Getting more Cancer-Fighting Nanoparticles to where they are Needed: University of Toronto

Credit: CC0 Public Domain

University of Toronto Engineering researchers have discovered a dose threshold that greatly increases the delivery of cancer-fighting drugs into a tumor.

Determining this threshold provides a potentially universal method for gauging nanoparticle dosage and could help advance a new generation of cancer therapy, imaging and diagnostics.

“It’s a very simple solution, adjusting the dosage, but the results are very powerful,” says MD/Ph.D. candidate Ben Ouyang, who led the research under the supervision of Professor Warren Chan.

Their findings were published today in Nature Materials, providing solutions to a drug-delivery problem previously raised by Chan and researchers four years ago in Nature Reviews Materials.

Nanotechnology carriers are used to deliver drugs to cancer sites, which in turn can help a patient’s response to treatment and reduce adverse side effects, such as hair loss and vomiting. However, in practice, few injected particles reach the tumor site.

In the Nature Reviews Materials paper, the team surveyed literature from the past decade and found that on median, only 0.7 percent of the chemotherapeutic nanoparticles make it into a targeted tumor.

“The promise of emerging therapeutics is dependent upon our ability to deliver them to the target site,” explains Chan. “We have discovered a new principle of enhancing the delivery process. This could be important for nanotechnology, genome editors, immunotherapy, and other technologies.”

Chan’s team saw the liver, which filters the blood, as the biggest barrier to nanoparticle drug delivery. They hypothesized that the liver would have an uptake rate threshold—in other words, once the organ becomes saturated with nanoparticles, it wouldn’t be able to keep up with higher doses. Their solution was to manipulate the dose to overwhelm the organ’s filtering Kupffer cells, which line the liver channels.

The researchers discovered that injecting a baseline of 1 trillion nanoparticles in mice, in vivo, was enough to overwhelm the cells so that they couldn’t take up particles quick enough to keep up with the increased doses. The result is a 12 percent delivery efficiency to the tumor.

“There’s still lots of work to do to increase the 12 percent but it’s a big step from 0.7,” says Ouyang. The researchers also extensively tested whether overwhelming Kupffer cells led to any risk of toxicity in the liver, heart or blood.

“We tested gold, silica, and liposomes,” says Ouyang. “In all of our studies, no matter how high we pushed the dosage, we never saw any signs of toxicity.”

The team used this threshold principle to improve the effectiveness of a clinically used and chemotherapy-loaded nanoparticle called Caelyx. Their strategy shrank tumors 60 percent more when compared to Caelyx on its own at a set dose of the chemotherapy drug, doxorubicin.

Because the researchers’ solution is a simple one, they hope to see the threshold having positive implications in even current nanoparticle-dosing conventions for human clinical trials. They calculate that the human threshold would be about 1.5 quadrillion nanoparticles.

“There’s a simplicity to this method and reveals that we don’t have to redesign the nanoparticles to improve delivery,” says Chan. “This could overcome a major delivery problem.”

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Researchers find more precise way to target tumours with anti-cancer drugs

Unmasking a hidden killer: Successfully detecting cancer in blood of patients undergoing treatment

Dr Yuling Wang. Credit: CNBP

Pancreatic cancer is one of the most lethal cancers, but difficult to diagnose: few sufferers have symptoms until the cancer has become large or already spread to other organs. Even then, symptoms can be vague and easily misconstrued as more common conditions.

This is why Dr. Yuling Wang is so excited by results of a trial completed in late 2019, which—using plasmonic nanoparticles developed by the Centre for Nanoscale BioPhotonics (CNBP)—successfully detected signs of the cancer in blood of patients undergoing treatment. The paper was recently published in the journal American Chemical Society—Sensors.

“The test gave a very high signal in the blood for late-stage or very serious tumors, where other techniques cannot detect anything,” said Dr. Wang, an associate investigator at the Centre’s Macquarie University node in Sydney, in work led by Prof Nicolle Packer. “We need to test many more patient samples to validate the approach, but the strength of the signal was very encouraging.”

They did this by developing a method, using surface-enhanced Raman spectroscopy nanotags, that simultaneously detects three known pancreatic cancer biomarkers in blood. Known as extracellular vesicles, or EVs, they contain DNA and proteins for cell-to-cell communication and are shed from pancreatic cancer cells into surrounding body fluids. The CNBP method zeros in on three: Glypican-1, epithelial cell adhesion molecules and CD44V6.

