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 cells. 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.
“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
The paper’s co-lead authors are Sunitha Nagrath, PhD, of the MGH
BioMEMS Resource Center, and Lecia Sequist, MD, MGH Cancer Center.
Additional co-authors are Shyamala Maheswaran, PhD, Daphne Bell,
PhD, Lindsey Ulkus, Matthew Smith, MD, PhD, Eunice Kwak, MD, PhD,
Subba Digumarthy, MD, Alona Muzikansky, and Paula Ryan, MD, MGH
Cancer Center; and Daniel Irimia, MD, PhD, and Ulysses Balis, MD,
MGH BioMEMS Resource Center.
The research was funded by grants from the National Institutes of
Health and a Doris Duke Distinguished Clinical Scientist Award.