A team of investigators from the Massachusetts
General Hospital (MGH) Biomicroelectromechanical
Systems (BioMEMS) Resource Center and the MGH Cancer Center has
developed a microchip-based device that can isolate, enumerate and
analyze circulating tumor cells (CTCs) from a blood sample. CTCs are
viable cells from solid tumors carried in the bloodstream at a level of
one in a billion cell. Because of their rarity and fragility, it has
not been possible to get information from CTCs that could help clinical
decision-making, but the new device – called the
“CTC-chip,”– has the potential to be an
invaluable tool for monitoring and guiding cancer treatment.
 | | Scanning electron microscope image of a lung cancer cell adhering to an antibody-coated micropost on the CTC-chip. |
“This use of nanofluidics to find such rare cells is
revolutionary, the first application of this technology to a broad,
clinically important problem,” says Daniel Haber, MD,
director of the MGH Cancer Center and a co-author of the report in the
December 20 issue of Nature. “While much work remains to be
done, this approach raises the possibility of rapidly and noninvasively
monitoring tumor response to treatment, allowing changes if the
treatment is not effective, and the potential of early detection
screening in people at increased risk for cancer.”
The existence of CTCs has been known since the mid-19th
century, but since they are so hard to find, it has not been possible
to adequately investigate their biology and significance.
Microchip-based technologies have the ability to accurately sense and
sort specific types of cells, but have only been used with
microliter-sized fluid samples, the amount of blood in a fingerprick.
Since CTCs are so rare, detecting them in useful quantities requires
analyzing samples that are 1,000 to 10,000 times larger.
To meet that challenge the MGH BioMEMS Resource Center
research team – led by Mehmet Toner, PhD, senior author of
the Nature report and director of the center in the MGH Department of
Surgery, and Ronald Tompkins, MD, ScD, chief of the MGH Burns Unit and
a co-author – first investigated the factors required for
microchip analysis of sufficiently large blood samples. The device they
developed utilizes a business-card-sized silicon chip, covered with
almost 80,000 microscopic posts coated with an antibody to a protein
expressed on most solid tumors. The researchers also needed to
calculate the correct speed and force with which the blood sample
should pass through the chip to allow CTCs to adhere to the microposts.
“We developed a counterintuitive approach, using a
tiny chip with critical geometric features smaller than a human hair to
process large volumes of blood in a very gentle and uniform manner
– almost like putting a ‘hose’ through a
microchip,” explains Toner.
Several tests utilizing cells from various types of tumors
verified that CTCs were captured by posts covered with the antibody
‘glue.’ Even tumor cells expressing low levels of
the target protein and samples containing especially low levels of CTCs
were successfully analyzed by the CTC-chip. In contrast to current
technology for detecting CTCs, the new microchip device does not
require any pre-processing of blood samples, which could damage or
destroy the fragile CTCs.
The researchers then tested the CTC-chip against blood samples
from 68 patients with five different types of tumors – lung,
prostate, breast, pancreatic and colorectal. A total of 116 samples
were tested, and CTCs were identified in all but one sample, giving the
test a sensitivity rating of 99 percent. No CTCs were found in samples
from cancer-free control volunteers. To evaluate the device’s
ability to monitor response to treatment, blood samples were taken from
nine cancer patients during their treatment for lung, colorectal,
pancreatic or esophageal tumors. Changes in levels of CTCs accurately
reflected changes in tumor size as measured by standard CT scans.
“We looked at four major cancer killers and were
able to consistently find these cells and correlate test results with
traditional monitoring techniques,” Toner says.
“Some of these tumors have several potential drugs to choose
from, and the ability to monitor therapeutic response in real time with
this device – which has an exquisite sensitivity to CTCs
– could rapidly signal whether a treatment is working or if
another option should be tried.”
CTCs also can provide the molecular information needed to
identify tumors that are candidates for the new targeted therapies and
should help researchers better understand the biology of cancer cells
and the mechanisms of metastasis. Considerable work needs to be done
before the CTC-chip is ready to be put to clinical use, and the MGH
investigators are establishing a Center of Excellence in CTC
Technologies to further explore the potential of the device, which also
has been licensed to a biotechnology company for commercial development.
Posted 20th December 2007
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