Newly created cancer stem cells
could aid breast cancer research
CAMBRIDGE, Mass. (August 13, 2007) — In some
ways, certain tumors resemble bee colonies, says pathologist
Tan Ince. Each cancer cell in the tumor plays a specific
role, and just a fraction of the cells serve as “queens,” possessing
the unique ability to maintain themselves in an unspecialized
state and seed new tumors. These cells can also divide
and produce the “worker” cells that form
the bulk of the tumor.
These “queens” are cancer stem cells. Now
the lab of Whitehead Member Robert
Weinberg has created
such cells in a Petri dish by isolating and transforming
a particular population of cells from human breast tissue.
After being injected with just 100 of these transformed
cells, mice developed tumors that metastasized (spread
to distant tissues).
“This work could provide a boon to researchers
who study these elusive cancer stem cells by
offering a bountiful source of them,” says
Whitehead Member Robert Weinberg. “Labs
can easily grow the newly created cells for use in experiments.” |
“The operational definition of a cancer stem
cell is the ability to initiate a tumor, so these are
cancer stem cells,” declares Weinberg, who is
also an MIT professor of biology.
Ince didn’t set out to engineer these potent
cells. As a post-doctoral researcher in the Weinberg
lab and gynecologic pathologist at Brigham and Women’s
Hospital, he was simply trying to create breast cancer
models that look like real human tumors under the microscope
and behave like those seen in many patients.
In more than 90 percent of human breast tumors, cancer
cells resemble those lining our body’s cavities.
A trained pathologist can spot the similarities under
a microscope. But the cancer cells previously engineered
from normal breast cells for laboratory studies looked
different. Ince suspected that researchers were transforming
the wrong type of cells.
Now an independent investigator at Brigham and Women’s
Hospital and an instructor at Harvard Medical School,
Ince developed a recipe for a new chemically defined
culture medium and managed to grow a different type
of human breast cell that ordinarily dies in culture.
He transformed it into a cancer cell by inserting specific
genes through a standard procedure.
The engineered cells proved to be extremely powerful.
When Ince injected more than 100,000 of them into a
mouse with a compromised immune system, it quickly
developed massive, deadly tumors. In initial experiments,
a few tissue slices revealed a primary tumor structure
that resembled that of cancer patients with metastases.
That prompted Ince to wonder whether the cancer cells
he created would metastasize if the mouse lived longer.
He repeated the experiment in other mice, reducing
the number of cells in the injection to as few as 100
in hopes of slowing tumor growth. The cancer cells
continued to seed tumors and those tumors metastasized.
In sharp contrast, scientists must inject about 1 million
cells to get a tumor when working with the cancer cell
lines routinely used in the laboratory.
“In the process of making a model that reflects
a tumor type common in patients, I created tumor-initiating
cells,” Ince explains. “That was a complete
surprise.”
“This work could provide a boon to researchers
who study these elusive cancer stem cells by offering
a bountiful source of them,” maintains Weinberg. “Labs
can easily grow the newly created cells for use in
experiments.”
The study, which appears in Cancer Cell on
August 13, also offers clues about the trajectory of
cancer cells. A normal cell is thought to evolve progressively
toward a malignant state through a series of genetic
mutations. The early alterations confer uncontrolled
growth, while later alterations enable the cell to
migrate and invade other tissues. Over the past decades,
considerable effort has gone into discovering these
tumor-initiating and metastasis-initiating genetic
alterations.
The new study suggests, however, that some normal
cells are more prone to become tumor-initiating cells
and have a higher metastatic potential when they become
cancer cells than other normal cells. The culture medium
Ince created favors the growth of the human breast
cells with high tumor-making and metastatic potential
while the standard culture medium favors cells with
low tumor-making potential. Although the two types
are only slightly different, the cells behave completely
differently after acquiring the same mutations.
Ince confirmed this behavioral difference by taking
a single human breast tissue sample, splitting it in
two and growing the cells in the two culture mediums,
which select for different cells. Next, he transformed
the two populations with the same tumor-initiating
genes, injected them in mice and watched the result.
The cells that were grown in the new culture medium
were 10,000 times more potent as tumor initiators and
were the only ones able to metastasize. Thus genes
that were previously thought to only initiate tumors
initiated metastasis, which is the main cause of cancer
mortality in the clinic.
“Tan has demonstrated that a critical determinant
of eventual metastasis is the identity of the normal
cell type that preexists in the breast and becomes
the object of mutation and selection,” Weinberg
says.
This research is funded by the Breast Cancer Research
Foundation and the National Institutes of Health. |
Overview
of pathologist Tan Ince's study [
