Tag: cancer

Categories : CancerTags :

Passing Through Tight Spaces Make Cancer Cells More Aggressive

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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

Categories : Cancer GeneticsTags :

How Cancer Cells Repair their DNA so Quickly

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DNA repair
Source: Pixabay/CC0

Research into how the body’s DNA repair process works has made a discovery into how the process works, and by understanding how cancer cells repair their DNA so rapidly may lead to potent new chemotherapy treatments.

One of the great mysteries of medical science is the ability of DNA to be repaired after damage, but complicating the study of this is how different pathways are involved in the repair process over the cell’s life cycle. In one of the repair pathways known as base excision repair (BER), the damaged material is removed, and proteins and enzymes work together to create DNA to fill in and then seal the gaps.

In a study appearing in Proceedings of the National Academy of Sciences, Eminent Professor Zucai Suo led a team that discovered that BER has a built-in mechanism to increase its effectiveness: it just needs to be captured at a very precise point in the cell life cycle.

In BER, an enzyme called polymerase beta (PolyB) fulfils two functions: It creates DNA, and it initiates a reaction to clean up the leftover ‘chemical junk’. Through five years of study, Prof Suo’s team learned that by capturing PolyB when it is naturally cross-linked with DNA, the enzyme will produce new genetic material 17 times faster than when the two are not cross-linked. This suggests that the two functions of PolyB are interlocked, not independent, during BER.

The research improves the understanding of cellular genomic stability, drug efficacy and resistance associated with chemotherapy.

“Cancer cells replicate at high speed, and their DNA endures a lot of damage,” Prof Suo said. “When a doctor uses certain drugs to attack cancer cells’ DNA, the cancer cells must cope with additional DNA damage. If the cancer cells cannot rapidly fix DNA damage, they will die. Otherwise, the cancer cells survive, and drug resistance appears.”

This research examined naturally cross-linked PolyB and DNA, unlike previous research that mimicked the process. Studies had previously identified the enzymes involved in BER but did not fully grasp how they work together.

“When we have nicks in DNA, bad things can happen, like the double strand breaking in DNA,” said Thomas Spratt, a professor of biochemistry and molecular biology at Penn State University College of Medicine who was not a part of the research team. “What Zucai found provides us with something we didn’t understand before, and he used many different methods to reach his findings.”

Source: Florida State University

Categories : CancerTags :

Statins Could Slow Metastases, Study Finds

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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

Categories : CancerTags :

Study Suggests Caution when Prescribing Metformin for Cancer Cases

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Source: National Cancer Institute on Unsplash

By making computer simulations of drugs, researchers have found that doctors need to be wary of prescribing metformin for all types of cancer and patients. Their findings are published in BioMed Central Cancer.

The diabetes drug metformin has been used in clinical settings as a cancer treatment in recent years. The researchers say while metformin shows great promise, it also has negative consequences for some types of cancers.

“Metformin is a wonder drug, and we are just beginning to understand all its possible benefits,” said Mehrshad Sadria, a PhD candidate in applied mathematics at the University of Waterloo. “Doctors need to examine the value of the drug on a case-by-case basis, because for some cancers and some patient profiles, it may actually have the opposite of the intended effect by protecting tumour cells against stress.”

The computer-simulated treatments use models that replicate both the drug and the cancerous cells in a virtual environment. Such models can give clinical trials in humans a considerable head-start and can provide insights to medical practitioners that would take much longer to be discovered in the field.

“In clinical settings, drugs can sometimes be prescribed in a trial and error manner,” said Anita Layton, professor of applied mathematics and Canada 150 Research Chair in mathematical biology and medicine at Waterloo. “Our mathematical models help accelerate clinical trials and remove some of the guesswork. What we see with this drug is that it can do a lot of good but needs more study.”

The researchers say their work shows the importance of precision medicine when considering the use of metformin for cancer and other diseases. Precision medicine is an approach that assumes each patient requires individualised medical assessment and treatment.

“Diseases and treatments are complicated,” Sadria said. “Everything about the patient matters, and even small differences can have a big impact on the effect of a drug, such as age, gender, genetic and epigenetic profiles. All these things are important and can affect a patient’s drug outcome. In addition, no one drug works for everyone, so doctors need to take a close look at each patient when considering treatments like metformin.”

Source: EurekAlert!

