Tag: metastasis

Metastasis and Atherosclerosis Share an Underlying Mechanism

Source: Wikimedia CC0

Researchers have identified a key signalling molecule for cancer metastasis. one which is already known for its involvement in atherosclerosis, suggesting a possible treatment approach for both diseases simultaneously. The discovery was published in the International Journal of Cancer.

In order to become malignant, metastasising cancer, tumour cells undergo a series of transformations involving interactions with the immune system. Growing evidence exists that in tumour progression to metastasis, inflammation of blood vessel-lining endothelial cells is a key process.

A team of researchers led by Professor Kyoko Hida at Hokkaido University have discovered that, in malignant tumours, endothelial cells accumulate low-density lipoprotein (LDL) and neutrophils. Neutrophils are immune suppressor cells which are known to contribute to tumour progression.

Previous work by the team had revealed that blood vessels in malignant tumorus expressed a high level of proteoglycans, and it is known that cancerous tissue is inflamed – similar to what is seen in atherosclerosis.

The research team showed that metastasising tumors, in contrast to non-metastasising ones, accumulate proteoglycan molecules; these, in turn, attach to and accumulate LDL to the walls of blood vessels, where it becomes oxidised. There are also high levels of its receptor, LOX-1, in the blood vessel-lining endothelial cells of metastasising tumours. This, they found, causes these cells to produce inflammation signals that attract neutrophils. Using a mouse model, they proved that the suppression of LOX-1 can significantly reduce tumour malignancy, and also that LOX-1 overexpression caused an increase in signalling molecules attracting neutrophils.

This sequence of interactions observed in malignant tumours is not novel: it occurs in atherosclerosis. “Atherosclerosis and cancer appear to be completely different diseases, but they share several common pathophysiological features in the blood vessels,” said Prof Hida.

Though some questions remain, especially on the mechanism of how neutrophils contribute to cancer malignancy, this study is the first to explicitly prove the mechanistic commonalities between cardiovascular disease and cancer progression and trace the mechanism involving LDL accumulation and LOX-1 expression in in vivo tumour tissue.

“Our present study focused on the importance of LOX-1 in endothelial cells as a common factor between cancer and atherosclerosis,” Prof Hida explained. “The presence of neutrophils in tumours is a telltale sign of tumor progression.”

The study also points to a promising approach for treating and preventing malignant cancer (and cardiovascular disease) by targeting neutrophil recruitment to endothelial cells. Prof Hida concluded: “The number of patients with cancer who die not of cancer, but of cardiovascular events, is increasing. Targeting the LOX-1/oxidised LDL axis might be a promising strategy for the treatment of the two diseases concomitantly.”

Source: Hokkaido University

Why Some Cells Move Faster in Thicker Mediums

Lung cancer metastasising. Photo by National Cancer Institute on Unsplash

Researchers have discovered that, counterintuitively, certain cells move faster in thicker fluid – such as mucus as opposed to blood – because their ruffled edges sense the viscosity of their environment and adapt to increase their speed.

The researchers’ combined results in cancer and fibroblast cells suggest that the viscosity of a cell’s surrounding environment is an important contributor to disease. The findings, published in Nature Physics, may help explain tumour progression, scarring in mucus-filled lungs affected by cystic fibrosis, and the wound-healing process.

“This link between cell viscosity and attachment has never been demonstrated before,” noted Sergey Plotnikov, assistant professor at the University of Toronto and a co-corresponding author of the study. “We found that the thicker the surrounding environment, the stronger the cells adhere to the substrate and the faster they move – much like walking on an icy surface with shoes that have spikes, versus shoes with no grip at all.”

Understanding why cells behave in this surprising way is important because cancer tumours create a viscous environment, which means spreading cells can move into tumours faster than non-cancerous tissues. Since the researchers observed that cancer cells speed up in a thickened environment, they concluded that the development of ruffled edges in cancer cells may contribute to cancer spreading to other areas of the body.