Non-invasive screening of cancer biomarkers from blood with handheld Raman reader. Credit: CNBP

For the experiment, biopsies of healthy donors were provided alongside those of known sufferers of pancreatic cancer, in double-blind tests where the researchers did not know which was which. Nevertheless, the blood of sufferers was easily identified. The technique was so sensitive it could spot EVs as small as 113 nanometres in diameter—or less than 1% the width of a human hair—in every millilitre of blood.

The pancreas is part of the digestive system, secreting insulin into the bloodstream to regulate the body’s sugar level as well as important enzymes and hormones into the small intestine to help break down food. Pancreatic cancer is the fifth biggest cancer killer in Australia and has a 5-year survival rate of 8.7%. More than 3000 Australians are diagnosed annually, and surgery to remove the cancer is a long and complex process, requiring long hospital stays.

Because existing blood tests for the protein biomarkers of pancreatic cancer are unreliable, imaging with endoscopic ultrasound or MRI scans is necessary. Even then, anomalies can only be confirmed with a biopsy of the organ, which is invasive and ultimately relies on a trained pathologist to recognize signs of the cancer under a microscope. As a result, there’s some subjectivity involved and cancer can be present but still be missed.

“Our approach is non-invasive—we don’t need to take tissue from the patient, we just use a handheld device to test blood for targeted biomarkers, which gives a very quick result,” Dr. Wang said. It may also help provide earlier diagnosis of the cancer.

While the work is a proof-of-concept, it was also able to detect colorectal and bladder cancer biomarkers—although not as clearly as those for pancreatic cancer. Nevertheless, the results are so encouraging that a commercial partner has committed funding to CNBP so it can develop a handheld spectrometer for cancer biomarkers in blood.

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UK urine test that can detect early-stage pancreatic cancer starts clinical study

Precious Metal Flecks Could be Catalyst for Better Cancer Therapies

 

Researchers have found a way to dispatch minute fragments of palladium—a key component in motor manufacture, electronics and the oil industry—inside cancerous cells.

Tiny extracts of a precious metal used widely in industry could play a vital role in new cancer therapies.

Scientists have long known that the metal, used in catalytic converters to detoxify exhaust, could be used to aid cancer treatment but, until now, have been unable to deliver it to affected areas.

A molecular shuttle system that targets specific cancer cells has been created by a team at the University of Edinburgh and the Universidad de Zaragoza in Spain.

The new method, which exploits palladium’s ability to accelerate—or catalyse—chemical reactions, mimics the process some viruses use to cross cell membranes and spread infection.

The team has used bubble-like pouches that resemble the biological carriers known as exosomes, which can transport essential proteins and genetic material between cells. These exosomes exit and enter cells, dump their content, and influence how the cells behave.

This targeted transport system, which is also exploited by some viruses to spread infection to other cells and tissues, inspired the team to investigate their use as shuttles of therapeutics.

The researchers have now shown that this complex communication network can be hijacked. The team created exosomes derived from lung cancer cells and cells associated with glioma—a tumour that occurs in the brain and spinal cord—and loaded them with palladium catalysts.

These artificial exosomes act as Trojan horses, taking the catalysts—which work in tandem with an existing cancer drug- straight to primary tumours and metastatic cells.

Having proved the concept in laboratory tests, the researchers have now been granted a patent that gives them exclusive rights to trial palladium-based therapies in medicine.

The study was funded by the Engineering and Physical Sciences Research Council and the European Research Council. It has been published in the journal, Nature Catalysis.

Professor Asier Unciti-Broceta, from the University of Edinburgh’s CRUK Edinburgh Centre, said: “We have tricked exosomes naturally released by cancer cells into taking up a metal that will activate chemotherapy drugs just inside the cancer cells, which could leave healthy cells untouched.”

Professor Jesús Santamaría, of the Universidad de Zaragoza, said: “This has the potential to be a very exciting technology. It could allow us to target the main tumour and metastatic cells, thus reducing the side effects of chemotherapy without compromising the treatment.”

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Materials provided by University of Edinburgh. Note: Content may be edited for style and length.

Researchers Develop Nanoparticle-Based Vaccine for Skin Cancer

Nano-particles developed by scientists at Tel Aviv University have proven effective to prevent and treat melanoma.

 

While scientists have made great strides over the years to treat cancer, a vaccine for the disease—which comes in many forms and with many complexities–has yet to be discovered.

