Category: Cancer

Categories : Cancer GastrointestinalTags :

Low-carb Diet’s Colorectal Cancer Risk is Mediated by the Gut Microbiome

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Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health

Researchers from the University of Toronto have shown how a low-carbohydrate diet can worsen the DNA-damaging effects of some gut microbes to cause colorectal cancer.

The study, published in the journal Nature Microbiology, compared the effects of three different diets: normal, low-carb, or Western-style with high fat and high sugar, each in combination with specific gut bacteria on colorectal cancer development in mice.

They found that a unique strain of E. coli bacteria, when paired with a diet low in carbs and soluble fibre, drives the growth of polyps in the colon, which can be a precursor to cancer.

“Colorectal cancer has always been thought of as being caused by a number of different factors including diet, gut microbiome, environment and genetics,” says senior author Alberto Martin, a professor of immunology at U of T’.

“Our question was, does diet influence the ability of specific bacteria to cause cancer?”

To answer this question, the researchers, led by postdoctoral fellow Bhupesh Thakur, examined mice that were colonized with one of three bacterial species that had been previously linked to colorectal cancer and fed either a normal, low-carb or Western-style diet.

Only one combination, a low-carb diet paired with a strain of E. coli that produces the DNA-damaging compound colibactin, led to the development of colorectal cancer.

The researchers found that a diet deficient in fibre increased inflammation in the gut and altered the community of microbes that typically reside there, creating an environment that allowed the colibactin-producing E. coli to thrive.

They also showed that the mice fed a low-carb diet had a thinner layer of mucus separating the gut microbes from the colon epithelial cells. The mucus layer acts as a protective shield between the bacteria in the gut and the cells underneath. With a weakened barrier, more colibactin could reach the colon cells to cause genetic damage and drive tumour growth. These effects were especially strong in mice with genetic mutations in the mismatch repair pathway that hindered their ability to fix damaged DNA.

While both Thakur and Martin emphasize the need to confirm these findings in humans, they are also excited about the numerous ways in which their research can be applied to prevent cancer.

Defects in DNA mismatch repair are frequently found in colorectal cancer, which is the fourth most commonly diagnosed cancer in Canada. An estimated 15 per cent of these tumours having mutations in mismatch repair genes. Mutations in these genes also underlie Lynch syndrome, a genetic condition that significantly increases a person’s risk of developing certain cancers, including colorectal cancer.

“Can we identify which Lynch syndrome patients harbour these colibactin-producing microbes?” asks Martin. He notes that for these individuals, their findings suggest that avoiding a low-carb diet or taking a specific antibiotic treatment to get rid of the colibactin-producing bacteria could help reduce their risk of colorectal cancer.

Martin points out that a strain of E. coli called Nissle, which is commonly found in probiotics, also produces colibactin. Ongoing work in his lab is exploring whether long-term use of this probiotic is safe for people with Lynch syndrome or those who are on a low-carb diet.

Thakur is keen to follow up on an interesting result from their study showing that the addition of soluble fibre to the low-carb diet led to lower levels of the cancer-causing E. coli, less DNA damage and fewer tumours.

“We supplemented fibre and saw that it reduced the effects of the low-carb diet,” he says. “Now we are trying to find out which fibre sources are more beneficial, and which are less beneficial.”

To do this, Thakur and Martin are teaming up with Heather Armstrong, a researcher at the University of Alberta, to test whether supplementation with a soluble fibre called inulin can reduce colibactin-producing E. coli and improve gut health in high-risk individuals, like people with inflammatory bowel disease.

 “Our study highlights the potential dangers associated with long-term use of a low-carb, low-fibre diet, which is a common weight-reducing diet,” says Martin.

“More work is needed but we hope that it at least raises awareness.”

Source: University of Toronto

Categories : CancerTags :

Scientists Discover How Aspirin Could Prevent Metastasis in Some Cancers

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Credit: Pixabay CC0

Scientists have uncovered the mechanism behind how aspirin could reduce the metastasis of some cancers by stimulating the immune system.

In the study published in Nature, the scientists say that discovering the mechanism will support ongoing clinical trials, and could lead to the targeted use of aspirin to prevent the spread of susceptible types of cancer and the development of more effective drugs to prevent cancer metastasis.

The scientists caution that aspirin can have serious side effects and that trials are underway to establish safety and efficacy.

A reduction in the spread of some cancers

Studies of people with cancer have previously observed that those taking daily low-dose aspirin have a reduction in the spread of some cancers, such as breast, bowel, and prostate cancers, leading to ongoing clinical trials. However, until now it wasn’t known exactly how aspirin could prevent metastases.

In this study, led by researchers at the University of Cambridge, the scientists say their discovery of how aspirin reduces cancer metastasis was serendipitous.

They were investigating the process of metastasis, because, while cancer starts out in one location, 90% of cancer deaths occur when cancer spreads to other parts of the body.