Targeting the spreading response in fibroblasts, on the other hand, may reduce tissue damage in the mucus-filled lungs affected by cystic fibrosis. Because ruffled fibroblasts move quickly, they are the first type of cells to move through the mucus to the wound, contributing to scarring rather than healing. These results also imply that cell movement might be controlled by changing the viscosity of the lung’s mucus.

“By showing how cells respond to what’s around them, and by describing the physical properties of this area, we can learn what affects their behaviour and eventually how to influence it,” says Ernest Iu, PhD student at the University of Toronto and study co-author.

Plotnikov added, “For example, perhaps if you put a liquid as thick as honey into a wound, the cells will move deeper and faster into it, thereby healing it more effectively.”

Asst Prof Plotnikov and Iu used advanced microscopy techniques to measure the traction that cells exert to move, and changes in structural molecules inside the cells. They compared cancer and fibroblast cells, which have ruffled edges, to cells with smooth edges. They determined that ruffled cell edges sense the thickened environment, triggering a response that allows the cell to pull through the resistance – the ruffles flatten down, spread out and latch on to the surrounding surface.

The experiment originated at Johns Hopkins, where assistant professor Yun Chen, lead author of the study, and Matthew Pittman, PhD student and first author, were first examining the movement of cancer cells. Pittman created a viscous, mucus-like polymer solution, deposited it on different cell types, and saw that cancer cells moved faster than non-cancerous cells when migrating through the thick liquid. To further probe this behaviour, Asst Prof Chen collaborated with U of T’s Plotnikov, who specialises in the push and pull of cell movement.

Plotnikov was amazed at the change in speed going into thick, mucus-like liquid. “Normally, we’re looking at slow, subtle changes under the microscope, but we could see the cells moving twice as fast in real time, and spreading to double their original size,” he explained.

Typically, cell movement depends on myosin proteins, which help muscles contract. Asst Prof Plotnikov and Iu reasoned that stopping myosin would prevent cells from spreading, however were surprised when evidence showed the cells still sped up despite this action. They instead found that columns of the actin protein inside the cell, which contributes to muscle contraction, became more stable in response to the thick liquid, further pushing out the edge of the cell.   

The teams are now investigating how to slow the movement of ruffled cells through thickened environments, which may open the door to new treatments for people affected by cancer and cystic fibrosis.

Source: EurekAlert!

Tissue-sparing Radiotherapy for Lung Cancer Brain Metastasis is Effective

MRI or CT machine
Photo by Mart Production on Pexels

A new study appearing in The Lancet Oncology suggests that a targeted radiation therapy is as effective as standard care for patients with lung cancer brain metastasis.

The findings suggests that patients could benefit from this targeted approach as it is known to have have fewer negative cognitive consequences.

In non-small-cell (NSLC) lung cancer, about 57% of patients present with metastatic disease, and 20% present with brain metastases. Brain metastasis is currently treated with whole brain radiation therapy, which targets the entire brain. While this approach treats even microscopic tumours, it results in memory problems and decreases cognitive function. The alternative, stereotactic radiosurgery, spares healthy brain tissue by precisely targeting the tumour, has been shown to have less severe cognitive consequences but has not yet been studied in patients with small cell lung cancer that has metastasised to the brain.

“For many years, it made sense to treat these patients with whole brain radiation because their survival was quite poor,” said Karolina Gaebe, a research student in Dr Sunit Das’s lab, who led the study.

“For them, long-term consequences of the treatment were not as crucial as reducing the impact of disease in the short-term. But now, as treatments for their lung cancer have improved, these patients are surviving much longer.”

The researchers set out to learn more after noticing patients with longer survival times were also living with severe cognitive impairments due to the treatments for their brain metastases. They wanted to understand whether a more targeted brain radiation regimen might be as beneficial for these patients, as has been demonstrated for most other cancer types.