Researchers at Tel Aviv University have made a breakthrough in this endeavor with the development of a nano-vaccine for the most aggressive type of melanoma—skin cancer. The vaccine—based on a novel nanoparticle—already has shown effective in preventing the development of melanoma in mice as well as in treating the initial tumors that result from the disease, researchers said.

Researchers have developed a new nano-vaccine for melanoma, the most aggressive type of skin cancer. The vaccine is the first of its kind for cancer and paves the way for promising new prevention and treatment methods for the disease, researchers said. (Image source: Tel Aviv University)

Melanoma develops in the skin cells that produce melanin or skin pigment, but then can metastasize quickly into the brain and other organs. It currently is treated in a number of ways, including chemotherapy, radiation therapy, and immunotherapy.

All of these methods attack the disease after the fact; so far, no treatment has emerged to prevent or delay its growth in the first place, Professor Ronit Satchi-Fainaro, chair of the Department of Physiology and Pharmacology at Tel Aviv University, said in a press statement.

“The vaccine approach, which has proven so effective against various viral diseases, has not materialized yet against cancer,” said Satchi-Fainaro, who also is head of the Laboratory for Cancer Research and Nanomedicine at the university’s Sackler Faculty of Medicine. “In our study, we have shown for the first time that it is possible to produce an effective nano-vaccine against melanoma and to sensitize the immune system to immunotherapies.”

A New Approach

Nanoparticles about 170 nanometers in size are key to the approach researchers took to developing their novel vaccine. They packed two peptides—or short chains of amino acids—into each particle, which are made of a biodegradable polymer. Peptides are present in melanoma cells.

To test their vaccine, researchers injected the nano-particles into a mouse with melanoma to test its effectiveness. What they found is that the nanoparticles acted similarly to existing vaccines for viruses, which long have proved effective against viral-borne diseases, Satchi-Fainaro said.

“They stimulated the immune system of the mice, and the immune cells learned to identify and attack cells containing the two peptides–that is, the melanoma cells,” she said in the statement. “This meant that, from now on, the immune system of the immunized mice will attack melanoma cells if and when they appear in the body.”

Researchers published a study on their work in the journal Nature Nanotechnology.

Successful Prevention and Treatment

Satchi-Fainaro’s team focused on three different conditions to determine the nano-vaccine’s effectiveness. The first was to see if it would prevent the growth of the disease if melanoma cells were injected into mice, which it did, she said.

Researchers also used the nano-vaccine to treat a primary melanoma tumor in combination with immunotherapy treatments, they said. The treatment delayed the progression of the disease and significantly extended the lives of the mice in this study, researchers said.

Finally, the researchers gauged the nano-vaccine’s effectiveness in treating brain metastases, which are associated with melanoma, using tissue from patients with these metastases. The vaccine showed it could also be a successful treatment in this case, paving the way for “effective treatment of melanoma, even in the most advanced stages of the disease,” Satchi-Fainaro said in the statement.

The team plans to continue its work to develop nano-particles to vaccinate people not only against melanoma, but potentially against other forms of cancer as well, she added.

 

MIT: Study Furthers Radically New View of Gene Control

MIT researchers have developed a new model of gene control, in which the cellular machinery that transcribes DNA into RNA forms specialized droplets called condensates.

Image: Steven H. Lee

Along the genome, proteins form liquid-like droplets that appear to boost the expression of particular genes.

In recent years, MIT scientists have developed a new model for how key genes are controlled that suggests the cellular machinery that transcribes DNA into RNA forms specialized droplets called condensates. These droplets occur only at certain sites on the genome, helping to determine which genes are expressed in different types of cells.

In a new study that supports that model, researchers at MIT and the Whitehead Institute for Biomedical Research have discovered physical interactions between proteins and with DNA that help explain why these droplets, which stimulate the transcription of nearby genes, tend to cluster along specific stretches of DNA known as super enhancers. These enhancer regions do not encode proteins but instead regulate other genes.

“This study provides a fundamentally important new approach to deciphering how the ‘dark matter’ in our genome functions in gene control,” says Richard Young, an MIT professor of biology and member of the Whitehead Institute.

Young is one of the senior authors of the paper, along with Phillip Sharp, an MIT Institute Professor and member of MIT’s Koch Institute for Integrative Cancer Research; and Arup K. Chakraborty, the Robert T. Haslam Professor in Chemical Engineering, a professor of physics and chemistry, and a member of MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MGH, MIT, and Harvard.

Graduate student Krishna Shrinivas and postdoc Benjamin Sabari are the lead authors of the paper, which appears in Molecular Cell on Aug. 8.