Lung cancer metastasis. Credit: National Cancer Institute

The scientists wanted to better understand how the immune system responds to metastasis. This is because when individual cancer cells break away from their originating tumour and spread to another part of the body, they are particularly vulnerable to immune attack.

An effect on cancer metastasis

The immune system can recognise and kill these lone cancer cells more effectively than cancer cells within larger originating tumours, which have often developed an environment that suppresses the immune system.

The researchers previously screened 810 genes in mice and found 15 that had an effect on cancer metastasis. In particular, they found that mice lacking a gene that produces a protein called ARHGEF1 had less metastasis of various primary cancers to the lungs and liver.

The researchers determined that ARHGEF1 suppresses T cells, which can recognise and kill metastatic cancer cells.

To find a suitable drug, the scientists traced signals in the cell to determine that ARHGEF1 is switched on when T cells are exposed to a clotting factor called thromboxane A2 (TXA2).

This was an unexpected revelation for the scientists, because TXA2 is already well-known and linked to how aspirin works.

Reduces the production of TXA2

TXA2 is produced by platelets; aspirin reduces the production of TXA2, leading to the anti-clotting effects, which underlies its ability to prevent heart attacks and strokes.

This new research found that aspirin prevents cancers from spreading by decreasing TXA2 and releasing T cells from suppression. They used a mouse model of melanoma to show that in mice given aspirin, the frequency of metastases was reduced compared to control mice, and this was dependent on releasing T cells from suppression by TXA2.

Professor Rahul Roychoudhuri, from the University of Cambridge, who led the study, said:

Despite advances in cancer treatment, many patients with early stage cancers receive treatments, such as surgical removal of the tumour, which have the potential to be curative, but later relapse due to the eventual growth of micrometastases – cancer cells that have seeded other parts of the body but remain in a latent state.

Most immunotherapies are developed to treat patients with established metastatic cancer, but when cancer first spreads there’s a unique therapeutic window of opportunity when cancer cells are particularly vulnerable to immune attack.

We hope that therapies that target this window of vulnerability will have tremendous scope in preventing recurrence in patients with early cancer at risk of recurrence.

More accessible globally

Dr Jie Yang, who carried out the research, at the University of Cambridge, said:

It was a Eureka moment when we found TXA2 was the molecular signal that activates this suppressive effect on T cells.

Before this, we had not been aware of the implication of our findings in understanding the anti-metastatic activity of aspirin. It was an entirely unexpected finding which sent us down quite a different path of enquiry than we had anticipated.

Aspirin, or other drugs that could target this pathway, have the potential to be less expensive than antibody-based therapies, and therefore more accessible globally.

In the future, the researchers plan to help the translation of their work into potential clinical practice by collaborating with Professor Ruth Langley, of the MRC Clinical Trials Unit at University College London, who is leading the Add-Aspirin clinical trial, to find out if aspirin can stop or delay early stage cancers from coming back.

Caution on aspirin use

Professor Langley, who was not involved in this study, commented:

This is an important discovery. It will enable us to interpret the results of ongoing clinical trials and work out who is most likely to benefit from aspirin after a cancer diagnosis.

In a small proportion of people, aspirin can cause serious side-effects, including bleeding or stomach ulcers. Therefore, it is important to understand which people with cancer are likely to benefit and always talk to your doctor before starting aspirin.

Source: UK Research and Innovation

Categories : Cancer Neurology PaediatricsTags :

Scientists Crack the Puzzle of How Retinoic Acid Works Against Neuroblastoma

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Photo by Anna Shvets

Neuroblastoma is a solid tumour that occurs in children. When high-risk, the disease has a poor prognosis. Decades ago, adding the drug retinoic acid to neuroblastoma treatment increased survival by 10–15%. However, this effect was only evident in post-chemotherapy consolidation after bulky primary tumours had largely been eliminated. Why retinoic acid is effective in this setting but not against primary tumours, has been speculated about for nearly 50 years. 

St. Jude Children’s Research Hospital scientists resolved the mystery in a new study, showing retinoic acid uses a novel mechanism to kill metastasised neuroblastoma. The drug “hijacks” a normal developmental pathway to trigger cancer cell death. The findings, which have implications for future combination therapy approaches, appears in Nature Communications. 

“We’ve come up with an explanation for a decades-long contradiction about why retinoic acid works in post-chemotherapy consolidation but has little impact on primary neuroblastoma tumours,” said senior co-corresponding author Paul Geeleher, PhD. “Retinoic acid’s activity heavily depends on the cellular microenvironment.” 