As a first step, they undertook this meta-analysis, reviewing current literature to examine survival and brain outcomes following stereotactic radiosurgery for patients with small cell lung cancer that had spread to the brain. The team analysed data from 31 studies and included 18 130 patients, the largest cohort of small cell lung cancer patients with brain metastases to be studied so far.

The next steps are to conduct a large clinical trial to investigate cognitive outcome differences between stereotactic radiosurgery and whole brain radiation therapy for such patients.

“Because this is a meta-analysis, we can’t use this as absolute evidence that all patients should be treated in this way,” Dr Das said. “But essentially, this means that we need to challenge our standing worldwide paradigms for treating patients with this disease and revisit the idea that these patients should receive whole brain radiation therapy.”

Source: EurekAlert!

Unlikely Allies: Bacteria can Promote Cancer Metastasis

Scanning Electron Micrograph of a breast cancer cell. Credit: NIH

Researchers have found that bacteria lurking inside tumours promote cancer metastasis. They do so by enhancing the strength of host cells against mechanical stress in the bloodstream, promoting cell survival during tumour progression, researchers report in the journal Cell.

“Our study reveals that the cancer cell’s behaviour is also controlled by the microbes hiding inside tumours, the majority of which were originally thought to be sterile,” said senior author Shang Cai of the Westlake Laboratory of Life Sciences and Biomedicine. “This microbial involvement is distinct from the genetic, epigenetic, and metabolic components that most cancer drugs target.”

“However, our study does not mean that using antibiotics during cancer treatment will benefit patients,” he cautioned. “Therefore, it is still an important scientific question of how to manage the intratumor bacteria to improve cancer treatment in the future.”

It is known that microbes play a critical role in affecting cancer susceptibility and tumour progression, particularly in colorectal cancers. New evidence suggests however that, in a broad range of cancer types, they also form integral components of the tumour tissue itself, such as pancreatic cancer, lung cancer, and breast cancer. Microbial features are linked to cancer risk, prognosis, and treatment responses, yet the biological functions of tumour-resident microbes in tumour progression remain unclear.

Whether these microbes are actually drivers of tumour progression has been an intriguing question. “Tumour cells hijacked by microbes could be more common than previously thought, which underscores the broad clinical value of understanding the exact role of the tumour-resident microbial community in cancer progression,” Cai explained.

To find answers, Cai’s team utilised a mouse model of breast cancer with significant amounts of bacteria inside cells, similar to human breast cancer. The bacteria were found to be capable of travelling through the circulatory system with the cancer cells, playing critical roles in tumour metastasis. These passenger bacteria have the capacity to modulate the cellular actin network, promoting cell survival against mechanical stress in circulation.

“We were surprised initially at the fact that such a low abundance of bacteria could exert such a crucial role in cancer metastasis. What is even more astonishing is that only one shot of bacteria injection into the breast tumour can cause a tumour that originally rarely metastasises to start to metastasise,” Cai said. “Intracellular microbiota could be a potential target for preventing metastasis in broad cancer types at an early stage, which is much better than to have to treat it later on.”

While intratumour bacteria was found to have a clear role in promoting cancer cell metastatic colonisation, the authors did not exclude the possibility that the gut microbiome and immune system may act together with intratumour bacteria to determine cancer progression. Future in-depth analyses of how bacteria invade tumour cells, how intracellular bacteria are integrated into the host cell system, and how bacteria-containing tumor cells interact with the immune system will help inform how to properly deploy antibiotics in cancer treatment.

Source: ScienceDaily

Passing Through Tight Spaces Make Cancer Cells More Aggressive

A scanning electron microscope image of a breast cancer cell.
Credit: Bruce Wetzel and Harry Schaefer, National Cancer Institute, National Institutes of Health

Squeezing through tight spaces makes cancer cells more aggressive and helps them evade cell death, a study published in eLife shows.

The researchers’ findings reveal how mechanical stress makes cancer cells more likely to metastasise. While metastasis is the cause of most cancer deaths, there are currently no available cures. However, the new results may help scientists develop novel approaches to treat or prevent metastasis.

