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Mature cells are designed to stay in one place, anchored in the
tissues that provide them with nutrients and growth signals.
Normally, when cells detach themselves from their neighborhood and
drift away, the body deems them potentially dangerous and assigns a
molecular "death squad" to kill them.
This special type of cell killing is called "anoikis," from the
Greek word for "homelessness." Some cancer cells, however, can
evade these death squads. When they break loose from their
moorings, they survive and can metastasize (spread) to other parts
of the body.
In a recent issue of the journal Science Signaling,
Jean Zhao, PhD, and a team of fellow Dana-Farber scientists added a
new piece to the puzzle of explaining how a series of molecular
changes enables free-floating cancer cells to survive and
The researchers discovered that a little-known protein called
SIK1 has a previously unsuspected role in the destruction of
unattached cells. In laboratory studies they found that when SIK1
is disabled in cancer cells, these cells can survive a loss of
attachment and migrate through the blood stream. Further, an
analysis of samples of human breast cancers revealed that patients
lacking SIK1 activity in their tumors had a worse prognosis.
"When a cell is displaced from its original site, it usually
dies," explains Zhao. "In response to a cell's loss of anchorage,
the protein P53 [a well-known tumor-suppressing gene] becomes
activated. P53 is a major regulator of apoptosis [cell
self-destruction] and anoikis, the specific type of apoptosis that
kills cells that have lost their anchorage."
Scientists still don't understand precisely how the detachment
of a cell triggers P53 activation. But they've shown in mice that
if a tumor is stripped of a functioning P53, it is more prone to
metastasize – in other words, cancer cells can disable P53 so that
they don't need to be tied down to their original location.
Zhao and her colleagues have now demonstrated that P53 needs a
signal from SIK1, a little-studied protein in a family of proteins
known as kinases, so that it can set anoikis in motion. If SIK1 is
knocked out experimentally, or somehow disabled in a cancer cell,
it is resistant to cell death.
In their experiments, the Dana-Farber team – including lead
author Hailing Cheng, PhD, and contributors Pixu Liu, MD, PhD;
ZhigangWang, MD, PhD; Lihua Zou, PhD; Stephanie Santiago; J. Dirk
Iglehart, MD; Alexander Miron, PhD; Andrea Richardson, MD, PhD; and
William Hahn, MD, PhD – showed that when human cells lacking SIK1
were injected into mice, they did not cause large tumors to form.
But further examination showed that the animals' lungs contained
tiny "micrometastases" – minuscule clumps of cancer cells. This
suggests to the scientists that precancerous cells without SIK1
activity can metastasize even before a tumor develops. Once they
have spread around the body, the cells may undergo further changes
making them cancerous.
These results, says Zhao, may explain a "longstanding clinical
mystery." About 10 percent of patients are diagnosed with cancer of
unknown primary (CUP), meaning physicians can't find the original
site of the malignancy. So it's possible that CUP stems from
precancerous cells that didn't initially form a tumor, but traveled
through the circulatory system and later became full-fledged cancer
"Our findings add to the picture that metastasis is not a result
of tumor formation but is a parallel, independent process," Zhao
says. "Metastases can develop before, after, or in parallel to the
– Richard SaltusRichard_Saltus@dfci.harvard.edu
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