Tissue Stiffness Drives Tumor Formation
Paying attention to the mechanical forces that regulate cell
is important to understanding tumorogenesis
(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.
Weaver 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 cytoskeleton.
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.
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