When cancer cells escape their tumour or enter called capillaries to spread throughout the body, it can be tight squeeze. The cells have to collapse and change shape – a process called confined migration. The cells must also evade the immune system as they spread outwards.

“Mechanical stress can cause cancer cell mutations, as well as an uncontrolled increase in cell numbers and greater tissue invasion,” explained first author Deborah Fanfone, Postdoctoral Fellow at the Cancer Research Center of Lyon. “We wanted to know if the mechanical stress of confined migration makes cancer cells more likely to metastasise, and how this happens.”

To find out, the researchers forced human breast cancer cells through a membrane with 3µm-sized holes to simulate a confined migration environment. After passing through the membrane just once, the cells became more mobile and resistant to anoikis –a form of programmed cell death that occurs when cells become detached from the extracellular matrix. The cells were also able to escape destruction by immune natural killer cells.

More testing showed that expression of inhibitory-of-apoptosis proteins (IAPs) increased the resistance of cancer cells to anoikis. A new type of cancer drug which degrades IAPs (called a SMAC mimetic), removed this protection in the cancer cells.

The team then examined how these squeezed cells behave when administered to immune-suppressed mice. They found these mice developed more lung metastases than mice that were administered with breast cancer cells that had not been exposed to confined migration.

“By mimicking confined migration, we’ve been able to explore its multifaceted effects on cancer aggressiveness,” says senior author Gabriel Ichim, who leads the Cancer Cell Death team at the Cancer Research Center of Lyon. “We’ve shown how the process boosts survival in cancer cells and makes them more prone to forming deadly metastases.”

The authors add that these results may lead to additional studies of potential metastasis treatments, such as therapies that soften tumours to reduce mechanical stress on cancer cells, or that block IAPs. These include SMAC mimetics, which are currently being tested in clinical trials as a possible new treatment approach.

Source: eLife Sciences

Statins Could Slow Metastases, Study Finds

Melanoma cells. Source: National Cancer Institute.

By screening various drugs to inhibit a cancer-driving gene, researchers have hit upon a familiar drug – statins.

Cancer patients rarely die from the primary tumour, but rather from the metastases – even after successful tumour surgery. This is because cancer cells sometimes metastasise when the tumour is still very small and may not have even been discovered yet. To do this, they must break away from the extracellular matrix and migrate into neighbouring lymphatic vessels or blood vessels that transport them to new tissue, where they settle and proliferate.

Understanding the molecular mechanisms of metastasis is therefore a key piece of the puzzle in the fight against cancer. More than a decade ago, Professor Ulrike Stein and her lab discovered an important driver of this process in human colorectal cancer: the metastasis-associated in colon cancer 1 (MACC1) gene.

When cancer cells express MACC1, their ability to proliferate, move around the body, and invade other tissues is enhanced. “Many types of cancers spread only in patients with high MACC1 expression,” Prof Stein explained. MACC1’s role as a key factor and biomarker of tumour growth and metastasis – in many solid tumours beside colorectal cancer – has since been studied by many other researchers worldwide and confirmed in more than 300 publications. Now together with Dr Robert Preißner of Charité, Stein has discovered what could disrupt metastatic progression in such cases: statins, normally prescribed for lowering cholesterol, can inhibit MACC1 expression in tumour cells. The scientists are presenting their findings in the journal Clinical and Translational Medicine.

In their search for MACC1 inhibitors, the researchers conducted high-throughput drug screening, and independently arrived at statins. Tests on various tumour cell lines were favourable: All seven drugs tested reduced MACC1 expression in the cells, but to varying degrees. The scientists then administered the cholesterol inhibitors to genetically modified mice with increased MACC1 expression. This almost completely suppressed the formation of tumours and metastases in the animals. “What is particularly remarkable is that the benefits continued in the animals even after we reduced the animal dose to a human equivalent dose,” Stein said.