The cellular microenvironment is the soup of chemicals, proteins and other signals that surround a cell, and which is unique to that part of the body. For example, the bone marrow microenvironment contains signals to grow blood cells and restructure bone. Metastasised neuroblastoma cells often migrate to bone marrow, where the bone morphogenetic protein (BMP) pathway signalling is highly active. The researchers showed that BMP signaling makes neuroblastoma cells much more vulnerable to retinoic acid. 

“Unexpectedly, we found that cells expressing genes from the BMP signaling pathway were very sensitive to retinoic acid,” said co-first and co-corresponding author Min Pan, PhD, St. Jude Department of Computational Biology. “However, since the bone marrow microenvironment causes neuroblastoma cells there to have higher BMP activity, it neatly explained why retinoic acid is very effective at treating those cells during consolidation therapy, but not the primary tumours during up-front treatment.” 

Hijacking development to drive metastatic neuroblastoma cell death 

Using gene editing technology, the scientists uncovered the relationship between BMP signaling and retinoic acid. They assembled a group of neuroblastoma cell lines susceptible to retinoic acid, then cut out genes to find which were responsible for the drug’s activity. Genes in the BMP pathway had the largest effect while providing a plausible explanation for retinoic acid’s varying outcomes in patients.

“We found that, in neuroblastoma, BMP signaling works with retinoic acid signaling in the same way as during development,” said co-first author Yinwen Zhang, PhD, who characterised how transcription factors, the proteins that bind DNA to regulate gene expression, led to different results in highly retinoic acid-sensitive or insensitive neuroblastoma cells. “If there are a lot of BMP-signaling pathway transcription factors already on DNA, then retinoic acid signaling combines with it to promote downstream cell death–related gene expression. This occurs both in normal embryonic development and neuroblastoma cells in certain microenvironments.” 

“We are the first to uncover such an example of ‘hijacking’ a normal embryonic developmental process preserved in cancer that we can exploit therapeutically,” Geeleher said. “Now, we can look for similar processes in other diseases to design less toxic and more effective treatment strategies.” 

Source: St. Jude Children’s Research Hospital

Categories : CancerTags :

Research Draws a Potential Association Between Tattoos and Cancer Risk

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Photo by Benjamin Lehman on Unsplash

Tattoo ink does not just stay under the skin – some of it makes its way into the lymph nodes. Researchers from the Department of Public Health and the Department of Clinical Research at the University of Southern Denmark (SDU), together with the University of Helsinki, have investigated whether this could have health consequences. Using data from Danish twin pairs, they found that tattooed individuals are more frequently diagnosed with skin and lymphoma cancers compared to those without tattoos.

Ink particles in the body may affect the immune system

When tattoo ink penetrates the skin, some of it is absorbed into the lymph nodes, a key part of the immune system. The researchers are particularly concerned that tattoo ink may trigger chronic inflammation in the lymph nodes, which over time could lead to abnormal cell growth and an increased risk of cancer.

“We can see that ink particles accumulate in the lymph nodes, and we suspect that the body perceives them as foreign substances,” explains Henrik Frederiksen, consultant in haematology at Odense University Hospital and clinical professor at SDU.

“This may mean that the immune system is constantly trying to respond to the ink, and we do not yet know whether this persistent strain could weaken the function of the lymph nodes or have other health consequences.”

Studying this link is challenging because cancer can take years to develop. This means that exposure in youth may not lead to illness until decades later, making it difficult to measure a direct effect.

Twin data provides a unique opportunity to study the link

The study is based on data from the Danish Twin Tattoo Cohort, where researchers have information from more than 5900 Danish twins. By analysing tattoo patterns alongside cancer diagnoses, they found a higher occurrence of both skin and lymphoma cancers in tattooed individuals.

“The unique aspect of our approach is that we can compare twin pairs where one has cancer, but they otherwise share many genetic and environmental factors,” says Jacob von Bornemann Hjelmborg, professor of biostatistics at SDU.

“This provides us with a stronger method for investigating whether tattoos themselves may influence cancer risk.”

The size of tattoos matters

The results show that the link between tattoos and cancer is most evident in those with large tattoos – defined as bigger than a palm. 

For lymphoma, the rate is nearly three times higher for the group of individuals with large tattoos compared to those without tattoos.  This rate (more specifically, ‘hazard rate’) accounts for age, the timing of the tattoo, and how long the individuals have been followed in the study. 

“This suggests that the bigger the tattoo and the longer it has been there, the more ink accumulates in the lymph nodes. The extent of the impact on the immune system should be further investigated so that we can better understand the mechanisms at play,” says Signe Bedsted Clemmensen, assistant professor of biostatistics at SDU.

Another study from the Danish Twin Tattoo Cohort shows that tattoos are becoming increasingly common. Researchers estimate that four in ten women and three in ten men will have tattoos by the age of 25.

The link to lymphoma has also been observed in an independent Swedish study from 2024.

Are some ink colours worse than others?

Previous research has suggested that certain pigments in tattoo ink may be more problematic than others.