“A biochemical factory”

Every cell in an organism has an identical genome, but cells such as neurons or heart cells express different subsets of those genes, allowing them to carry out their specialized functions. Previous research has shown that many of these genes are located near super enhancers, which bind to proteins called transcription factors that stimulate the copying of nearby genes into RNA.

About three years ago, Sharp, Young, and Chakraborty joined forces to try to model the interactions that occur at enhancers.

In a 2017 Cell paper, based on computational studies, they hypothesized that in these regions, transcription factors form droplets called phase-separated condensates. Similar to droplets of oil suspended in salad dressing, these condensates are collections of molecules that form distinct cellular compartments but have no membrane separating them from the rest of the cell.

In a 2018 Science paper, the researchers showed that these dynamic droplets do form at super enhancer locations. Made of clusters of transcription factors and other molecules, these droplets attract enzymes such as RNA polymerases that are needed to copy DNA into messenger RNA, keeping gene transcription active at specific sites.

“We had demonstrated that the transcription machinery forms liquid-like droplets at certain regulatory regions on our genome, however we didn’t fully understand how or why these dewdrops of biological molecules only seemed to condense around specific points on our genome,” Shrinivas says.

As one possible explanation for that site specificity, the research team hypothesized that weak interactions between intrinsically disordered regions of transcription factors and other transcriptional molecules, along with specific interactions between transcription factors and particular DNA elements, might determine whether a condensate forms at a particular stretch of DNA. Biologists have traditionally focused on “lock-and-key” style interactions between rigidly structured protein segments to explain most cellular processes, but more recent evidence suggests that weak interactions between floppy protein regions also play an important role in cell activities.

In this study, computational modeling and experimentation revealed that the cumulative force of these weak interactions conspire together with transcription factor-DNA interactions to determine whether a condensate of transcription factors will form at a particular site on the genome. Different cell types produce different transcription factors, which bind to different enhancers. When many transcription factors cluster around the same enhancers, weak interactions between the proteins are more likely to occur. Once a critical threshold concentration is reached, condensates form.

“Creating these local high concentrations within the crowded environment of the cell enables the right material to be in the right place at the right time to carry out the multiple steps required to activate a gene,” Sabari says. “Our current study begins to tease apart how certain regions of the genome are capable of pulling off this trick.”

These droplets form on a timescale of seconds to minutes, and they blink in and out of existence depending on a cell’s needs.

“It’s an on-demand biochemical factory that cells can form and dissolve, as and when they need it,” Chakraborty says. “When certain signals happen at the right locus on a gene, the condensates form, which concentrates all of the transcription molecules. Transcription happens, and when the cells are done with that task, they get rid of them.”

“A functional condensate has to be more than the sum of its parts, and how the protein and DNA components work together is something we don’t fully understand,” says Rohit Pappu, director of the Center for Science and Engineering of Living Systems at Washington University, who was not involved in the research. “This work gets us on the road to thinking about the interplay among protein-protein, protein-DNA, and possibly DNA-DNA interactions as determinants of the outputs of condensates.”

A new view

Weak cooperative interactions between proteins may also play an important role in evolution, the researchers proposed in a 2018 Proceedings of the National Academy of Sciences paper.

The sequences of intrinsically disordered regions of transcription factors need to change only a little to evolve new types of specific functionality. In contrast, evolving new specific functions via “lock-and-key” interactions requires much more significant changes.

“If you think about how biological systems have evolved, they have been able to respond to different conditions without creating new genes.

We don’t have any more genes that a fruit fly, yet we’re much more complex in many of our functions,” Sharp says. “The incremental expanding and contracting of these intrinsically disordered domains could explain a large part of how that evolution happens.”

Similar condensates appear to play a variety of other roles in biological systems, offering a new way to look at how the interior of a cell is organized.

Instead of floating through the cytoplasm and randomly bumping into other molecules, proteins involved in processes such as relaying molecular signals may transiently form droplets that help them interact with the right partners.

“This is a very exciting turn in the field of cell biology,” Sharp says. “It is a whole new way of looking at biological systems that is richer and more meaningful.”

Some of the MIT researchers, led by Young, have helped form a company called Dewpoint Therapeutics to develop potential treatments for a wide variety of diseases by exploiting cellular condensates.

There is emerging evidence that cancer cells use condensates to control sets of genes that promote cancer, and condensates have also been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease.

