Detecting cancer cells in blood with a new microfluidic device

Diagram shows how the microfluidics device separates cancer cells from blood. The green circles represent cancer cells.
(Credit: Ian Papautsky)

Researchers at the University of Illinois at Chicago and Queensland University of Technology of Australia, have developed a device that can isolate individual cancer cells from patient blood samples.

The microfluidic device works by separating the various cell types found in blood by their size. The device may one day enable rapid, cheap liquid biopsies to help detect cancer and develop targeted treatment plans. The findings are reported in the journal Microsystems & Nanoengineering.

“This new microfluidics chip lets us separate cancer cells from whole blood or minimally-diluted blood,” said Ian Papautsky, the Richard and Loan Hill Professor of Bioengineering in the UIC College of Engineering and corresponding author on the paper. “While devices for detecting cancer cells circulating in the blood are becoming available, most are relatively expensive and are out of reach of many research labs or hospitals. Our device is cheap, and doesn’t require much specimen preparation or dilution, making it fast and easy to use.”

The ability to successfully isolate cancer cells is a crucial step in enabling liquid biopsy where cancer could be detected through a simple blood draw. This would eliminate the discomfort and cost of tissue biopsies which use needles or surgical procedures as part of cancer diagnosis. Liquid biopsy could also be useful in tracking the efficacy of chemotherapy over the course of time, and for detecting cancer in organs difficult to access through traditional biopsy techniques, including the brain and lungs.

However, isolating circulating tumor cells from the blood is no easy task, since they are present in extremely small quantities. For many cancers, circulating cells are present at levels close to one per 1 billion blood cells. “A 7.5-milliliter tube of blood, which is a typical volume for a blood draw, might have ten cancer cells and 35-40 billion blood cells,” said Papautsky. “So we are really looking for a needle in a haystack.”

Microfluidic technologies present an alternative to traditional methods of cell detection in fluids. These devices either use markers to capture targeted cells as they float by, or they take advantage of the physical properties of targeted cells — mainly size — to separate them from other cells present in fluids.

Papautsky and his colleagues developed a device that uses size to separate tumor cells from blood. “Using size differences to separate cell types within a fluid is much easier than affinity separation which uses ‘sticky’ tags that capture the right cell type as it goes by,” said Papautsky. “Affinity separation also requires a lot of advanced purification work which size separation techniques don’t need.”

Learn more: New microfluidics device can detect cancer cells in blood

 

 

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An engineered virus kills cancer cells more effectively than another virus currently used in treatments

Comparison of cancer cells and normal cells after being infected with the dl355 adenovirus. The top four cell types listed on the left (HeLa, C33A, A549, and H1299) are cancer cells, and the bottom two (BJ and WI38) are normal cells. As the amount of dl355 virus administered to the cancer cells increased (represented by MOI), more cancer cells died within 7 days, while the normal cells continued to live. (Yanagawa-Matsuda, et. al, Oncology Reports, November 12, 2018)

An engineered virus kills cancer cells more effectively than another virus currently used in treatments, according to Hokkaido University researchers.

Hokkaido University researchers have engineered a virus that selectively targets and kills cancer cells. The virus, called dl355, has an even stronger anticancer effect than another engineered virus currently used in clinical practice, according to a study published in the journal Oncology Reports.

Molecular oncologist Fumihiro Higashino and colleagues deleted a gene involved in viral replication, called E4orf6, from a type of adenovirus. The team previously discovered that E4orf6 stabilizes a type of mRNA called ARE-mRNAs in the infected cells enabling viral replication. ARE-mRNAs are known to be stable in stressed cells and cancer cells, but rapidly degrade in normal cells.

In laboratory tests, they found that their modified adenovirus, called dl355, replicated and increased its number significantly more in cancer cells than it did in normal cells. Higashino explains “The E4orf6-lacking virus relies on the stable ARE-mRNAs in cancer cells for its replication.”

Some viruses can be used to treat cancers, as they replicate within the cells until they burst and die. The researchers infected several types of cultured cancer cells with 100 dl355 virus particles per cell and found that nearly all the cancer cells died within seven days. In contrast, most normal cells infected with the virus did not die, even after seven days. Several cancer cell lines managed to survive low doses of dl355, but all cancer cells were killed by the virus as the dose was increased. Tumour growth was also significantly suppressed when dl355 was administered to human tumour cells grown in mice.