Categories : CancerTags :

Report Shows a Long Road Ahead for Cancer Treatment in South Africa

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Source: National Cancer Institute

In their recently released Middle East and Africa regional report on cancer, the Swedish Institute for Health Economics (IHE) highlighted challenges for the country’s under-resourced healthcare system. It also highlighted the need to provide training for South African GPs in early detection of cancer.

Cancer is a growing challenge for South Africa. The incidence of cancer cases in South Africa is predicted to double over the next two decades, from 110 per 100 000 in 2018 to 226 per 100 000 in 2040. It is also gradually becoming one of the leading causes of death, from 9% in 2000 to 10% in 2016, even as the share of deaths from cardiovascular diseases and diabetes grows as well. Prostate cancer is the most common (31%) in men by far, while in women breast cancer (27%) was closely followed by cervical cancer (22%).

The COVID pandemic has largely overshadowed the Department of Health’s 207-2022 cancer plan, though successes with HIV have allowed it to move up in priority. A major challenge will be getting it moved up in priority.

The direct costs to the healthcare system from cancer are USD11 (R165) per capita and USD19 (R285) per capita in indirect costs to society (premature death, early retirement, sick leave etc). Yet South Africa’s public healthcare spending is only 4% of GDP, below the World Health Organization informal target of 5%.

In terms of prevention, anti-smoking campaigns have had some effect, though more work needs to be done on tackling obesity. The HPV vaccination campaign is a step in the right direction, the report says, though the hepatitis B vaccination programme is flagging.

In early detection, GPs need better training in recognising the early signs of cancer. Public health literacy is also a priority, along with expanding breast and cervical cancer screening. Given rising incidence, colorectal cancer screening should also be considered, the IHE recommended.

Universal health care continues to be a priority, with the proportion of the population covered by medical schemes remaining static at 17% from 2012 to 2019. Public healthcare, which only offers a defined set of services, suffers from a lack of resources and personnel.

As far as cancer treatment in South Africa goes, public healthcare resembles global standards 20 years ago. Though radiation machines adequately serve the population on a national level, there are significant disparities with long waiting times and machines that can provide modern radiation techniques are limited and not listed in prescribed minimum benefits. Targeted drugs and immunotherapy remain almost exclusively the province of private healthcare, with a lengthy procedure to get drugs listed on the EML. Streamlining this should be a priority, the report recommends.

Categories : CancerTags :

A Protein’s Role in Why Some Tumours Metastasise

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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!

Categories : Cancer COVIDTags :

Many Young People with Cancer Experiencing Distress in the Pandemic

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Photo by Sydney Sims on Unsplash

A new study has reported that many adolescents and young adults with cancer are suffering high psychological distress during the COVID pandemic. During the pandemic, adolescents and young adults with cancer had an 85% higher odds of experiencing psychological distress compared with a similar group surveyed in 2018.

For the study, which was published in Psycho-Oncology, 805 individuals in Canada who were diagnosed with cancer between 15 and 39 years of age completed an online survey.  

More than two‐thirds of the group (68.0%) experienced high psychological distress. Additionally, those whose employment had been disrupted during the pandemic and those with blood cancer were more likely to experience high psychological distress, while those who were older and those with a personal income in 2020 that was less than $40 000 tended to have lower distress.  

The survey revealed overarching themes of pandemic experiences that included inferior quality of life, impairment of cancer care, COVID–related concerns, and extreme social isolation.  

“The pandemic has adversely impacted the mental health of adolescents and young adults with cancer,” said senior author Sapna Oberoi, MBBS, MD, DM, of the University of Manitoba. “The findings of this study underscore the importance of providing enhanced and tailored interventions to combat psychological distress among these patients. Cancer organisations and policymakers must prioritise mental health supports for adolescents and young adults with cancer to optimise their health outcomes and quality of life.”

Source: Wiley

Categories : CancerTags :

Why Cancer Cells Linger to Create Metastatic Cancer

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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

Categories : CancerTags :

How Epithelial Cells Kick out Precancerous Neighbours

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Melanoma cells. Source: National Cancer Institute.

Researchers have discovered the mechanism behind how normal epithelial cells push out precancerous ones present in the epithelium with  ‘cell competition’. Researchers have unravelled the interactions and cellular pathways leading to this extrusion, allowing them to identify a candidate for a therapeutic target for future cancer prevention research.