The research was funded by the National Science Foundation, the National Institutes of Health, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Chemists build a better cancer-killing drill: Rice University designs molecular motors with an upgrade for activation with near-infrared light

Houston, TX | Posted on May 29th, 2019

Researchers at Rice University, Durham (U.K.) University and North Carolina State University reported their success at activating the motors with precise two-photon excitation via near-infrared light. Unlike the ultraviolet light they first used to drive the motors, the new technique does not damage adjacent, healthy cells.

The team’s results appear in the American Chemical Society journal ACS Nano.

The research led by chemists James Tour of Rice, Robert Pal of Durham and Gufeng Wang of North Carolina may be best applied to skin, oral and gastrointestinal cancer cells that can be reached for treatment with a laser. 

In a 2017 Nature paper, the same team reported the development of molecular motors enhanced with small proteins that target specific cancer cells.

Once in place and activated with light, the paddlelike motors spin up to 3 million times a second, allowing the molecules to drill through the cells’ protective membranes and killing them in minutes.

Since then, researchers have worked on a way to eliminate the use of damaging ultraviolet light. In two-photon absorption, a phenomenon predicted in 1931 and confirmed 30 years later with the advent of lasers, the motors absorb photons in two frequencies and move to a higher energy state, triggering the paddles.

A video produced in 2017 explains the basic concept of cell death via molecular motors. Video produced by Brandon Martin/Rice University.

“Multiphoton activation is not only more biocompatible but also allows deeper tissue penetration and eliminates any unwanted side effects that may arise with the previously used UV light,” Pal said. 

The researchers tested their updated motors on skin, breast, cervical and prostate cancer cells in the lab. Once the motors found their targets, lasers activated them with a precision of about 200 nanometers.

In most cases, the cells were dead within three minutes, they reported. They believe the motors also drill through chromatin and other components of the diseased cells, which could help slow metastasis.

Because the motors target specific cells, Tour said work is underway to adapt them to kill antibiotic-resistant bacteria as well.

“We continue to perfect the molecular motors, aiming toward ones that will work with visible light and provide even higher efficacies of kill toward the cellular targets,” he said.

Rice postdoctoral researcher Dongdong Liu is lead author of the paper. Co-authors are Rice alumni Victor Garcia-López, Lizanne Nilewski and Amir Aliyan, visiting research scientist Richard Gunasekera, and senior research scientist Lawrence Alemany and graduate student Tao Jin of North Carolina State.

Wang is an assistant professor of chemistry at North Carolina State. Pal is an assistant professor of chemistry at Durham. Tour is the T.T. and W.F. Chao Chair in Chemistry as well as a professor of computer science and of materials science and nanoengineering at Rice.

The Royal Society, the United Kingdom’s Engineering and Physical Sciences Research Council, the Discovery Institute, the Pensmore Foundation and North Carolina State supported the research.

About Rice University
Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,962 undergraduates and 3,027 graduate students, Rice’s undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 2 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.

Follow Rice News and Media Relations via Twitter @RiceUNews.

Copyright © Rice University

University of Georgia – Microfluidic device may help researchers better understand (and isolate) Metastatic Cancer – “Finding the Needle in the Haystack”

Instead of searching for a needle in a haystack, what if you were able to sweep the entire haystack to one side, leaving only the needle behind? That’s the strategy researchers in the University of Georgia College of Engineering followed in developing a new microfluidic device that separates elusive circulating tumor cells (CTCs) from a sample of whole blood.

CTCs break away from cancerous tumors and flow through the bloodstream, potentially leading to new metastatic tumors. The isolation of CTCs from the blood provides a minimally invasive alternative for basic understanding, diagnosis and prognosis of metastatic cancer. But most studies are limited by technical challenges in capturing intact and viable CTCs with minimal contamination.

“A typical sample of 7 to 10 milliliters of blood may contain only a few CTCs,” said Leidong Mao, a professor in UGA’s School of Electrical and Computer Engineering and the project’s principal investigator. “They’re hiding in whole blood with millions of white blood cells. It’s a challenge to get our hands on enough CTCs so scientists can study them and understand them.”

Leidong Mao (right) and graduate student Yang Liu stand in Mao’s lab at UGA.

Circulating tumor cells are also difficult to isolate because within a sample of a few hundred CTCs, the individual cells may present many characteristics. Some resemble skin cells while others resemble muscle cells. They can also vary greatly in size.

“People often compare finding CTCs to finding a needle in a haystack,” said Mao. “But sometimes the needle isn’t even a needle.”

