NEWS

Cell Fusion Theory: Can It Explain What

Triggers Metastasis?
By Andrea Carter

jnci.oxfordjournals.org

develop blood vessels. These vessels form a

conduit that nourishes the tumor and provide a path for cells to enter the bloodstream. These mobile cells then must land
at another tissue and survive until they can
form more blood vessels.
But no one is sure what drives this process.
One idea is that the gene mutations that lead
to tumors also can result in a cancer cells
becoming metastatic. Another is the epithelial
mesenchymal transition theory, according to
which tumor epithelial cells become more
mobile by turning on transcription factors
used in early embryonic development.
Weinbergs group at MIT has identied several transcription factors expressed by metastatic cells that can contribute to their migration
and ability to form blood vessels. Some of
these are also expressed in immune cells, such
as macrophages, during wound healing.
The fusion theory is consistent with existing knowledge of macrophages. Part of their
job is to travel throughout the body where
needed. Whenever or for whatever, theyll
be there, said Agnes Vignery, D.D.S.,
Ph.D., who studies macrophage fusion at the
Yale School of Medicine. They act as the
immune systems rst defense against invaders, such as viruses and bacteria, and as a
repair system in wound healing, bringing
more blood to the injury. Macrophages also
cluster around cancer cells and have been
associated with a poor prognosis.
Macrophages fuse as part of their job.
They join to form giant cells that wrap around
an intruder so that it cant travel throughout
the body. Macrophages also fuse to become
osteoclasts, cells that recycle bone. According
to Vignery, three macrophages that merge
into one can absorb 10 times as much bone as
they can working separately.
Evidence from laboratory studies shows
that when macrophages fuse with malignant
cells, tumors are more likely to metastasize.
Pawelek has made more than 75 hybrid
clones of human melanoma cells and mac-

rophages and found that more than half of

them were more metastatic in mice than
melanoma cells alone. He injected the hybrid
cells under the skin, killed the animals at
5 months or before, and found that the cancer
had spread in 75% of the cases compared
with the original melanoma cell line, which
spread only 10%15% of the time.
Moreover, human melanoma pathology
and macrophages share some common characteristics. Cytological tests show that when
aggressive melanoma cells break through
the epidermis and spread to the next layer of
skin, the dermis, they express a protein commonly found on macrophages.
Studies since the late 1960s have reported
examples of cancer cells fusing with host
cells in animals and becoming metastatic,
although identifying the type of host cell
involved is difcult. In the early 1970s, scientists injected human brain cancer cells
into the cheeks of hamsters. Harvesting the
metastatic cells, they found human and
hamster genes in the cells chromosomes.
In one experiment, Pawelek put melanoma cells in an albino mouse that could
not produce pigment because of a mutation
in the tyrosinase gene. He found cells in a
metastatic tumor in the lung that produced
pigment. Through fusion, they had gained
the working copy of the tyrosinase gene.
Pawelek said he cant say for certain that it
was macrophages with which the melanoma cells fused, but he did see macrophages surrounding the tumor, and the
cancer cells produced certain sugars that
macrophages produce.
Also consistent with the fusion theory,
researchers have found fused cells in areas of
inammation. A 2008 study in mice reported
that transplanted bone marrowderived
cells that included white blood cells often
fused with brain neurons affected by encephalitis and severe dermatitis. The nding is
intriguing to cell fusion researchers because
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n 1992, John Pawelek, Ph.D., was working with melanoma cells when he read an
article that asked whether the fusion of
cancer cells and white blood cells could lead
to metastasis. Intrigued, he found that his
cells fused easily to white blood cells called
macrophages and that these hybrids resembled metastatic melanoma cells.
Since then, I havent looked back, said
Pawelek, a senior research scientist at Yale
School of Medicine in New Haven, Conn.,
whose primary research focus is now the cell
fusion theory of metastasis. In a May 2008
article in Nature Reviews Cancer, Pawelek and
Ashok K. Chakraborty, Ph.D., also at Yale, lay
out the case for the theory, which could
explain one of the mysteries of metastasis:
What is the trigger that enables cells to break
free from the original tumor and travel to distant sites?
Still unproven, cell fusion theory is
very speculative, said Robert Weinberg,
Ph.D., at the Massachusetts Institute of
Technology in Cambridge, who is also
studying metastasis. But preclinical studies
have convinced Pawelek and others that it
is an intriguing and worthwhile possibility.
His results make it appear likely that cell
fusion happens, he said, but to what extent
and whether it results in metastasis is still
under investigation.
Fusion theory is not new. Digging into
the literature, Pawelek found that the
German pathologist Otto Aichel had proposed the idea in 1911. While viewing cancer biopsy samples under the microscope,
Aichel saw that white blood cells attacked
tumor cells. He proposed that cancer cells
and white blood cells might join, resulting
in the greater number of chromosomes
common in cancer cells and conferring a
malignant cell with the ability to move
through the bloodstream as white blood
cells do.
Scientists know what a cell must do to
metastasize. First, the original tumor must

NEWS

Cell Fusion, continued from page 1279

Oxford University Press 2008. DOI: 10.1093/jnci/djn336

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of evidence associating chronic inammation with some cancers.

There is logical evidence for this theory
in pathology, said Andrzej Slominski, M.D.,
Ph.D., an investigator at the University of
Tennessee Health Science Center in
Memphis, who studies tumor progression.
But the tricky part will be proving it in
people, said Dominik Duelli, Ph.D., of
Rosalind Franklin University of Medicine
and Science, who studies cancer cell fusion
caused by viruses. Researchers cant ethically inject foreign cancer cells into healthy
humans to see whether cancer hybrids form.
And examining hybrid cells from a cancer
patient wont give much insight because all a
persons cells have the same genes.
However, some studies suggest that cancer
cell fusion is happening in people. A 2006
study by Thomas L. Andersen of Southern
Denmark University and colleagues published in the Journal of Pathology found that
30% of osteoclasts collected from a group of
multiple myeloma patients had a gene translocation specic to myeloma cancer cells.
This is a suggestion that fusion is happening,
but it doesnt go beyond that, Duelli said.
Patients who receive bone marrow transplants and later develop cancer also show
evidence of cell fusion. A woman suffering
from lymphoma 20 years ago received a bone
marrow transplant from her son. Years later
she developed a renal cell carcinoma. Pawelek
studied a piece of the tumor, which had cells
with male Y chromosomes. He has looked at
three similar cases. His focus in the next years
is to study more examples of cancer cell fusion
in patients to learn how often it occurs.
In October 2007, Pawelek helped organize the rst meeting on cell fusion and
cancer in Sweden. Seventy-ve scientists
attended, suggesting that interest in the
eld has expanded since Pawelek rediscovered Aichels work 16 years ago. But those
interested in the idea agree that ultimately
it will have to be documented in humans to
have any clinical relevance. Until you can
nd it in people, its still just an idea,
Duelli said.