Finally, the team compared the anticancer effects of dl355 with another anticancer adenovirus currently used in clinical practice, called dl1520. dl355 replication was higher in all cancer cell lines tested, including cervical and lung cancer cells, and was better at killing all but one type of cancer cell, compared to dl1520. Both viruses only killed very few normal cells.

The findings suggest that dl355 has potential to be an effective anticancer treatment, the team concludes. They suggest enhancing the stabilization of ARE-mRNAs in cancer cells could even further strengthen its effect, but Professor Higashino notes that further research is required. “While we think dl355 has the potential to be an effective treatment method in dealing with many types of cancers, much more research needs to be done. When we think of a timeline, at least five more years of further research may be required, possible more, on top of clinical trials,” Professor Higashino noted.

Learn more: Engineering a cancer-fighting virus

 

 

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A new drug shows potential to halt cancer cells growth by stunting the cells biological clock

Research by Steve Kay of biological sciences at USC Dornsife and the USC Michelson Center for Convergent Bioscience points to a possible new weapon against cancer. Composite image by Dennis Lan.

Scientists at USC Michelson Center for Convergent Bioscience and Japan’s Nagoya University find and test a promising drug that stops cancer by interfering with the cancer cells’ metabolism and other circadian-related functions

A new drug shows potential to halt cancer cells’ growth by stunting the cells’ biological clock.

The findings from scientists at the USC Michelson Center for Convergent Bioscience and Nagoya University’s Institute of Transformative BioMolecules (ITbM) advance a burgeoning area of research: turning the body’s circadian rhythms against cancer.

Their study, conducted on human kidney cancer cells and on acute myeloid leukemia in mice, was published Jan. 23 in the journal Science Advances.

Scientists know that disrupting sleep and other elements of humans’ circadian rhythm can harm health. The same is true for the circadian clock of cells themselves. If researchers could disturb the circadian clock of cancer cells, they theorize, they could potentially hurt or kill those cells.

The scientists found that a molecule named GO289 targets an enzyme that controls the cell’s circadian rhythm. This drug-protein interaction then disrupts the functions of four other proteins that are important for cell growth and survival.

Human bone cancer cells stopped growing when a drug molecule jammed their circadian rhythm during a study that appears in Science Advances. Photo courtesy of the Kay lab at the USC Michelson Center for Convergent Bioscience.

In effect, GO289 can jam the cogs of the cell’s circadian clock, slowing its cycles. And it can do so with little impact to healthy cells.

“In some cancers, the disease takes over the circadian clock mechanism and uses it for the evil purpose of helping itself grow,” said Steve Kay, director of convergent biosciences at the USC Michelson Center and USC Provost Professor of Neurology, Biomedical Engineering and Biological Sciences. “With GO289, we can interfere with those processes and stop the cancer from growing.”

Kay is among several scientists from USC Dornsife College of Letters, Arts and Sciences, USC Viterbi School of Engineering and Keck School of Medicine of USC who are collaborating across multiple disciplines to find new solutions for treating cancer, neurological disease and cardiovascular disease.

Finding the right candidate

On its initial interactions with human bone cancer cells, GO289 appeared to slow the tumors’ circadian clock as it targeted an enzyme, named CK2.

To see if GO289 consistently hindered other cancers in the same way, the scientists then tested it on human kidney cancer cells and on mice with acute myeloid leukemia. They found that GO289 specifically affected cancer cell metabolism and other circadian-related functions that normally would enable the cancer to grow and spread.

Kay is optimistic about the findings. “This could become an effective new weapon that kills cancer,” he said.

Learn more: Cancer has a biological clock and this drug may keep it from ticking

 

 

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Nanoparticle targets tumor-infiltrating immune cells and tells them to fight

This graphic demonstrates how STING-NPs enhance uptake of cGAMP. (Jennifer Fairman/Fairman Studios)

New research builds on Nobel-winning immune checkpoint blockade work

Immunotherapy’s promise in the fight against cancer drew international attention after two scientists won a Nobel Prize this year for unleashing the ability of the immune system to eliminate tumor cells.

But their approach, which keeps cancer cells from shutting off the immune system’s powerful T-cells before they can fight tumors, is just one way to use the body’s natural defenses against deadly disease. A team of Vanderbilt University bioengineers today announced a major breakthrough in another: penetrating tumor-infiltrating immune cells and flipping on a switch that tells them to start fighting. The team designed a nanoscale particle to do that and found early success using it on human melanoma tissue.

“Tumors are pretty conniving and have evolved many ways to evade detection from our immune system,” said John T. Wilson, assistant professor of chemical and biomolecular engineering and biomedical engineering. “Our goal is to rearm the immune system with the tools it needs to destroy cancer cells.