To more quickly and efficiently isolate these rare cells for analysis, Mao and his team have created a new microfluidic chip that captures nearly every CTC in a sample of blood ­- more than 99% – a considerably higher percentage than most existing technologies.

The team calls its novel approach to CTC detection “integrated ferrohydrodynamic cell separation,” or iFCS. They outline their findings in a study published in Lab on a Chip (“Tumor antigen-independent and cell size variation-inclusive enrichment of viable circulating tumor cells”).

The new device could be “transformative” in the treatment of breast cancer, according to Melissa Davis, an assistant professor of cell and developmental biology at Weill Cornell Medicine and a collaborator on the project.

“Physicians can only treat what they can detect,” Davis said. “We often can’t detect certain subtypes of CTCs, but with the iFCS device we will capture all the subtypes of CTCs and even determine which subtypes are the most informative concerning relapse and disease progression.”

Davis believes the device may ultimately allow physicians to gauge a patient’s response to specific treatments much earlier than is currently possible.

While most efforts to capture circulating tumor cells focus on identifying and isolating the few CTCs lurking in a blood sample, the iFCS takes a completely different approach by eliminating everything in the sample that’s not a circulating tumor cell.

The device, about the size of a USB drive, works by funneling blood through channels smaller in diameter than a human hair. To prepare blood for analysis, the team adds micron-sized magnetic beads to the samples. The white blood cells in the sample attach themselves to these beads. As blood flows through the device, magnets on the top and bottom of the chip draw the white blood cells and their magnetic beads down a specific channel while the circulating tumor cells continue into another channel.

The device combines three steps in one microfluidic chip, another advance over existing technologies that require separate devices for various steps in the process.

“The first step is a filter that removes large debris in the blood,” said Yang Liu, a doctoral student in UGA’s department of chemistry and the paper’s co-lead author. “The second part depletes extra magnetic beads and the majority of the white blood cells. The third part is designed to focus remaining white blood cells to the middle of channel and to push CTCs to the side walls.”

Wujun Zhao is the paper’s other lead author. Zhao, a postdoctoral scholar at Lawrence Berkeley National Laboratory, worked on the project while completing his doctorate in chemistry at UGA.

“The success of our integrated device is that it has the capability to enrich almost all CTCs regardless of their size profile or antigen expression,” said Zhao. “Our findings have the potential to provide the cancer research community with key information that may be missed by current protein-based or size-based enrichment technologies.”

The researchers say their next steps include automating the iFCS and making it more user-friendly for clinical settings. They also need to put the device through its paces in patient trials. Mao and his colleagues hope additional collaborators will join them and lend their expertise to the project.

Source: University of Georgia

MIT: How Tumors Behave on Acid: Acidic Environment Triggers Genes that Help Cancer Metastasize

In these tumor cells, acidic regions are labeled in red. Invasive regions of the cells, which express a protein called MMP14, are labeled in green. Image: Nazanin Rohani

Acidic environment triggers genes that help cancer cells metastasize.

Scientists have long known that tumors have many pockets of high acidity, usually found deep within the tumor where little oxygen is available. However, a new study from MIT researchers has found that tumor surfaces are also highly acidic, and that this acidity helps tumors to become more invasive and metastatic.

The study found that the acidic environment helps tumor cells to produce proteins that make them more aggressive. The researchers also showed that they could reverse this process in mice by making the tumor environment less acidic.

“Our findings reinforce the view that tumor acidification is an important driver of aggressive tumor phenotypes, and it indicates that methods that target this acidity could be of value therapeutically,” says Frank Gertler, an MIT professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

Former MIT postdoc Nazanin Rohani is the lead author of the study, which appears in the journal Cancer Research.

Mapping acidity

Scientists usually attribute a tumor’s high acidity to the lack of oxygen, or hypoxia, that often occurs in tumors because they don’t have an adequate blood supply. However, until now, it has been difficult to precisely map tumor acidity and determine whether it overlaps with hypoxic regions.

In this study, the MIT team used a probe called pH (Low) Insertion Peptide (pHLIP), originally developed by researchers at the University of Rhode Island, to map the acidic regions of breast tumors in mice. This peptide is floppy at normal pH but becomes more stable at low, acidic pH. When this happens, the peptide can insert itself into cell membranes. This allows the researchers to determine which cells have been exposed to acidic conditions, by identifying cells that have been tagged with the peptide.

To their surprise, the researchers found that not only were cells in the oxygen-deprived interior of the tumor acidic, there were also acidic regions at the boundary of the tumor and the structural tissue that surrounds it, known as the stroma.

