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Once the tumor cells get stuck, they then have to invade
the tissue of the target organ. To do this, proteins known
as matrix metalloproteinases are necessary. Felding-Habermann
has discovered a connection between a metalloproteinase, called
MMP-9, and the activated form of adhesion receptor integrin
avb3,
which is typical for metastatic breast cancer cells.
MMPs are secreted as latent enzymes that need to be trimmed
into their active formats. The active enzymes play a number
of important biological roles in both the early development
of organ structures and in tissue remodeling. Their physiological
function is to remodel the extracellular matrix, and because
of the potential damage that this could do to tissues, MMPs
are some of the most highly regulated enzymes in the body.
Unfortunately, this sophisticated regulation does not prevent
cancer cells from subverting MMPs for their own purposes.
Cancer cells and the surrounding host tissuesecrete these
enzymes. Invasive cancer cells can undo the tight regulation
of MMP activation in order to break free of the extracellular
matrix and tissue stroma, allowing them to move. It also allows
them to dissolve barriers that get in their way to the bloodstream
or to distant tissues during metastasis. Not surprisingly,
MMPs are often overexpressed in cancer cells.
Felding-Habermann says that metastatic breast cancer tumor
cells that carry activated integrin avb3
seem to be able to convert MMP-9 into its active form. She
is looking at how this interaction leads to the invasion of
tissue by the cancer cells. But that will have to wait for
another day.
"Hopefully in a couple months," she says.
Targeting Breast Cancer Metastasis
The title of Felding-Habermann's talk, is, after all, Targeting
Breast Cancer Metastasis. "So can we target this molecule?"
she asks.
Felding-Habermann has found a way to inhibit the attachment
and remove the metastatic ability of breast cancer cells with
special antibodies.
She teamed up with TSRI Professor Kim Janda, who had generated
a phage display antibody library from blood samples from 20
cancer patients.
Phage display is a method for selecting from billions of
protein variants those that bind to a particular target. In
the technique, libraries of antibodies are fused to the viral
coat protein of the phage—a filamentous virus that infects
bacteria. Then the virus is allowed to reproduce in culture,
where it makes new copies of itself and the antibody library.
Since the phage particles display these proteins at their
surface, a scientist can select antibodies in vitro by passing
the viral stew over a stationary phase containing the target
substrate—in this case metastatic breast cancer cells
that carry the activated integrin. Since metastatic and non-metastatic
breast cancer cells share so many surface molecules, the trick
was to pull out first all of those antibodies that would react
with both cell types.
This allows one to isolate antibodies that were present
in the blood of cancer patients and recognize metastatic tumor
cells.
"It's not representing the entire antibody repertoire, but
what was actually expressed at the time these blood samples
were taken," says Felding-Habermann.
Presumably some of these antibodies target the cancer cells.
After all, one of the jobs of the immune system is to reject
tumor cells. The question was if any of these antibodies would
bind to the activated form of integrin avb3
on the metastatic cancer cells she was studying.
"We wound up with some antibodies that are very interesting,"
says Felding-Habermann. "They bind to the integrins, and they
bind in a way that natural ligands would bind."
Importantly, they bind selectively to the activated form
of the avb3
integrin. This, Felding-Habermann found, allows them to inhibit
the integrin's binding functions, which in turn prevents the
cancer cell from attaching to platelets, and effectively blocks
their ability to arrest in the blood stream.
"What this tells us is that cancer patients can produce
antibodies that may very actively interfere with [metastasis],"
she says. In fact, in her early in vivo tests, the
antibodies effectively inhibited metastasis of human breast
cancer cells in a mouse model.
The Felding-Habermann and Janda labs are now trying different
ways of applying the antibodies to see how they might be useful
in the clinic. They are still in the very early stages of
developing this technology, but it might be used as a vehicle
to target a powerful anticancer drug to metastatic cells.
This, she says, is the information she is going to present
at the Molecular and Experimental Medicine retreat—whose
participants include some collaborators with whom she made
these discoveries.
"One great thing I appreciate here at Scripps is that you
can have very exciting collaborations," says Felding-Habermann.
"My work has really benefited from all of these interactions."
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