“Checkpoint blockade has been a major breakthrough, but despite the huge impact it continues to have, we also know that there are a lot of patients who don’t respond to these therapies. We’ve developed a nanoparticle to find tumors and deliver a specific type of molecule that’s produced naturally by our bodies to fight off cancer.”

That molecule is called cGAMP, and it’s the primary way to switch on what’s known as the stimulator of interferon genes (STING) pathway: a natural mechanism the body uses to mount an immune response that can fight viruses or bacteria or clear out malignant cells. Wilson said his team’s nanoparticle delivers cGAMP in a way that jump-starts the immune response inside the tumor, resulting in the generation of T-cells that can destroy the tumor from the inside and also improve responses to checkpoint blockade.

While the Vanderbilt team’s research focused on melanoma, their work also indicates that this could impact treatment of many cancers, Wilson said, including breast, kidney, head and neck, neuroblastoma, colorectal and lung cancer.

His findings appear today in a paper titled “Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy” in the journal Nature Nanotechnology.

Daniel Shae, a Ph.D. student on Wilson’s team and first author of the manuscript, said the process began with developing the right nanoparticle, built using “smart” polymers that respond to changes in pH that he engineered to enhance the potency of cGAMP. After 20 or so iterations, the team found one that could deliver cGAMP and activate STING efficiently in mouse immune cells, then mouse tumors and eventually human tissue samples.

“That’s really exciting because it demonstrates that, one day, this technology may have success in patients,” Shae said.

Learn more: Nanoparticle targets tumor-infiltrating immune cells, flips switch telling them to fight

 

 

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Seeing inside tumors to monitor how effective an anticancer treatment is

Mapping of tumor models’ rigidity. Dark red indicates the most rigid areas, towards the interior of the tumor. The edge is less rigid (yellow-green).
via Thomas Dehoux/ILM/CNRS

A team of physicists at the Institut Lumière Matière (CNRS/Université Claude Bernard Lyon 1), in collaboration with the Cancer Research Center of Lyon (CNRS/INSERM/ Université Claude Bernard Lyon 1/Centre Léon Bérard/Hospices civils de Lyon), has demonstrated the potential, for oncology, of an imaging technique based only on the physical properties of tumors. It can differentiate populations of malignant cells and monitor how effective an anticancer treatment is. These results, published in Physical Review Letters on January 8, 2019, should help in the design of new therapeutic molecules and in the personalization of treatments.

Despite a good understanding of the biology of cancer, 90% of experimental drugs fail during clinical trials. It is also increasingly suspected that the mechanical properties of tumors influence disease progression, and treatment efficacy. Although we can evaluate tumor elasticity globally, it is more difficult to measure local rigidity deep down and to see whether the core of the tumor resists the penetration of therapeutic liquids. To probe these physical properties, the researchers have used a noncontact imaging technique that does not require the use of contrast agents – therefore that does not disturb tissue function – that exploits natural infinitesimal vibrations of matter.

To recapitulate the behavior of colorectal tumors in vitro, the researchers created organoids, spheres with diameter 0.3 mm formed by the aggregation of tumor cells. They focused a red laser beam onto these objects. The infinitesimal vibrations of the sample, generated by thermal agitation, modify very slightly the color of the light beam that exits the sample. By analyzing this light, a map of the mechanical properties of the model tumors is created: the more rigid the area scanned by the laser, the faster the vibrations and, in a manner comparable to the Doppler effect (the mechanism that makes a siren sound increasingly shrill as it gets closer), the greater the color change.

From organoids composed of two cell lines with different malignancies, the researchers have shown that they could distinguish the two cell types from their mechanical properties. Such information is crucial because it may allow diagnosis from biopsy analysis to be refined and offer better assessment of tumor grade. Local variations in mechanical properties after a drug treatment have also been monitored using this technique: the center of the tumor remains rigid longer than the edge, demonstrating the treatment’s efficacy gradient. So local measurement of mechanical properties could confirm the total destruction of the tumor and help in choosing as low a treatment dose and duration as possible.

This approach allows exploring the impact of mechanical properties on the therapeutic response. It should lead to more predictive in vitro tumor models for testing new therapeutic molecules and for combined therapies, which act for example on tissue rigidity to accelerate the penetration of active molecules in the center of the tumor. It could also provide new indicators to guide clinicians in personalization of therapies.

Learn more: Physics can show us the inside of tumors

 

 

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