Photo by Clay Eals
Getting to know your neighbors can go a long way toward building a healthier community, leading to lower crime rates and safer streets.
Likewise, skin cells benefit from neighborly communication. It may even prevent the body's version of urban sprawl - the onset of cancer.
Signals between adjacent cells provide essential cues for normal growth and division. Just one missing component of this cell-to-cell communication network may be enough to turn cordial relationships sour and trigger the earliest events of cancer.
Understanding the language between cells is the research focus of Hutchinson Center cancer biologist Dr. Valeri Vasioukhin, who studies the interplay between cell-to-cell adhesion - properties that enable cells to seal tightly against one another - and malignant disease.
Skin and other epithelial layers that line organs and body cavities can form smooth barriers because they consist of cells anchored together by specialized junctions. More than just intercellular glue, these so-called "adherens junctions" consist of proteins that connect cells, form the telephone wires for the passage of messages and even the messages themselves.
When intact, this communication system relays signals that prevent epithelial cells from overstepping their bounds. Pre-cancerous cells, on the other hand, may have incomplete junctions and turn a deaf ear toward communication, growing beyond their property lines and ultimately forming tumors.
Their behavior, said Vasioukhin, who joined the Human Biology Division in September, is distinctly unneighborly.
"What I think is happening is that these cells are unable to sense that they have neighbors," he said. "When grown in the laboratory, instead of forming a layer of cells in a culture dish, they begin to pile up on top of one another."
In fact, Vasioukhin said, these cells exhibit characteristics of those located near a wound site.
"In epithelial layers, cell membranes are sealed against one another by specialized junctions that might prevent cells from overgrowing and over-dividing," he said. "But when there is a wound, cells recognize that they have lost contact with their neighbors and begin to divide and migrate toward the wound. In some cancers, we know that proteins that help form the junctions are defective, preventing important signals from being transmitted between neighboring cells."
Vasioukhin discovered that loss of a single key component of adherens junctions, a protein known as alpha-catenin, seems to play a direct role in abnormal cell growth, a finding that division director Dr. Barbara Trask described as a tour de force.
Cancer biology 'on fire'
"Valeri's work to understand the relationship between cell adhesion and cell proliferation and metastasis is really going to set the field of cancer biology on fire," she said. "And his ability to move with ease among the disciplines of proteomics, cell biology, biochemistry and animal models epitomizes the type of interdisciplinary research we're trying to foster."
Vasioukhin, who completed postdoctoral studies with Dr. Elaine Fuchs at the University of Chicago, embarked on this project after noting observations that had been made in several tumor types.
"It was known already that in a number of cancers, cadherin and alpha-catenin - two proteins found in adherens junctions - are down-regulated or absent," he said. "We decided to test whether, in the absence of other mutations, the loss of alpha-catenin causes skin cells to adopt characteristics of cancer."
No contact inhibition
The results were striking. Mice whose skin lacks alpha-catenin have characteristics similar to squamous-cell carcinoma in situ, a precancerous skin condition. What's more, those same skin cells, when cultured in the laboratory, grow rapidly and no longer exhibit contact inhibition - the cessation of growth when cells bump into those around them.
Most intriguing about Vasioukhin's findings is that they point to a previously undescribed role for alpha-catenin. Earlier studies had suggested that defects in adherens junctions primarily affect a tumor's ability to become invasive and to metastasize, or spread to distant sites. But Vasioukhin is the first to show that defects in cell adhesion can trigger the earliest steps of tumor growth.
The key now, he said, is to define both the signals sent by adherens-junctions proteins and their targets.
"What are the molecular mechanisms at work here?" he asked. "We still don't understand. One possibility is that these proteins regulate specific pathways that play important roles in governing cell proliferation."
Vasioukhin's next goal is to compare patterns of gene expression in normal and alpha-catenin-deficient cells to identify the pathways that are sensitive to cell adhesion function.
He also plans to expand his research to include the study of prostate tumors, which have been shown to have defects in cell adhesion. The first step will be to investigate the mechanisms of normal cell adhesion in the prostate gland and compare that to the cancerous condition.
Studies of the fruit fly Drosophila also may shed light on the connection between cell adhesion and cancer.
"Several known tumor-suppressor proteins in Drosophila also disrupt cell adhesion," he said. "We plan to look for the analogous genes in higher organisms to investigate their potential role in cancer."
Trained as a cell biologist at the Institute of Cytology of the Academy of Sciences of the USSR, in Leningrad, Vasioukhin, a native of Russia, has spent most of his career tackling problems in cancer biology.
As a graduate student, he developed techniques that could be used to detect cancers by using a simple blood test.
"Cancer patients have DNA from tumor cells in their blood that could potentially be used for early disease detection," he said. "The technique also could be useful for monitoring response to treatment."
After graduate school, he conducted research in Dr. Angela Tyner's lab at the University of Illinois at Chicago, studying breast-tumor kinase, a signaling protein that has been implicated in breast and colon cancer.
With his background in cancer biology, Vasioukhin hoped to move to a cancer research center with a collaborative environment. He found his match at the Hutch.
"There is such a collegial atmosphere here," he said. "You can feel the difference here as soon as you enter the building."