A syringe needle serves as the heart of a new, experimental microfluidic
protocol to expose cancer cells to fluid shear stress. A new UI study suggests
that resistance to fluid shear stress may be a biomarker for cancer cells,
which could be used to improve detection and monitoring of circulating cancer
cells in blood.
A surprising discovery about the
physical properties of cancer cells could help improve a new diagnostic
approach – a liquid biopsy – that detects, measures, and evaluates cancer cells
in blood.
Cancer cells circulating in the
bloodstream can form metastases – new tumors. Detecting these rare circulating
cancer cells in a blood sample is much less invasive than a standard tumor
biopsy, and could prove useful for monitoring cancer progression and
detecting recurrence.
While studying what happens to
cancer cells when they are subjected to powerful fluid forces, like those
encountered in the bloodstream, researchers at the University of Iowa
unexpectedly discovered that cancer cells are actually more likely to survive this
turbulent fluid environment than normal epithelial cells.
The researchers suggest this
surprising "hardiness" could be a potential biomarker for detecting and
studying cancer cells in the blood. The findings were published Dec. 3 in the
journal PLOS ONE.
"For many years, it's been
assumed that these circulating cancer cells are quite fragile, and they
essentially get 'blended' by the fluid forces in the blood," says Michael
Henry, Ph.D., associate professor of molecular physiology and
biophysics at the UI Carver College of Medicine and lead study author.
"But there was no real direct evidence for how fluid forces in the blood
affect cancer cells.
"What we found was that
normal cells were, as expected, quite sensitive to the fluid forces and most
did not survive. But, surprisingly, the cancer cells seemed to be remarkably
resistant."
Henry suggests that resistance to
fluid shear stress might be a way to distinguish benign from malignant cells in
circulating tumor cell samples.
"By adding this really
simple physical test to the isolation of circulating tumor cells,
this technique might let us sort out malignant cells from benign cells. Being
able to quantify the numbers of 'dangerous' cells might be a more accurate
prognostic marker for the patient than simply counting the total number of
circulating tumor cells," says Henry, who also is deputy director for
research with Holden Comprehensive Cancer Center at the UI.
A simple system
Using a simple syringe and
precise mathematical calculations of fluid dynamics, the UI team created an
experimental system to mimic the short bursts of turbulent flow that a cancer
cell might experience in the blood. Passing a suspension of cells through the
syringe needle allowed the researchers to study the effect of a series of
millisecond pulses of high fluid shear stress on a variety of different cancer
cell types (prostate, breast, and melanoma) as well as normal epithelial cells
from breast and prostate tissue.
After 10 passages though the
syringe needle at high flow rate, around half of the cancer cells were still
alive. In contrast, very few normal epithelial cells survived the process.
Closer examination of the cell
survival data revealed an additional twist. The rate at which the cancer cells
are destroyed by passage through the syringe is not constant over all 10
passages. Instead, exposure to fluid shear stress during the earlier passages
seems to trigger adaptive responses in cancer cells that actually increase the
cells' resistance to fluid shear stress.
The UI team went on to show that
this "toughening up" process appears to involve expression of common
cancer-causing genes. They also showed that blocking the signaling pathway
controlled by one of these oncogenes reduced the cancer cells' resistance to
fluid shear stress.
Many different cellular pathways
can go wrong to create cancer cells. Henry suggests that this newly discovered
physical characteristic of cancer cells may be a common, convergent
manifestation of these various, separate molecular abnormalities.
If that is true, simply measuring
cancer cells' ability to resist fluid shear stresses might allow researchers to
examine the behavior of cancer
cells and investigate the effects of cancer drugs on tumor cells.
Translating to clinical
With the surprising findings and
their potential for clinical use, the study has grown from a side project of
study author and then-graduate student J. Matthew Barnes, and has now garnered
external funding to support further research. Jones Nauseef, study author and a
UI MSTP student in Henry's lab, has taken up the research, and Henry has
established a collaboration with UI urologist James Brown, M.D., to test the
technique with blood samples from patients with prostate cancer. That study is
being funded by a grant from the Department of Defense.
"A next step for us is to
translate these findings into patient specimens and determine whether this can
be useful in a context that is clinically meaningful," Henry says, such as
determining whether a cancer is progressing or if it may respond to a
particular therapy.
More information: http://dx.plos.org/10.1371/journal.pone.0050973
No comments:
Post a Comment