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Cancer answers skin-deep?
Bill Carter's lab investigates wound repair to learn
more about how the body triggers coordinated growth of cells
By BARBARA BERG
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A protein gel, with data
showing production of variants of laminin 5, a key protein in
the would-repair pathway, draws the attention of (from left)
postdocs Dr. Beth Nguyen and Randy Sigle and Dr. Bill Carter,
whose lab studies the healing of wounds.
-Photo by Theresa Naujack
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Are you accident-prone?
Take comfort!
Your skin's ability to heal wounds from cuts, scrapes and
other insults has a lot to tell scientists about cancer and other
diseases.
Most people take for granted that an unintentional slice of
a finger instead of an onion will heal, with scar tissue taking
the place of an open wound.
But upon closer look, the act of wound healing the growth
of skin cells adjacent to the cut site over a wound area raises
questions remarkably similar to those asked when studying cancer.
How do skin cells know when to begin growing? How do they
know where to grow? And how do they stop growing before invading
surrounding tissue?
By analyzing molecules critical for wound repair, researchers
in the Basic Sciences Division learn more about how the body
triggers coordinated growth of skin cells at the right time and
place.
Cancers of epithelial tissue skin and other body linings account
for 80 percent of all cancers. Dr. Bill Carter, a Basic Sciences
investigator, reasons that regulation of wound repair is an excellent
model for studying skin's normal growth processes.
"Wound repair occurs in a predictable pattern every time,
allowing us to learn more about the steps involved in the pathway
and to use that to understand what might be disrupted in cancer
cells," he says. "In tumors, the only consistency is
variability."
Improved treatment
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Discussing a skin-graft gel
are (from left) medical student Stephen Sullivan and Drs. Paula
Zook and Randy Sigle, postdoctoral fellows, all of the Carter
lab.
-Photo by Theresa Naujack
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In addition to discovering clues to cancer, what researchers
learn may lead to improved treatment for people with chronic
wounds, skin disorders and diabetes. Basic discoveries in wound
repair also are helping Hutch cancer biologists design studies
to test whether molecules important to the repair process could
serve as diagnostic tools to detect epithelial skin and other
body-lining cancers.
"The wound-repair process is like a road-building machine,"
says Dr. Bill Carter, who studies skin healing in his Basic Sciences
lab.
If a hole is poked in skin, the body begins the repair process
by activating cells at the wound site, Carter says.
The activated cells synthesize a protein called laminin 5,
which is deposited in the wound opening much like tar is applied
to a highway under construction.
Carter and his colleagues in 1990 discovered laminin 5 as
a protein that helps skin cells stick to the structural support
called the basement membrane that lies beneath skin.
Inherited disorder
The critical role of laminin 5 is apparent in patients who
suffer from epidermolysis bullosa, an inherited disorder in which
skin fails to adhere to the basement membrane. Sometimes called
blistering disease, EB results from inadequate production of
laminin 5. The acute form of the disease is commonly fatal within
the first year of life.
Interestingly, tumor cells also do not produce laminin 5.
Carter, in collaboration with University of Washington dermatologists,
analyzes skin samples from patients with chronic wounds or skin
disorders to determine whether faulty laminin 5 production is
the culprit.
Cultured skin cells are analyzed for their healing properties
in lab dishes coated with collagen, a protein component of basement
membranes.
As the earliest known molecule to be synthesized after wounding,
laminin 5 is critical to start the healing process.
"Four to six hours after an injury, cells at the edge
of a wound begin to make laminin 5," Carter says.
These cells begin a shift from their normal resting phase
in which they don't synthesize laminin 5 to an activated migratory
phase. The molecular signal that triggers laminin 5 production
is still not known, although likely candidates include growth
factors released by newly exposed underlying connective tissue
and blood clots.
An ant-like walk
Cells at the edge of the wound then literally move, walking
their way across the newly deposited laminin 5 layer much like
ants follow a chemical trail to food.
Just behind the leading edge of migratory cells is a layer
of proliferating cells, triggered to divide so that enough new
cells fill in the wound space.
What is remarkable, Carter says, is that the proliferating
cells are restricted to an area about three or four cells behind
the leading edge, and extend no further.
Recently, he began a project to examine whether improper laminin
5 production plays a role in the chronic wounds which sometimes
lead to amputations after severe infection frequently experienced
by diabetic patients.
"Diabetics can develop skin ulcers, usually because they
can't detect a wound since they suffer from nerve damage,"
Carter says. "We see that these patients have normal cell
proliferation, but that the cells fail to migrate possibly due
to lack of laminin 5 synthesis."
Skin and other epithelial tissues, like those that line the
digestive tract, behave as a continuous sheet with remarkable
intercellular communication properties. Cell-to-cell communication
is mediated by channels between adjacent cells that allow passage
of molecules and enable epithelial sheets to act as synchronous
units.
Dr. Paul Lampe, an investigator in the Public Health Sciences
Division, discovered with Carter that once cells adhere to laminin
5, they begin to form cell communication channels, called gap
junctions.
Gap junctions are not formed between the migratory cells that
make up the leading edge. Interestingly, cell-to-cell communication
also is severely decreased in cancer cells, which typically pay
no mind to their neighbors.
In collaboration with Dr. John Potter in PHS, Lampe will examine
whether gap junction proteins are reduced or absent in colon
tissue of people at risk for colon cancer.
Carter postulates that some aspect of intercellular communication
shuts off synthesis of laminin 5 once cells have adhered to the
basement membrane. Studying how laminin 5 production disrupts
gap junctions in the leading edge of wounds may help scientists
learn more about lack of cellular communication in cancer cells.
Direct applications
Researchers hope that future work with this fascinating molecule
may translate directly into applications for wound healing.
"A possible way to benefit patients would be to provide
a source of laminin 5 and other proteins involved in wound repair
to wounded tissues that lack them," Carter says.
To that end, medical student Stephen Sullivan and postdoctoral
fellow Dr. Randy Sigle are testing whether laminin 5 protein
attached to pieces of plastic termed "Lam-Aids" can
improve wound healing in diabetic mice.
Band-Aids, look out for competition.
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