“In our study, we do not see a clear link between cancer occurrence and specific ink colours, but this does not mean that colour is irrelevant. We know from other studies that ink can contain potentially harmful substances, and for example, red ink more often causes allergic reactions. This is an area we would like to explore further,” says Signe Bedsted Clemmensen.

What are the next steps?

The researchers now plan to investigate how ink particles affect the function of lymph nodes at a molecular level and whether certain types of lymphoma are more linked to tattoos than others.

“We want to gain a better understanding of the biological mechanisms – what happens in the lymph nodes when they are exposed to ink particles over decades? This can help us assess whether there is a real health risk and what we might do to reduce it,” concludes Signe Bedsted Clemmensen.

Source: University of Southern Denmark Faculty of Health Sciences

Categories : Cancer Surgeries & ProceduresTags :

‘Ultra-rapid’ Testing for Cancer Genes in the Operating Theatre

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A novel tool for rapidly identifying the genetic “fingerprints” of cancer cells may enable future surgeons to more accurately remove brain tumours while a patient is in the operating room, new research reveals. Many cancer types can be identified by certain mutations, changes in the instructions encoded in the DNA of the abnormal cells.

Led by a research team from NYU Langone Health, the new study describes the development of Ultra-Rapid droplet digital PCR, or UR-ddPCR, which the team found can measure the level of tumour cells in a tissue sample in only 15 minutes while also being able to detect small numbers of cancer cells (as few as five cells/mm2).

The researchers say their tool is fast and accurate enough, at least in initial tests on brain tissue samples, to become the first practical tool of its kind for detecting cancer cells directly using mutations in real time during brain surgery.

The researchers showed that UR-ddPCR had markedly faster processing speed than standard droplet digital polymerase chain reaction (ddPCR). Standard ddPCR can accurately quantify tumor cells, but it typically takes several hours to produce a result, making it impractical as a surgical guide.

“For many cancers, such as tumors in the brain, the success of cancer surgery and preventing the cancer’s return is predicated on removing as much of the tumor and surrounding cancer cells as is safely possible,” said study co-senior study investigator and neurosurgeon Daniel A. Orringer, MD.

“With Ultra-Rapid droplet digital PCR, surgeons may now be able to determine what cells are cancerous and how many of these cancer cells are present in any particular tissue region at a level of accuracy that has never before been possible,” said Dr Orringer.

Published in the journal Med, the study showed that UR-ddPCR produced the same results as standard ddPCR and genetic sequencing in more than 75 tissue samples from 22 patients at NYU Langone undergoing surgery to remove glioma tumours. Results from UR-ddPCR were also checked against known samples with cancer cells and samples without any cancer.

“Our study shows that Ultra-Rapid droplet digital PCR could be a fast and efficient tool for making a molecular diagnosis during surgery for brain cancer, and it has potential to also be used for cancers outside the brain,” said senior study investigator Gilad Evrony, MD, PhD.

To develop UR-ddPCR, researchers looked for efficiencies in each of the steps involved in standard ddPCR. The team shortened the time needed to extract DNA from tumour samples from 30 minutes to less than 5 minutes in a manner that is still compatible with subsequent ddPCR. The researchers also found efficiencies by increasing the concentrations of the chemicals used in testing, reducing the overall time needed for some steps from two hours to less than three minutes. Time savings were also achieved by using reaction vessels prewarmed to each of the two temperatures required by the PCR rather than repeatedly cycling the temperature of a single reaction vessel between two temperatures.

For the study, researchers used UR-ddPCR to measure the levels of two genetic mutations, IDH1 R132H and BRAF V600E, which are prevalent in brain cancers. They combined UR-ddPCR with another technique the researchers developed earlier, called stimulated Raman histology, to calculate both the fraction and the density of tumour cells within each tissue sample.

Researchers caution that widespread use of the tool awaits further refinements and clinical trials. They say their next step is to automate UR-ddPCR to make it faster and simpler to use in the operating room. Subsequent clinical trials will be necessary to compare patient outcomes using their tool compared to current diagnostic technologies. They also plan to develop the technology to identify other common genetic mutations for other cancer types.

Source: NYU Langone Health / NYU Grossman School of Medicine

Categories : CancerTags :

Case Reveals a Rare Side Effect of Cancer Immunotherapy

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The genetically modified CAR-T cells meant to treat the cancer themselves turned cancerous

Depiction of multiple myeloma. Credit: Scientific Animations

Some forms of blood cancer, such as multiple myeloma and lymphoma, are malignant diseases that originate from immune cells, specifically lymphocytes. In recent years, CAR-T cell therapies have become an essential part of the treatment of patients whose lymphoma or multiple myeloma has relapsed. This involves genetically modifying the patient’s own T lymphocytes (T cells) in order to specifically recognise and eliminate the cancer cells using a chimeric antigen receptor (CAR).