Dr Preißner and collaborators also examined data from a total of 300 000 patients who had been prescribed statins. This analysis found a correlation: “Patients taking statins had only half the incidence of cancer compared to the general population,” Preißner explains.

Prof Stein warned against taking statins as a preventive measure without consulting a doctor and having their lipid levels checked.

“We are still at the very beginning,” Dr Stein cautioned. “Cell lines and mice are not human beings, so we cannot directly transfer the results.” The experimental studies and retrospective data analysis will now be followed up by a clinical trial, she said. Only after that will it be possible to say with certainty whether statins actually prevent or reduce metastasis in patients with high MACC1 expression.

Source: Max Delbrück Center for Molecular Medicine

A Protein’s Role in Why Some Tumours Metastasise

Melanoma cells. Source: National Cancer Institute.

Researchers have identified a protein which explains why some tumours metastasise, contributing to a better understanding of the process in certain types of cancer. 

In a study published in Frontiers in Oncology, researchers focused on MFSD1 – the mammalian relative of a protein they had previously identified as affecting cell migration in fruit flies. created mouse cancer cells lacking the protein. Without the protein, cells travelled much faster, suggesting that MFSD1 prevents the cells from moving. The team tested their theory in living mice with breast, colon, and skin cancer. “In the absence of MFSD1, there was a strong increase in metastasis,” said lead researcher Professor Daria Siekhaus.

“We wanted to know why lower MFSD1 levels were beneficial to the tumour apart from allowing them to move more freely. As cancer cells travel through the blood for example, they experience a lot of mechanical stress,” explained first author Marko Roblek. 

So the researchers performed a stress test on cancer cells with and without the protein. Using a tiny rubber scraper, Roblek tried to scrape the cells off the surface of the Petri dish in which he had grown them. While the cancer cells with MFSD1 quickly died under the mechanical stress, those without the protein tended to remain intact. Without the protein, the team concluded, certain tumour cells could more easily enter the bloodstream and find their way to other parts of the body. In another experiment, the researcher tested the cancer cell’s resistance to nutrient starvation with a similar result. Again, the cells lacking MFSD1 survived for longer.

The protein MFSD1 appeared to cause the cells’ reaction to starvation and mechanical stress by affecting specific receptors located at the cell surface. These receptors, known as integrins, ensure the cells stick to each other and the extracellular matrix. The cell produces these receptors, transports them to the cell surface and back inside the cell. If a tumour cell lacks MFSD1, they fail to recycle a certain type of integrin. “The result is that the cells stick less to the surrounding tissue and each other, which makes it easier for them to migrate,” said Prof Siekhaus.

Anonymised patient data supported this, showing a correlation between the level of MFSD1 and the patient’s prognosis. “We’ve seen that patients suffering from specific forms of breast, gastric and lung cancer who had lower levels of MFSD1 had a worse outcome. A high level of MFSD1 seems to be protective – it works like a suppressor of tumor metastasis,” said cancer researcher Roblek.

To optimise therapy for their patients, doctors are already analysing the expression of certain genes. Now, they can also look for the gene encoding the protein MFSD1. “If this marker becomes more established, doctors can use it to help classify how aggressive the cancer is and to decide between different treatment options,” suggested Prof Siekhaus. 

In future studies, the team wants to focus in detail on how the protein functions on a molecular level and is curious to learn if artificially raising the amount of MFSD1 could help suppress the spread of certain tumours. The long term goal is to examine if it can be used as a therapeutic target.

Source: EurekAlert!

New Guidelines for Brain Cancer Care

Credit: National Cancer Institute

New guidelines for managing and treating brain metastases have been published in the Journal of Clinical Oncology and are set to improve care for cancer patients and extend and improve the quality of their lives.

The new guidelines come from an expert panel assembled by the American Society of Clinical Oncology (ASCO). The panel included a diverse range of top cancer doctors, as well as a patient representative.

