 50% [in
women with HER2 positive breast cancer], although that remains to be
proven," he says.

Stem Cells Drive Colon Cancer

In another experiment, Chu and colleagues sorted colon cancer cells
according to a molecular marker known as CD44 that appears on their
surface.

The marker was chosen because it fit the bill for a cancer stem cell, with
earlier studies showing it "possessed a capacity to reproduce itself,
regenerate, and produce tumors similar to the tumor of origin," he
says.

Then, the researchers injected cells producing various amounts of CD44 into
mice. Results showed that the mice developed tumors after being injected with
as few as 10 cells producing high amounts of CD44. That's not many, when you
consider there are billions of cells in the body, Chu says.

Cancer cells that did not have CD44 on their surface were far less driven.
Researchers had to inject 5,000 or more of these cells into the mouse to induce
tumor growth, he says.

Wicha notes that CD44 is present on the surface of lung, breast, and many
other types of cancers as well. What this suggests, he says, is that novel drug
treatments blocking CD44 would curb the growth of many tumor types, not just
that of the colon.

Radiation Enhances Cancer Stem Cell Growth

In a third study reported at the meeting, researchers from the Ontario
Cancer Institute found that cancer stem cells may help explain why women with
breast cancer who are successfully treated with radiation are at increased risk
of developing leukemia down the road. Radiation therapy in mice enhanced blood
stem cell growth which could lead to increased risk for leukemia.

Wicha cautions that while all the research is exciting, there's still a long
way to go.B "This is obviously a very important and exciting area of
research with great potential," says Len Lichtenfeld, MD, deputy chief
medical officer of the American Cancer Society in Atlanta.

"A lot of people believe, and rightly so, that it may help provide the
answers we have been looking for," he tells WebMD.

At the same time, "we do have to be cautious," says Lichtenfeld,
noting that researchers have had other promising theories about how cancer
develops that did not prove to hold true after rigorous examination.

By Charlene Laino
Reviewed by Louise Chang
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