One special case is the subject of an article published in Nature Medicine. A 63-year-old patient with multiple myeloma developed T cell lymphoma in the blood, skin and intestine nine months after undergoing CAR-T cell therapy at the University Hospital of Cologne. The tumour developed from the genetically modified T cells that were used in the treatment.

The initiators of this collaborative project, Professor Marco Herling, managing senior physician at the University of Leipzig Medical Center and Dr Till Braun, research group leader at the University Hospital of Cologne, have world-renowned expertise in understanding the rare but difficult-to-treat T cell lymphomas. “This is one of the first documented cases of such lymphoma following CAR-T cell therapy. The findings of this study will help us to better understand the risks associated with the therapy and possibly prevent them in the future,” says Professor Maximilian Merz, who led the current study as corresponding author together with Professor Marco Herling from the University of Leipzig Medical Center. 

The researchers discovered that it was not just current genetic alterations of the T cells that caused the tumour. Pre-existing genetic changes in the patient’s haematopoietic cells also played a role. The researchers used cutting-edge technologies to study the tumour’s development in detail. Various methods of next-generation sequencing – an advanced, high-throughput technology for analysing DNA and RNA sequences – were used to study the phenomenon. Whole-genome sequencing was used to identify genetic alterations, while single-cell RNA sequencing analysed the transcriptome of the CAR-T cells to investigate genes and signalling pathways.  

These methods had previously been developed in close collaboration between the research groups of Professor Merz at the University of Leipzig Medical Center and Dr Kristin Reiche at the Fraunhofer IZI. The close collaboration between clinicians and basic scientists in the field of CAR-T cell therapy allowed for the case to be analysed in a very short time. The University of Leipzig Medical Center is one of the leading centres in Europe for the treatment of multiple myeloma with CAR-T cells and of T cell lymphoma. “This case provides valuable insights into the emergence and development of CAR-bearing T cell lymphoma following innovative immunotherapies and highlights the importance of genetic predispositions for potential side effects,” says Professor Merz, Senior Physician at the Department for Hematology, Cell Therapy and Hemostaseology at the University of Leipzig Medical Center. 

The researchers are planning further scientific studies to better understand similar cases and identify risk factors. The aim is to be able to predict and prevent such side effects after CAR-T cell therapies, which are currently being used more and more widely, in the future. The high relevance of the topic of secondary tumours after CAR-T cell therapy has now been highlighted in a second scientific paper. The same research team submitted a manuscript to the high-impact journal Leukemia that systematically summarises this patient case and the nine other recently published cases of T cell lymphoma from CAR-T cells worldwide. Normally, it takes several weeks to months for peer reviewers to accept a scientific paper for publication. In this case, the manuscript was accepted for publication within a day. “It is important to create a real, data-based awareness of the rarity of this complication, at far less than one per cent, and the mechanisms by which it occurs,” says Professor Herling.

Source: Universität Leipzig

Categories : Cancer New Compounds and TreatmentsTags :

A Protein from Tardigrades may Blunt the Effects of Radiotherapy

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A tardigrade, otherwise known as a “water bear”. Credit: NIH

Drawing inspiration from a tiny organism that can withstand huge amounts of radiation, researchers have developed a new strategy that may protect patients from this kind of damage. Their approach makes use of a protein from tardigrades, often also called “water bears,” which are usually less than a millimetre in length. 

When the researchers injected messenger RNA encoding this protein into mice, they found that it generated enough protein to protect cells’ DNA from radiation-induced damage. If developed for use in humans, this approach could benefit many cancer patients, the researchers say.

“Radiation can be very helpful for many tumours, but we also recognise that the side effects can be limiting. There’s an unmet need with respect to helping patients mitigate the risk of damaging adjacent tissue,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital.

Traverso and James Byrne, an assistant professor of radiation oncology at the University of Iowa, are the senior authors of the study, which appears in Nature Biomedical Engineering. The paper’s lead authors are Ameya Kirtane, an instructor in medicine at Harvard Medical School and a visiting scientist at MIT’s Koch Institute for Integrative Cancer Research, and Jianling Bi, a research scientist at the University of Iowa.

Extreme survival

Radiation is often used to treat cancers of the head and neck, where it can damage the mouth or throat, making it very painful to eat or drink. It is also commonly used for gastrointestinal cancers, which can lead to rectal bleeding. Many patients end up delaying treatments or stopping them altogether.

“This affects a huge number of patients, and it can manifest as something as simple as mouth sores, which can limit a person’s ability to eat because it’s so painful, to requiring hospitalization because people are suffering so terribly from the pain, weight loss, or bleeding. It can be pretty dangerous, and it’s something that we really wanted to try and address,” Byrne says.