The guidelines reflect the enormous advances in care for brain metastases  over the last few decades. In the 1970s, early attempts to develop guidelines largely emphasised steroids and whole-brain radiation therapy, without controlled, randomised studies to guide the use of surgery and chemotherapy.

Far more encompassing and far more evidence-based, the new guidelines will help doctors and patients make the best treatment decisions and achieve the best outcomes.

“When I started in this field 30 years ago, the average survival with brain metastases was 4 months, and most patients died from the brain disease. With improvements in therapies, fewer than one-quarter of patients die from the brain metastases, and some patients live years or are even cured,” said David Schiff, MD, a co-chair of the ASCO panel and the co-director of UVA Cancer Center’s Neuro-Oncology Center. “Equally importantly, the use of advanced localised radiation techniques and new targeted chemotherapies and immunotherapies have improved the quality of survival for most patients suffering from brain metastases.”

Up to 30% of cancer patients will have it spread to the brain, where it can be extremely difficult to treat. In the United States, approximately 200 000 new brain metastases are diagnosed each year.

The likelihood of a solid tumour spreading to the brain varies by cancer type, with approximately 20% of lung cancers spreading to the brain within a year after diagnosis. For patients with breast cancer, renal cell cancer or melanoma, that number is up to 7%. That is in addition to the patients found to have brain metastases at the time of their initial diagnosis.

Bringing together a diverse range of disciplines, the ASCO panel incorporated the results of more than 30 randomised trials published since 2008. The resulting guidelines cover everything from when surgery is appropriate and when and in what form radiation should be used to those circumstances in which medication alone may be employed.

The guidelines emphasise the importance of local therapies (surgery or stereotactic radiosurgery) for symptomatic brain metastases and lay out when these options are feasible. They highlight situations in which local therapy or whole brain radiotherapy can be deferred in place of chemotherapy, targeted therapy or immunotherapy depending on tumour type and molecular features. They also lay out how, in many cases, doctors can avoid the cognitive toxicity of whole brain radiotherapy by using either stereotactic radiosurgery or hippocampal-avoidant whole brain radiotherapy with the drug memantine.

“Patients with brain metastases may initially see a neurosurgeon, radiation or medical oncologist. The rigorous analysis underpinning these guidelines will provide each subspecialist a comprehensive picture of the treatment options appropriate for a given patient,” Dr Schiff said. “The result will allow patients the optimal personalised approach to maximise long-term control of brain metastases with good functional outcome.”

 Additional information is available at the ASCO website.

Source: EurekAlert!

Why Cancer Cells Linger to Create Metastatic Cancer

Colon cancer cells. Source: National Cancer Institute on Unsplash

A major mystery in cancer research has been solved: How cancer cells remain dormant for years after leaving a tumour before awakening to create metastatic cancer.

According to findings by Mount Sinai researchers which were reported in Nature Cancer, the cells remain quiet by secreting a type of collagen, called type III collagen, in the environment around themselves, and only turn malignant once the level of collagen tapers off. The researchers found that by enriching the environment around the cells with this collagen, they could force the cells to remain in a dormant state and prevent tumour recurrence.

“Our findings have potential clinical implications and may lead to a novel biomarker to predict tumour recurrences, as well as a therapeutic intervention to reduce local and distant relapses,” said senior author Jose Javier Bravo-Cordero, PhD, Associate Professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at Mount Sinai. “This intervention aimed at preventing the awakening of dormant cells has been suggested as a therapeutic strategy to prevent metastatic outgrowth. As the biology of tumour dormancy gets uncovered and new specific drugs are developed, a combination of dormancy-inducing treatments with therapies that specifically target dormant cells will ultimately prevent local recurrence and metastasis and pave the way to cancer remission.”

Most cancer deaths result from metastases, which can occur several years after removal of a tumour. Previous work looked at how dispersed tumour cells awaken from dormancy; this new work showed how the cells remain dormant.

