(Philadelphia, PA) - The relationship between
tissue rigidity and tumor formation is fairly well established;
however, what is not so well understood is what happens on a molecular
level that contributes to such stiffness. Now, for the first time,
researchers at the University of Pennsylvania School of
Medicine have shown that tumor formation is generated by
a complex interaction of both mechanical as well as chemical signals,
and the resulting tissue stiffening induces molecular signals that
promote the cancerous behavior of cells. Penn’s interdisciplinary
research team – drawn from the fields of Biomedical Engineering
and Cell and Developmental Biology – has demonstrated clearly
that force, growth, and tumor behavior are inextricably linked and
this enhanced understanding of the necessary fusion of these factors
may lead to the development of new tumor therapies or targets.
“This study identifies the connection between oncogenes and
the mechanics of the cell and its microenvironment in animal and
culture experimental models,” explains senior author Valerie
Weaver, PhD, Assistant Professor of Pathology and Laboratory
Medicine. “Specifically, we have defined the vitality of mechanical
force as an integral factor in tumor development.” Weaver
and colleagues published their findings as the cover-story in the
September issue of Cancer Cell.
and first authors, Matthew J. Pascek and Nastaran
Zahir – both graduate students in Bioengineering
– used a three-dimensional gel on which they grew breast cancer
cells and could precisely control and measure the stiffness of the
surrounding microenvironment. “We found that tissue rigidity
enhances cell growth and destroys tissue organization to promote
tumor-like behavior in normal cells,” says Pascek. “This
happens because the stiffness helps to activate key growth signaling
pathways and increase cell tension.”
Cells use surface receptors called integrins to communicate with
the outside tissue environment, which consists primarily of connective
tissue. Integrins regulate cell growth, death, and movement, as
well as tissue organization. Integrins also play a role in cell
division and proliferation through ERK, an extracellular signal-regulating
molecule. Despite the fact that integrins were discovered and their
activity found to be aberrant in tumors decades ago, how integrins
could become altered and their importance to cancer has remained
contentious among researchers.
Weaver and colleagues found that tissue stiffness induces tumor-like
behavior in cells through ERK and Rho, another regulatory molecule.
Although researchers have long appreciated that oncogenes such as
Ras and Erb2 drive cell growth via the ERK pathway, this study showed
how high levels of ERK also prime a cell to contract more via integrins.
Integrin activity also regulates the Rho molecular pathway, which
in tumors regulates the stiffness of the cytoskeleton, a collection
of protein filaments within a cell that give shape and the capacity
for directed movement. When the researchers increased the stiffness
of the gel in which experimental cells were grown, Rho activity
increased, as well as the number and size of focal adhesions, clusters
of integrins that create a connection between integrins and the
Overall, the researchers found that a self-perpetuating program
of tissue destruction is set up – through changed integrin
signaling – to create a double-pronged drive toward aberrant
cell behavior. Both the stiffness of connective tissue surrounding
developing tumors and the increased activity or expression of oncogenes
can promote cells to become cancerous. For example, the researchers
found that as stiffness increased in connective tissue, the cells
of a normal breast duct started to grow atypically, causing the
structure of the duct to degrade, as the uncontrolled cell growth
of duct-lining cells invaded the duct tube.
The researchers also discovered that when cell tension becomes great
enough, it overrides normal tissue behavior, but is reversible.
“We showed that some breast tumors with elevated signaling
for the growth factor ERK also have high tension and that their
behavior would return to normal by inhibiting cell tension,"
says Zahir. With this knowledge, Weaver's group is now looking to
see whether drugs that inhibit cell contractility could help prevent
early metastasis. They are also fine-tuning how different cell types
react to different levels of stiffness and how this is important
for normal cell behavior, as well as aberrant activity and structure.
This research was funded by the Department of Defense and the National
Institutes of Health. Co-authors are Kandice R. Johnson, Johnathon
N. Lakins, Gabriela I. Rozenberg, Amit Gefen, Cynthia A, Reinhart-King,
Susan S. Margulies, David Boettinger, and Daniel A. Hammer, all
from Penn; as well as Mica Dembo from Boston University.
PENN Medicine is a $2.7 billion enterprise
dedicated to the related missions of medical education, biomedical
research, and high-quality patient care. PENN Medicine consists
of the University of Pennsylvania School of Medicine (founded in
1765 as the nation's first medical school) and the University of
Pennsylvania Health System.
Penn’s School of Medicine is ranked #2 in the nation
for receipt of NIH research funds; and ranked #4 in the nation in
U.S. News & World Report’s most recent ranking of top
research-oriented medical schools. Supporting 1,400 fulltime faculty
and 700 students, the School of Medicine is recognized worldwide
for its superior education and training of the next generation of
physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes: its
flagship hospital, the Hospital of the University of Pennsylvania,
consistently rated one of the nation’s “Honor Roll”
hospitals by U.S. News & World Report; Pennsylvania Hospital,
the nation's first hospital; Penn Presbyterian Medical Center; a
faculty practice plan; a primary-care provider network; two multispecialty
satellite facilities; and home health care and hospice.