The
Petersen-Bissell collaboration used milk mucin (MM) to mark luminal-like and
CD271 to mark basal-like cancer cells in primary tumors and tumor cell lines.
The MM stain is red, the CD271 stain is green, and nuclei are stained blue.
Inset in A shows staining of normal breast tissue for comparison. Credit:
Bissell-Petersen collaboration
New findings in breast cancer research by an
international team of scientists contradict the prevailing belief that only
basal-like cells with stem cell qualities can form invasive tumors. Research
led by Ole William Petersen at the University of Copenhagen (CU) and Mina
Bissell of the Lawrence Berkeley National Laboratory and has shown that luminal-like
cells with no detectable stem cell qualities can generate larger tumors than
their basal-like counterparts. This may hold important implications for the
diagnosis and the treatment of breast cancer as well as future personalized
cancer medicine.
"It
is fashionable to think of breast cancer as a disease that can be treated if
cancer stem cells are
killed off, but we are reporting a sub-population of cancer cells that have no
obvious stem cell properties and yet can be tumorigenic and highly
aggressive," Bissell says. "The existence of these additional
sub-populations of tumorigenic cells tells us that the entire tumor needs to be
eradicated, not just one sub-population of basal-like cells."
Bissell
is a leading authority on breast cancer and a Distinguished Scientist with
Berkeley Lab's Life Sciences Division. Petersen is a professor of Tissue
Morphogenesis and Differentiation for CU's Cellular and Molecular Medicinedepartment
and a principal investigator for the Danish Stem Cell Center.
They
are the corresponding authors of a paper in the Proceedings
of the National Academy of Sciences that describes this work. The
paper is titled "Tumor initiating but differentiated luminal-like breast cancer cells are
highly invasive in the absence of basal-like activity."
Other
co-authors were Jiyoung Kim, René Villadsen, Therese Sørlie, Louise Fogh, Signe
Grønlund, Agla Fridriksdottir, Irene Kuhn, Fritz Rank, Vera Timmermans
Wielenga, Hiroko Solvang, Paul Edwards, Anne-Lise Børresen-Dale and Lone
Rønnov-Jessen.
"Our
findings were a surprise to us as we had hypothesized the opposite
scenario," Petersen says. "We wanted to learn more about possible
tumor suppressive properties so we set out to characterize the bulk of the
tumor, which we assumed would not be tumor-initiating."
Most
breast cancers originate in the milk ducts and lobules, which consist of
luminal cells surrounded by basal cells, and the two most frequent subtypes of
human breast cancer cells are named luminal-like and basal-like after their
resemblance to the two major lineages in the normal human breast.
For the
past several years, it has been widely believed that basal-like cells with the
undifferentiated qualities of stem cells were the source of invasive tumors.
However, since a majority of breast cancers exhibit luminal cell
differentiation, the Petersen-Bissell collaboration investigated whether
luminal-like differentiated cells within a basal-like cell hierarchy could also
become tumorigenic, or must these luminal-like cells acquire basal-like traits
to become malignant.
"We
applied some rare and mutually exclusive lineage markers to isolate subsets of
luminal-like and basal-like breast cancer cells, which enabled us to do single
cell cloning with a reasonable success rate," Petersen says. "We
enriched for populations with or without prominent basal-like traits from
individual tumors, and from single cell cloning of cell lines and recovered
cells with a luminal-like phenotype."
What
they discovered was that luminal-like cells without specific basal-like traits
were fully capable of initiating tumors in laboratory test mice; in fact, the
tumors generated by luminal-like cells were larger than those from basal-like
cells. In addition, when tested in an invasion assay, these phenotypically pure
luminal-like cells were more invasive than the basal-like cells.
"Our
findings demonstrate that basal-like cells, as defined currently, are not a
requirement for breast tumor aggressiveness and that within a single tumor
there are multiple cells with tumorigenic potential," Bissell says.
"This casts doubt on the current hypothesis of hierarchical or
differentiative loss of tumorigenicity."
The
marker used by the Petersen-Bissell collaboration to isolate the luminal-like
cancer cells was milk mucin (MM), one of the glycans, the sugar molecules that
are ubiquitous to cell surfaces and central to cellular signaling. Basal-like
cancer cells were marked with the protein CD271. The MM glycan was detected by
the antibody M18. The CD271 marker was detected by the ME20.4 antibody.
In
their investigation, the collaborators found that the ability of the
luminal-like breast cancer cells to form large invasive tumors depended on the
expression of the glycoprotein gene GCNT1, which in turn is required for the MM
glycan to be detected by the M18 antibody. The collaborators believe this
finding might be of potential clinical importance for breast cancer as
co-author Kuhn, a member of Bissell's research group, explains.
"There
has been an increasing appreciation that glycans play an important role in
malignant behavior and our work shows that inhibiting the activity of GCNT1
could prevent the invasive behavior of the aggressive luminal-like cancer cells
if they express the MM epitope," she says.
While
Petersen emphasizes that any clinical implications of this work remains
speculative at this time, the finding that multiple types of cells in breast
cancers are capable of initiating invasive tumors, he says, could hold
implications for future personalized medicine.
"While
new avenues in breast cancer targeting have been strongly influenced by the
concepts of tumor subtypes and cancer stem cells, we believe our data and
recent data from other laboratories opens the possibility of targeting
individual stages of differentiation of breast cancer cells within a
tumor," Petersen says. "In that way personalized medicine in the
future could rely on a cellular-composition-profile with each cellular
component accounted for in the treatment design."
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