Recent studies have shown that the human body has defence mechanisms run by non-immune epithelial cells. These epithelial cells can recognise and extrude neighbouring precancerous cells from the epithelium, known as cell competition. This form of immune-like surveillance has garnered attention in recent years based on its potential for future immune-like therapeutic targets for cancer preventive treatment. However, it is still unknown what kind of ligand-receptor interactions are involved in the recognition of precancerous cells by normal epithelial cells.

Discussing the study, Professor Takeshi Maruyama, an Associate Professor at the Waseda Institute for Advanced Study at Waseda University, who led the research group, says, “During the process of cell competition, normal epithelial cells can be primed by contact with precancerous cells. However, it was previously unclear how neighbouring normal epithelial cells recognise precancerous cells to eliminate them.”

In this work, the researchers identified a plasma membrane protein, leukocyte immunoglobulin-like receptor B3 (LILRB3). AltR/LILRB3 interacts with major histocompatibility complex class I (MHC class I) that is expressed on precancerous epithelial cells.

MHC class I-AltR/LILRB3 interaction causes the activation of AltR/LILRB3, which triggers an intracellular SHP2–ROCK2 pathway. This SHP2–ROCK2 pathway leads to the “accumulation of cytoskeletal components”, creating a mechanical force to extrude precancerous cells, in the normal epithelial cells at the boundary with precancerous cells. This pushes the precancerous cells out of the epithelium to eliminate them from the body.

However, this occurs independently of natural killer or CD8+ T cell-mediated immune responses. “Our study describes a new immune-like mechanism by non-immune epithelial cells to suppress tumorigenesis,” said Prof Maruyama.

The researchers hope that these findings can be applied to cancer treatment. “The recombinant MHC-I-α3 protein used in this study enhances the elimination of precancerous cells and suppresses the formation of tumours and precancerous lesions,” added Prof Maruyama. “We hope that this biomolecule would contribute to a therapeutic candidate for cancer prevention by the elimination of precancerous cells.”

Source: Waseda University

Categories : Cancer Obstetrics & GynaecologyTags :

Synthetic Progestogen in Utero Leads to Doubled Cancer Rate in Offspring

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Photo by Shvets Productions on Pexels

In utero exposure to a synthetic progestogen used to prevent miscarriage can lead to an increased risk of developing cancer, according to a new study.

The study by researchers at The University of Texas Health Science Center at Houston (UTHealth Houston) was published in the American Journal of Obstetrics and Gynecology.

The drug, 17α-hydroxyprogesterone caproate (17-OHPC), is a synthetic progestogen frequently used by women in the 1950s and 1960s, and is still prescribed today to women to help prevent preterm birth. Progesterone helps the uterus grow during pregnancy and prevents early contractions that may lead to miscarriage.

“Children who were born to women who received the drug during pregnancy have double the rate of cancer across their lifetime compared to children born to women who did not take this drug,” said the study’s lead author, Caitlin C. Murphy, PhD, MPH, associate professor in the Department of Health Promotion and Behavioral Sciences at UTHealth School of Public Health in Houston. “We have seen cancers like colorectal cancer, pancreatic cancer, thyroid cancer, and many others increasing in people born in and after the 1960s, and no one really knows why.”

Researchers reviewed data from the Kaiser Foundation Health Plan on women who received prenatal care between June 1959 and June 1967, and the California Cancer Registry, which traced cancer in offspring through 2019.

Out of more than 18 751 live births, researchers discovered 1008 cancer diagnoses were made in offspring ages 0 to 58 years. Additionally, a total of 234 offspring were exposed to 17-OHPC during pregnancy. Offspring exposed in utero had cancer detected in adulthood at more than twice the rate of of those unexposed: 65% of cancers occurred in adults younger than 50.

“Our findings suggest taking this drug during pregnancy can disrupt early development, which may increase risk of cancer decades later,” Murphy said “With this drug, we are seeing the effects of a synthetic hormone. Things that happened to us in the womb, or exposures in utero, are important risk factors for developing cancer many decades after we’re born.”

A new randomised trial shows there is no benefit of taking 17-OHPC, and that it does not reduce the risk of preterm birth, according to Murphy.

The U.S. Food and Drug Administration proposed in October 2020 that this particular drug be withdrawn from the market.

Source: University of Texas Health Science Center at Houston