“There was a great deal of tumor tissue that did not have any hallmarks of hypoxia that was quite clearly exposed to acidosis,” Gertler says. “We started looking at that, and we realized hypoxia probably wouldn’t explain the majority of regions of the tumor that were acidic.”

          A new study explores how an acidic environment drives tumor spread.

Read More: How Does Tumor Acidity Help Cancer Spread

Further investigation revealed that many of the cells at the tumor surface had shifted to a type of cell metabolism known as aerobic glycolysis. This process generates lactic acid as a byproduct, which could account for the high acidity, Gertler says. The researchers also discovered that in these acidic regions, cells had turned on gene expression programs associated with invasion and metastasis. Nearly 3,000 genes showed pH-dependent changes in activity, and close to 300 displayed changes in how the genes are assembled, or spliced.

“Tumor acidosis gives rise to the expression of molecules involved in cell invasion and migration. This reprogramming, which is an intracellular response to a drop in extracellular pH, gives the cancer cells the ability to survive under low-pH conditions and proliferate,” Rohani says.

Those activated genes include Mena, which codes for a protein that normally plays a key role in embryonic development. Gertler’s lab had previously discovered that in some tumors, Mena is spliced differently, producing an alternative form of the protein known as Mena^INV (invasive). This protein helps cells to migrate into blood vessels and spread though the body.

Another key protein that undergoes alternative splicing in acidic conditions is CD44, which also helps tumor cells to become more aggressive and break through the extracellular tissues that normally surround them. This study marks the first time that acidity has been shown to trigger alternative splicing for these two genes.

Reducing acidity

The researchers then decided to study how these genes would respond to decreasing the acidity of the tumor microenvironment. To do that, they added sodium bicarbonate to the mice’s drinking water. This treatment reduced tumor acidity and shifted gene expression closer to the normal state. In other studies, sodium bicarbonate has also been shown to reduce metastasis in mouse models.

Sodium bicarbonate would not be a feasible cancer treatment because it is not well-tolerated by humans, but other approaches that lower acidity could be worth exploring, Gertler says. The expression of new alternative splicing genes in response to the acidic microenvironment of the tumor helps cells survive, so this phenomenon could be exploited to reverse those programs and perturb tumor growth and potentially metastasis.

“Other methods that would more focally target acidification could be of great value,” he says.

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Howard Hughes Medical Institute, the National Institutes of Health, the KI Quinquennial Cancer Research Fellowship, and MIT’s Undergraduate Research Opportunities Program.

Other authors of the paper include Liangliang Hao, a former MIT postdoc; Maria Alexis and Konstantin Krismer, MIT graduate students; Brian Joughin, a lead research modeler at the Koch Institute; Mira Moufarrej, a recent graduate of MIT; Anthony Soltis, a recent MIT PhD recipient; Douglas Lauffenburger, head of MIT’s Department of Biological Engineering; Michael Yaffe, a David H. Koch Professor of Science; Christopher Burge, an MIT professor of biology; and Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science.

Sprayable gel could help the body fight off cancer … after surgery

A scanning electron microscope image of a gel developed by UCLA researchers that could help prevent cancer from recurring after surgery. Credit: University of California, Los Angeles

Many people who are diagnosed with cancer will undergo some type of surgery to treat their disease—almost 95 percent of people with early-diagnosed breast cancer will require surgery and it’s often the first line of treatment for people with brain tumors, for example. But despite improvements in surgical techniques over the past decade, the cancer often comes back after the procedure.

Now, a UCLA-led research team has developed a spray gel embedded with immune-boosting drugs that could help. In a peer-reviewed study, the substance was successful half of the time in awakening lab animals’ immune systems to stop the cancer from recurring and inhibit it from spreading to other parts of the body.

A paper describing the work is published online in the journal Nature Nanotechnology.

The researchers, led by Zhen Gu, a professor of bioengineering at the UCLA Samueli School of Engineering and member of the UCLA Jonsson Comprehensive Cancer Center, tested the biodegradable spray gel in mice that had advanced melanoma tumors surgically removed. They found that the gel reduced the growth of the tumor cells that remained after surgery, which helped prevent recurrences of the cancer: After receiving the treatment, 50 percent of the mice survived for at least 60 days without their tumors regrowing.

The spray not only inhibited the recurrence of tumors from the area on the body where it was removed, but it also controlled the development of tumors in other parts of the body, said Gu, who is also a member of the California NanoSystems Institute at UCLA.