The study used high-resolution imaging techniques, including intravital two-photon microscopy, a technology that allows the visualisation of dormant cells in their environment in real time in a living animal. This technology allowed the researchers to track dormant tumour cells in mouse models using cancer cell lines. By using this technology, the researchers were able to visualise the changes in the architecture of the extracellular matrix as tumour cells became dormant and how it changed when these cells awoke.

The researchers demonstrated that an abundance of the collagen could potentially be used as a predictor of tumour recurrence and metastasis. In the mouse models, when type III collagen was increased around cancer cells that had left a tumour, cancer progression was interrupted and the disseminated cells were forced into a dormant state. Similar to wound treatment, in which collagen scaffolds have been proposed to treat complex skin wounds, this study suggests that by enriching the tumour microenvironment in type III collagen, metastasis may be prevented by sending tumour cells into a dormant state.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Plant Virus-based Treatment Protects Against Lung Tumours

Image source: CDC/Unsplash

Using a virus that grows in black-eyed pea plants, nanoengineers developed a new treatment that could keep metastatic cancers at bay from the lungs. 

Not only did the treatment slow tumour growth in the lungs of mice with either metastatic breast cancer or melanoma, it also prevented or drastically minimised the spread of these cancers to the lungs of healthy mice that were challenged with the disease. The research was published in Advanced Science.

Researchers developed an experimental treatment that combats metastatic spread. This involves a plant virus called the cowpea mosaic virus, harmless to animals and humans, but which the body still registers as a foreign invader, thus triggering an immune response that could also boost the body’s cancer-fighting ability.

The idea is to use the plant virus to help the body’s immune system recognise and destroy cancer cells in the lungs. The virus itself is not infectious in our bodies, but it has all these danger signals that alarm immune cells to go into attack mode and search for a pathogen, said Nicole Steinmetz, professor of nanoengineering at the University of California San Diego.

To draw this immune response to lung tumours, Prof Steinmetz’s lab engineered nanoparticles made from the cowpea mosaic virus to target a protein in the lungs. The protein, called S100A9, is expressed and secreted by immune cells that help fight infection in the lungs. Overexpression of S100A9 has been observed to play a role in tumour growth and spread.

“For our immunotherapy to work in the setting of lung metastasis, we need to target our nanoparticles to the lung,” said Prof Steinmetz. “Therefore, we created these plant virus nanoparticles to home in on the lungs by making use of S100A9 as the target protein. Within the lung, the nanoparticles recruit immune cells so that the tumors don’t take.”

“Because these nanoparticles tend to localise in the lungs, they can change the tumor microenvironment there to become more adept at fighting off cancer — not just established tumors, but future tumors as well,” said Eric Chung, a bioengineering PhD student in Steinmetz’s lab who is one of the co-first authors on the paper.

To make the nanoparticles, the researchers infected black-eyed pea plants with cowpea mosaic virus, and harvested the virus in the form of ball-shaped nanoparticles. They then fixed S100A9-targeting molecules to the particles’ surfaces.

The researchers performed both prevention and treatment studies. In the prevention studies, they first injected the plant virus nanoparticles into the bloodstreams of healthy mice, and then later injected either triple negative breast cancer or melanoma cells into these mice. Treated mice showed a dramatic reduction in the cancers spreading to their lungs compared to untreated mice.

In the treatment studies, the researchers administered the nanoparticles to mice with metastatic tumours in their lungs. The treated mice exhibited smaller lung tumours and survived longer than untreated mice.

Prof Steinmetz envisions that the treatment could be useful after tumourectomy. “It wouldn’t be meant as an injection that’s given to everyone to prevent lung tumours. Rather, it would be given to patients who are at high risk of their tumors growing back as a metastatic disease, which often manifests in the lung. This would offer their lungs protection against cancer metastasis,” she said.

More detailed immunotoxicity and pharmacology studies are needed before this can progress to a treatment. Future studies will also explore combining this with standard cancer therapies such as chemotherapy.

Source: University of California – San Diego