Stanford Scientists Identify Molecular Powerbrokers Involved in Cancer`s Spread

STANFORD, Calif.--(Business Wire)--
You know the guy-he`s your Facebook friend. The one who knows everyone. Secure
at the center of a dense web of relationships, he suggests causes and reconnects
old friends like a skilled matchmaker. Scientists have known for some time that
biological molecules interact with one another in a similarly complex pattern.
Now researchers at the Stanford University School of Medicine have determined
that hamstringing these molecular powerbrokers is a good way to derail processes
such as cancer development.

"It`s like social networking," said Paul Khavari, MD, PhD, professor of
dermatology at the medical school. "If you take the most highly interconnected
person and somehow hinder his access to a computer, the network may fall apart."
Although the Stanford researchers were focusing on tumor invasion and
metastasis, their expectation is that a similar approach could be used to
identify potential targets for many different diseases.

Khavari, who is also a member of Stanford`s Cancer Center and Bio-X, is the
senior author of the research, which will be published in the June issue of
Cancer Cell. He is also the clinical chief of the dermatology service at the
Veterans Affairs Palo Alto Health Care System.

Khavari and genetics graduate student Jason Reuter used the concept of
biological networks to investigate how cancers progress from a growing lump of
unruly cells to an invasive, potentially deadly tumor. They found that
inhibiting a molecule called beta-1 integrin blocked the ability of the cells to
grow and invade surrounding tissue.

"Ninety percent of all human tumors, including breast, lung, prostate, colon,
pancreatic and skin cancers, arise in the epithelial tissue that lines body
surfaces," said Khavari. "None of these tumors become highly dangerous to a
person unless they invade through the underlying basement membrane and begin to
spread to other tissue."

To conduct the research, Khavari and Reuter devised the first-ever
three-dimensional model of inducible human tissue tumor development by grafting
genetically engineered human skin tissue onto mice with compromised immune
systems. They then treated the mice with a compound that activated an introduced
cancer-causing gene in the modified human tissue, and monitored gene expression
in the tumor and the surrounding tissue as the skin cancer developed and began
to invade.

"This approach has been able to recapitulate in real time the progression from
normal epithelial tissue to invasive cancer," said Khavari, "and now this model
is being used to systematically identify the key genes in this process." He and
Reuter identified more than 700 genes whose expression patterns deviated from
normal during cancer development. They used an existing database to map the
genes into functional networks, which varied as the tumor developed.

"A specific set of genes emerged during early tumor development," said Khavari,
"which gave way to others as the tumor began to invade surrounding tissue."
During early growth, for example, the researchers identified networks in the
cancer cells that were involved in cell division and in the surrounding tissue
that were involved in the formation of blood vessels to feed the growing tumor.
As the cancer progressed, they saw the emergence of networks involved in cell
movement and attachment and in remodeling of the extracellular matrix.

As in the Facebook example, the researches focused on those gene products in the
networks that were the most highly connected. Sixteen of the top 25 molecules
are found either on the surface or between the tumor cells, indicating that the
tumor is actively involved in remodeling its surrounding environment. Beta-1
integrin, a member of a family of proteins involved in mediating attachments
between cells, was the third-most well-connected. Khavari and Reuter found that
blocking the activity of beta-1, which has been implicated in the growth of
several human cancer cell lines, slowed the growth of both established and newly
developing tumors in their model and seemed to lead to a more clearly defined
border between the tumor cells and the surrounding normal tissue.

"Beta-1 integrin proved important in the co-evolution of the tumor and its
supporting framework, the stroma, toward malignancy," said Khavari. He and his
lab members plan to continue their analysis of other genes in the network, and
to try to optimize their model for other types of cells and cancers. "We are
working to build models like this for many other epithelial tissues so we can
begin to identify the underlying global mediators of cancer progression."

In addition to Khavari and Reuter, other Stanford researchers involved in the
study include postdoctoral scholars Susana Ortiz-Urda, MD, PhD; Anna Pasmooij,
PhD; and Markus Kretz, PhD; graduate student John Garcia; research associate
Florence Scholl, PhD; and associate professor of dermatology Howard Chang, MD,
PhD. The research was funded by the Veterans Affairs Office of Research and
Development and by the National Institutes of Health.

The Stanford University School of Medicine consistently ranks among the nation`s
top 10 medical schools, integrating research, medical education, patient care
and community service. For more news about the school, please visit
http://mednews.stanford.edu. The medical school is part of Stanford Medicine,
which includes Stanford Hospital & Clinics and Lucile Packard Children`s
Hospital. For information about all three, please visit
http://stanfordmedicine.org/about/news.html.

Stanford University School of Medicine
Krista Conger, 650-725-5371 (Print Media)
kristac@stanford.edu
M.A. Malone, 650-723-6912 (Broadcast Media)
mamalone@stanford.edu

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