The substance will have to go through further testing and approvals before it could be used in humans. But Gu said that the scientists envision the gel being applied to the tumor resection site by surgeons immediately after the tumor is removed during surgery.

“This sprayable gel shows promise against one of the greatest obstacles in curing cancer,” Gu said. “One of the trademarks of cancers is that it spreads. In fact, around 90 percent of people with cancerous tumors end up dying because of tumor recurrence or metastasis. Being able to develop something that helps lower this risk for this to occur and has low toxicity is especially gratifying.”

The researchers loaded nanoparticles with an antibody specifically targeted to block CD47, a protein that cancer cells release as a “don’t-eat-me” signal. By blocking CD47, the antibody enables the immune system to find and ultimately destroy the cancer cells.

The nanoparticles are made of calcium carbonate, a substance that is the main component of egg shells and is often found in rocks. Researchers chose calcium carbonate because it can be gradually dissolved in surgical wound sites, which are slightly acidic, and because it boosts the activity of a type of macrophage that helps rid the body of foreign objects, said Qian Chen, the study’s lead author and a postdoctoral researcher in Gu’s lab.

“We also learned that the gel could activate T cells in the immune system to get them to work together as another line of attack against lingering cancer cells,” Chen said.

Once the solution is sprayed on the surgical site, it quickly forms a gel embedded with the nanoparticles. The gel helps stop at the surgical site and promotes would healing; the nanoparticles gradually dissolve and release the anti-CD47 antibodies into the body.

The researchers will continue testing the approach in animals to learn the optimal dose, best mix of nanoparticles and ideal treatment frequency, before testing the gel on human patients.

 Explore further: Gradual release of immunotherapy at site of tumor surgery prevents tumors from returning

More information: Qian Chen et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment, Nature Nanotechnology (2018). DOI: 10.1038/s41565-018-0319-4

Journal reference: Nature Nanotechnology  

Provided by: University of California, Los Angeles

 

Nanoscale blood test technique could lead to accelerated early diagnosis and personalized medicines

A technique to get more information from the blood of cancer patients than previously possible has been developed.

“We hope this technique could be a springboard for further research, from monitoring disease progression or recurrence, to identifying which treatment is best for each patient and potentially finding new biomarkers for early diagnosis.”- Professor Kostas Kostarelos

The discovery could potentially accelerate early diagnosis, speed up drug discovery and lead to advancements in personalised medicines.

The Cancer Research UK-funded study* is published in Advanced Materials today (Wednesday).

The scientists, from the University of Manchester, collected blood samples from women with advanced ovarian cancer who were treated with a type of chemotherapy called CAELYX®.

This chemotherapy drug is contained in a soft, lipid-based nanoparticle, called a liposome, which acts as a vessel to help minimise side effects**.

Women gave a sample of blood, following an injection of CAELYX® over a course of 90 minutes as part of their treatment. By extracting the injected liposomes, the scientists were able to detect a wide variety of biomolecules that stuck to the surface of the liposome – called the ‘biomolecule corona’.

Professor Kostas Kostarelos, lead author from the University of Manchester, said: “We’re astonished at how rich the information was on the surface of the liposomes taken from the blood. We hope this technique could be a springboard for further research, from monitoring disease progression or recurrence, to identifying which treatment is best for each patient and potentially finding new biomarkers for early diagnosis.”

This is a step forward in developing a better technique to gather information from patients’ blood – a ‘halo effect’ of biomolecules sticking to the liposomes has been seen before, but only after dipping the nanoparticles in blood samples in a tube outside the patient’s body.

Dr Marilena Hadjidemetriou, study author from the University of Manchester, said: “The blood is a potential goldmine of information, but there’s a challenge to amplify cancer signals that would otherwise be buried within the ‘noise’.

“More abundant proteins mask rarer and smaller molecules that could be significant in helping us to understand disease progression or finding potential new drug targets. This technique overcomes this challenge.”

Professor Caroline Dive, Cancer Research UK’s expert in liquid biopsies, said: “Finding a test to help diagnose, track and treat cancer is something many scientists are pursuing. Liquid biopsies are quicker, cheaper and less invasive than many other tests, and this technique is an important early step in developing such a test. Further work will reveal what the information captured using liposomes can tell us about the disease.”

The researchers now hope to use this technique in mice to help find the best patterns of biomarkers to identify cancers in the early stages of disease as part of their Cancer Research UK Pioneer Award, which funds innovative ideas from any discipline that could revolutionise our understanding of cancer.

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