Exposing the genetic roots of metastasis
CAMBRIDGE, Mass. (June 12, 2007) — Cancer patients
dread hearing that their disease has metastasized (spread
to distant tissues) because this usually means a poor prognosis.
Take breast cancer patients. According to the National
Cancer Institute, nearly 90 percent of women diagnosed
with breast cancer will survive at least 5 years, but
their average life expectancy drops to just 18 to 24
months if the cancer cells have already colonized distant
parts of the body when their initial diagnosis is made.
Scientists are teasing apart the molecular details
of this deadly colonization process.
In 2004, Whitehead Member Robert
Weinberg’s
lab identified two key genes—Twist and FOXC2—that
are generally dormant in adult tissues, but active
in metastatic cells. Working with breast carcinomas
in mice, postdoctoral researchers Jing Yang (now at
the University of California, San Diego) and Sendurai
Mani showed that Twist causes cells to become
invasive, to separate from one another and to spread
to distant sites, which is a prerequisite for
the eventual formation of metastases (see New
insight into cancer metastasis). The results of
this investigation were published in the journal Cell.
Now the Weinberg lab has uncovered the other gene’s
role.
“FOXC2 is very potent in enhancing a cancer
cell’s ability to move and invade through tissues,” says
Weinberg, who is also an MIT professor of biology.
“Most strikingly, FOXC2 is
strongly over-expressed in almost half of invasive
basaloid carcinomas of the breast, which represent
a particularly grim prognosis for the breast
cancer patient,” Whitehead Member Robert
Weinberg says. |
This aggressive behavior is reminiscent of certain
cells in a developing embryo. During the course of
embryo growth, some of the cells within the embryo
lose their connections to one another and travel to
new areas, where they settle and form a number of essential
structures and tissues. Twist helps these “explorers” break
down their associations with their neighbors and FOXC2 helps
them move. The entire process—loss of cell-to-cell
adhesion plus migration—is called the epithelial-mesenchymal
transition (EMT).
The new study, published June 12 in the Proceedings
of the National Academy of Sciences, contributes
to the growing body of evidence that cancer cells
hijack the normal embryonic EMT process and exploit
it for their own purposes. Cancer cells appear to
activate important EMT genes, which are ordinarily
turned off in adult cells, in order to advance metastasis.
“We’ve shown that FOXC2 is necessary
and sufficient to promote metastatic ability in some
cancer cells,” says Mani, first author on the
study.
He began with a colony of fully metastatic breast
cancer cells—capable of seeding primary and secondary
tumors—turned off the FOXC2 gene and
injected the altered cells into the mammary gland of
a mouse. These cells generated primary tumors, but
failed to produce secondary tumors. Mani then reversed
the experiment by taking a colony of nonmetastatic
breast cancer cells, activating FOXC2 and
injecting them into a mouse. In addition to forming
a primary tumor, the former homebodies ventured to
distant tissues and created secondary tumors.
Further experiments allowed him to pinpoint exactly
when FOXC2 arrives on the metastatic scene.
The gene performs heavy lifting after the cancer cell
has already lost its adhesive properties (i.e., after Twist and
other genes initiate an EMT). FOXC2 then directs
the cell to secrete proteins that clear a path around
it, facilitating movement.
But do these results have clinical relevance? Mani
collected a number of human breast cancer samples in
collaboration with Andrea Richardson at Brigham and
Women’s Hospital and checked for FOXC2 activity.
A relationship began to emerge.
“Most strikingly, FOXC2 is strongly over-expressed
in almost half of invasive basaloid carcinomas of the
breast, which represent a particularly grim prognosis
for the breast cancer patient,” Weinberg explains. “It’s
attractive to speculate that the FOXC2 present
in the nucleus of a lot of these tumors is causally responsible
for their aggressive clinical behavior, but we haven’t
proven that yet.” |