Currently, there are very few ways to prevent radiation damage in cancer patients. There are a handful of drugs that can be given to try to reduce the damage, and for prostate cancer patients, a hydrogel can be used to create a physical barrier between the prostate and the rectum during radiation treatment.

For several years, Traverso and Byrne have been working on developing new ways to prevent radiation damage. In the new study, they were inspired by the extraordinary survival ability of tardigrades. Found all over the world, usually in aquatic environments, these organisms are well known for their resilience to extreme conditions. Scientists have even sent them into space, where they were shown to survive extreme dehydration and cosmic radiation.

One key component of tardigrades’ defence systems is a unique damage suppressor protein called Dsup, which binds to DNA and helps protect it from radiation-induced damage. This protein plays a major role in tardigrades’ ability to survive radiation doses 2000 to 3000 times higher than what a human being can tolerate.

When brainstorming ideas for novel ways to protect cancer patients from radiation, the researchers wondered if they might be able to deliver messenger RNA encoding Dsup to patient tissues before radiation treatment. This mRNA would trigger cells to transiently express the protein, protecting DNA during the treatment. After a few hours, the mRNA and protein would disappear.

For this to work, the researchers needed a way to deliver mRNA that would generate large amounts of protein in the target tissues. They screened libraries of delivery particles containing both polymer and lipid components, which have been used separately to achieve efficient mRNA delivery. From these screens, they identified one polymer-lipid particle that was best-suited for delivery to the colon, and another that was optimized to deliver mRNA to mouth tissue.

“We thought that perhaps by combining these two systems – polymers and lipids – we may be able to get the best of both worlds and get highly potent RNA delivery. And that’s essentially what we saw,” Kirtane says. “One of the strengths of our approach is that we are using a messenger RNA, which just temporarily expresses the protein, so it’s considered far safer than something like DNA, which may be incorporated into the cells’ genome.”

Protection from radiation

After showing that these particles could successfully deliver mRNA to cells grown in the lab, the researchers tested whether this approach could effectively protect tissue from radiation in a mouse model.

They injected the particles into either the cheek or the rectum several hours before giving a dose of radiation similar to what cancer patients would receive. In these mice, the researchers saw a 50 percent reduction in the amount of double-stranded DNA breaks caused by radiation.

The researchers also showed that the protective effect of the Dsup protein did not spread beyond the injection site, which is important because they don’t want to protect the tumour itself from the effects of radiation. To make this treatment more feasible for potential use in humans, the researchers now plan to work on developing a version of the Dsup protein that would not provoke an immune response, as the original tardigrade protein likely would.

If developed for use in humans, this protein could also potentially be used to protect against DNA damage caused by chemotherapy drugs, the researchers say. Another possible application would be to help prevent radiation damage in astronauts in space.

Source: MIT

Categories : Cancer GeneticsTags :

Research Challenges the Understanding of Cancer Predisposition Gene NF-1

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Photo by National Cancer Institute on Unsplash

Despite what was previously thought, new research has shown that genetic changes alone cannot explain why and where tumours grow in those with genetic condition neurofibromatosis type 1 (NF-1). Understanding more about the factors involved could, in the future, facilitate early cancer detection in NF-1 patients and even point towards new treatments.

Researchers from the Wellcome Sanger Institute and collaborating institutions, focused on NF-1, a genetic condition that causes specific types of tumours, and investigated how and why these developed.

The study, published in Nature Genetics, reports that the genetic changes thought to cause tumours can be found in normal tissues throughout the body, suggesting that other factors are also necessary for tumour development.

They also uncovered a pattern of changes in the affected gene, NF1, that may explain why the nervous system in particular is a common site for these tumours to develop.

Understanding what other factors are involved in developing these tumours could help inform monitoring programmes for patients with NF-1, who require regular screening to detect tumours early on and could potentially require multiple surgeries and chemotherapy.

In the future, refining our knowledge of why tumours grow in some places and not others may help us identify the patients most likely to need early medical intervention.

This model of tumour development is not unique to NF-1, raising the possibility that similar events occur in related genetic conditions, meaning many more could benefit from tailored management.

NF-1 is a genetic condition that causes brown skin patches, similar to birthmarks, and tumours1. While the tumours are often benign, they can become cancerous over time and may cause a range of symptoms depending on where they are1. For example, NF-1 can cause soft tissue and brain tumours that may restrict movement and vision.

The symptoms and impact of NF-1 can vary greatly from person to person. It is one of the most common inherited genetic conditions, impacting around one in 2500 people. Those with NF-1 have a genetic change that means one copy of the gene encoding the neurofibromin protein, NF1, does not work. It was previously thought that tumours and brown skin patches occurred when the second copy of the gene was lost.

In a new study, researchers from the Sanger Institute, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, Cambridge University Hospitals NHS Foundation Trust, and their collaborators, studied nearly 500 tissue samples from a child with NF-1 and compared them to tissues from children without the condition.

They found that changes causing a loss of NF1 gene function were not limited to tumours and skin changes but instead can be found throughout other tissues of the child with NF-1 as well. This suggests, whilst advantageous to the affected cells, the mutation is insufficient to cause tumour formation.

For this research, the team applied a new sequencing technology that allowed them to look at genetic changes at a higher resolution than was previously possible and studied additional tissue samples from nine adults with NF-1, showing similar findings.

The team found a pattern of mutations across all patients that showed these were particularly common in tissues of the nervous system. This is a common place for tumours to form in those with NF-1, which can help explain why these tissues are specifically impacted.

“We were astonished to see such extensive genetic changes in the normal tissues of patients with NF-1, seemingly without consequence. This is contrary to our understanding of tumour development in the condition and other related conditions. Additional factors must clearly play a role, perhaps including the cell type and anatomical location affected. Whilst further investigation is needed, I hope this work represents the first step towards developing more personalised care for these patients, such as better identifying who is at greater risk of developing tumours, and adjusting screening to intervene early on and minimise complications.”

Dr Thomas Oliver,co-first author from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust

“NF-1 can have many different impacts on a person’s life. In order to better treat and support those with NF-1, we have to understand more about what is going on at a biological and genetic level, especially in the parts of the body that are most affected, such as the brain and nervous system. Our study showed that these areas of the body have a different pattern of DNA changes, suggesting that if we look further, there could be a potential target for new therapies to help treat or stop tumour development.”

Professor Thomas Jacques,co-senior author from UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital

“Loss of the second NF1 gene had always been thought to cause tumours in individuals with NF-1. Our findings fundamentally question this decade-old paradigm and force us to rethink how tumours arise, to pave the way for better screening, prevention, and treatment of cancers.”

Professor Sam Behjati,co-senior author from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust

Source: Wellcome Trust Sanger Institute

Categories : CancerTags :

Caner Signals may Promote Blood Clot Formation in the Lungs

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Thrombophilia. Credit: Scientific Animations CC4.0.

Blood clots form in response to signals from the lungs of cancer patients—not from other organ sites, as previously thought—according to a preclinical study. Clots are the second-leading cause of death among cancer patients with advanced disease or aggressive tumours.

While blood clots usually form to stop a wound from bleeding, cancer patients can form clots without injury, plugging up vessels and cutting off circulation to organs. The study, published in Cell, shows that tumours drive thrombosis by releasing chemokines, secreted proteins which then circulate to the lung. Once there, the chemokines prompt macrophages to release small vesicles that attach to platelets, forming life-threatening clots.

The findings may lead to diagnostic tests to determine blood clotting risk and safer therapies that target the root of the problem to prevent blood clots.

“This work redefines the concept of how thrombosis develops in cancer patients, compared to the traditional view that factors on blood vessel walls or tumour cells themselves are responsible,” said study lead Dr David Lyden, professor in paediatric cardiology, and cell and developmental biology at Weill Cornell Medicine. “It’s a revolutionary concept that thrombosis is initiated in the lung, which wasn’t appreciated before.”

Tumors in the Driver’s Seat

“We reviewed post-mortem studies and found that up to 60% of cancer patients died because of clots rather than cancer itself,” said first author Dr Serena Lucotti,  instructor of cell biology in paediatrics at Weill Cornell Medicine. “It is unfortunate because we have drugs that can prevent clots, but we can’t give them unconditionally to all patients because they can cause excessive bleeding in some. At the same time, we can’t predict who is at high risk for clots and would benefit from the drugs.”

In a series of experiments in mice and human tissues, the researchers showed that different tumours release varying amounts of the chemokine CXCL13. Breast cancers and melanomas release relatively small quantities of CXCL13. However, if these tumour cells spread to the lung, they can trigger clot formation by releasing CXCL13 and locally influencing interstitial macrophages. “In contrast, pancreatic cancer secretes high levels of CXCL13 into the bloodstream,” said Dr Lyden. “It’s so high that it circulates all the way to the macrophages in the lung, so these tumour cells don’t need to be close by.”

Blocking Clots—and Metastases

Other experiments revealed that after interacting with CXCL13, lung interstitial macrophages send out small vesicles loaded with an adhesion molecule, integrin β2, on their surface. The integrin β2 is in an open conformation that can attach to platelets and trigger clot formation.

Mice treated with an antibody that blocks vesicle-bound integrin β2 from binding to platelets had no side effects and didn’t have excessive bleeding. Strikingly, mice with early or advanced cancers that were treated with the antibody not only had fewer clots, but also had significantly fewer metastases than untreated controls. “This is important because there aren’t effective treatments for patients with metastases and will be further investigated,” Dr Lucotti said. She is developing a human antibody to block the integrin β2-platelet interaction in patients.

The researchers are also hopeful that integrin β2 can be a biomarker that indicates a patient’s risk for developing clots. As proof of concept, the team analyzed blood samples from some pancreatic cancer patients from Moores Cancer Center at the University of California San Diego Health. By analyzing blood samples collected before and after the patients experienced blood clots, the authors could easily and accurately distinguish between low-risk and high-risk patients based on integrin β2 levels on extracellular vesicles in the blood.

The study highlights that cancer is a disease that can affect many parts of the body. “Cancer is a systemic disease. We have to pay attention to not only future sites of metastasis, but other organs that may be affected independent of metastasis by systemic complications such as thrombosis, leading to morbidity and mortality,” Dr Lyden said.

Source: Weill Cornell Medicine

Categories : Cancer GastrointestinalTags :

Nerves Electrify Stomach Cancer, Sparking Growth and Spread

On By ModernMedia
Image from Pixabay.

Researchers have discovered that stomach cancers in mice make electrical connections with nearby sensory nerves and use these malignant circuits to stimulate the cancer’s growth and spread.

Reported in Nature, this is the first time that electrical contacts between nerves and a cancer outside the brain have been found, raising the possibility that many other cancers progress by making similar connections.

“We know that many cancers exploit nearby neurons to fuel their growth, but outside of cancers in the brain, these interactions have been attributed to the secretion of growth factors broadly or through indirect effects,” says Timothy Wang, the Silberberg Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons, who led the study and is one of the leaders in the growing field of cancer neuroscience.

“Now that we know the communication between the two is more direct and electrical, it raises the possibility of repurposing drugs designed for neurological conditions to treat cancer.”

The wiring of neurons to cancer cells also suggests that cancer can commandeer a particularly rapid mechanism to stimulate growth.

“There are many different cells surrounding cancers, and this microenvironment can sometimes provide a rich soil for their growth,” Wang says. Researchers have been focusing on the role of the microenvironment’s immune cells, connective tissue, and blood vessels in cancer growth but have only started to examine the role of nerves in the last two decades.

“What’s emerged recently is how advantageous the nervous system can be to cancer,” Wang adds. “The nervous system works faster than any of these other cells in the tumour microenvironment, which allows tumours to more quickly communicate and remodel their surroundings to promote their growth and survival.”

Cancer-neuron connections resemble synapses

As a gastroenterologist, Wang’s research has focused on stomach and other GI cancers. About 10 years ago, he discovered that cutting the vagus nerve in mice with stomach cancer significantly slowed tumour growth and increased survival rate.

Many different types of neurons are contained in the vagus nerve, but the researchers focused here on sensory neurons, which reacted most strongly to the presence of stomach cancer in mice. Some of these sensory neurons extended themselves deep into stomach tumours in response to a protein released by cancer cells called Nerve Growth Factor (NGF), drawing the cancer cells close to the neurons. After establishing this connection, tumours signalled the sensory nerves to release the peptide Calcitonin Gene Related Peptide (CGRP), inducing electrical signals in the tumour.  

Though the cancer cells and neurons may not form classical synapses where they meet – the team’s electron micrographs are still a bit fuzzy – “there’s no doubt that the neurons create an electric circuit with the cancer cells,” Wang says. “It’s a slower response than a typical nerve-muscle synapse, but it’s still an electrical response.”

The researchers could see this electrical activity with calcium imaging, a technique that uses fluorescent tracers that light up when calcium ions surge into a cell as an electrical impulse travels through.  

“There’s a circuit that starts from the tumour, goes up toward the brain, and then turns back down toward the tumour again,” Wang says. It’s like a feed-forward loop that keeps stimulating the cancer and promoting its growth and spread.”

Migraine drugs as a potential cancer treatment

For stomach cancer, CGRP inhibitors that are currently used to treat migraines could potentially short-circuit the electrical connection between tumours and sensory neurons.

In Wang’s study, CGRP inhibitors administered to mice with stomach cancer reduced the size of the tumors, prolonged survival, and prevented the tumors from spreading.

“Based on our analysis of stomach cancer data from patients, we believe that the circuits we’ve found in mice also exist in humans and targeting them could be an additional useful therapy,” Wang says.

Sensory neurons may also use CGRP to stimulate cancer through more indirect pathways. Unpublished findings from Wang’s lab suggest that the neurons promote stomach cancer growth via contact with connective tissue cells in the tumour microenvironment. And other researchers have found that sensory nerves may, possibly through CGRP, cause T cell exhaustion and turn off immune responses directed at other types of cancers.

“But we think it all starts with the cancer cell setting up a neural circuit,” Wang says.

“Nerves are an underappreciated master regulator of normal growth and regeneration in animals. We know that when organs form during development, the nerves lead the way. From that point of view, it was not unexpected that nerves would be driving tumour growth as well.”

Source: Columbia University Irving Medical Center