Pre-implantation genetic diagnosis (PGD) technologies allow identification of genetic disorders in human pre-implantation embryos after in vitro fertilisation (IVF) and before the embryo is transferred back to the patient. This technique allows couples with a high-risk of passing on inherited diseases, to increase their chances of having a healthy baby. Despite the theoretical benefits of PGD, clinical outcomes using these technologies vary, possibly because of the need to remove one or more cells from the embryo using biopsy.
In a recent study a group of researchers from Italy and the United Kingdom sought to achieve diagnose of genetic disease in embryonic DNA without the use of a biopsy. By extracting fluid from human embryos at the blastocyst stage they found that it contains DNA from the embryo. Blastocysts are 5 or 6 day old embryos and are at the last free-living stage that can be studied in the laboratory prior to transfer into the uterus. They contain between 50 and 300 cells that surround a fluid-filled cavity called the blastocoels. The researchers carefully removed fluid from the blastocoel, leaving the cells intact; the sampled blastocysts were subsequently cryopreserved. Analysis of this fluid showed that it contained cell-free DNA in a state good enough to determine several known genes of the sex chromosomes by polymerase chain reaction (PCR); whole genome amplification and followed by analysis using a specialized tool for genetic testing called a DNA microarray were also used and revealed whether the embryos had a normal number of chromosomes – chromosome abnormalities are one of the main causes of miscarriage and failure of embryos to form pregnancies during IVF treatments.
‘This is the first time that embryonic DNA has been detected in the human blastocyst without the use of biopsy,’ explained lead researchers Dr. Simone Palini Ph.D., from the IVF Unit at Cervesi Hospital in Cattolica, Italy and Dr. Galluzzi from University of Urbino in Italy and Dr. Dagan Wells from University of Oxford, United Kingdom.
‘This is a technique that most embryologists can easily master,’ Dr. Buletti who directs the IVF team at Cervesi Hospital Cattolica and Prof. Magnani, Chairman of the Department of Biomolecular Sciences of the University of Urbino, added. ‘More work needs to be done to confirm our results, but we hope that this approach will ultimately help infertile couples achieve their dream of having a family. It may also improve the options for families affected by severe inherited conditions, helping them to have healthy babies.’
‘Even though it is only a preliminary finding, this approach may allow for genetic testing of the embryo without the complexity of cell sampling,’ Dr. Joe Leigh Simpson MD, Senior Vice President for Research Programs, March of Dimes Foundation and President, International Federation of Fertility Societies (IFFS), a pioneer in reproductive medicine and genetics, commented on the research.
EurekAlert
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Johns Hopkins scientists have found out how a gout-linked genetic mutation contributes to the disease: by causing a breakdown in a cellular pump that clears an acidic waste product from the bloodstream. By comparing this protein pump to a related protein involved in cystic fibrosis, the researchers also identified a compound that partially repairs the pump in laboratory tests.
The mutation in question, known as Q141K, results from the simple exchange of one amino acid for another, but it prevents the protein ABCG2 from pumping uric acid waste out of the bloodstream and into urine. A build-up of uric acid in the blood can lead to its crystallisation in joints, especially in the foot, causing excruciatingly painful gout.
‘The protein where the mutation occurs, ABCG2, is best known for its counterproductive activity in breast cancer patients, where it pumps anti-cancer drugs out of the tumour cells we are trying to kill,’ says William Guggino, Ph.D., professor and director of the Department of Physiology at the Johns Hopkins University School of Medicine. ‘In kidney cells, though, ABCG2 is crucial for getting uric acid out of the body. What we figured out is exactly how a gout-causing genetic mutation inhibits ABCG2 function.’
Gout affects 2 to 3 percent of Americans, approximately 6 million people. It usually involves sudden attacks of severe pain, often in the joint at the base of the big toe and frequently in the wee hours of the morning, when body temperature is lowest. It has been nicknamed the ‘disease of kings,’ because it usually results from high-purine diets, food that only kings and other noblemen could afford in large quantities in bygone years: red meat, organ meats, oily fishes and some vegetables like asparagus and mushrooms.
Guggino notes that the ABCG2 Q141K mutation was first connected with gout in 2008 through a large genomic study directed, in part, by Josef Coresh, M.D., a biostatistician and epidemiologist at the Johns Hopkins University School of Public Health. At the time, Guggino’s laboratory was studying a protein frequently found mutated in cystic fibrosis patients: cystic fibrosis transmembrane conductance regulator, or CFTR. The structure of ABCG2 is quite similar to CFTR’s, so Coresh suggested that Guggino’s team apply their knowledge of CFTR to characterise ABCG2.
The team first genetically engineered several standard mammalian cell types to make regular or mutant versions of ABCG2. Cells with the mutated ABCG2 gene contained much less of the ABCG2 protein than cells making the regular form. Additionally, the researchers found that the mutation made it difficult for ABCG2 molecules to get to their proper place on the cell surface. Since ABCG2 pumps molecules from the inside of the cell to the outside, it is not functional anywhere but the cell surface.
The team then lowered the temperature at which the ABCG2-making cells were growing, and found more mutant ABCG2 at the cell surface. Guggino says this finding suggested that the lower temperature had stabilised ABCG2 and helped it achieve its proper 3-D conformation, because proteins that don’t assume the right shape are likely to be broken into pieces for reuse, preventing them from reaching their final destinations.
When ABCG2 and CFTR are lined up, their structures are very similar. In fact, one of the most common cystic fibrosis mutations, a CFTR deletion of amino acid F508, lines up next to the Q141K mutation in ABCG2 and causes similar results in the protein’s location and processing.
Knowing that the F508 deletion in CFTR creates instability in a certain part of the protein, the researchers introduced additional mutations intended to stabilise the wobbly region of the Q141K mutant ABCG2. As predicted, they found that this stabilisation increased the amount of ABCG2 on the cell surface, suggesting again that ABCG2 had been saved from the recycling bin.
To confirm the involvement of the recycling process, the team fed the cells several small molecules known to help malformed proteins avoid degradation. One molecule, VRT-325, partially restores CFTR’s activity. The same molecule was also able to increase the amount of mutant ABCG2 found in the cells and on their surfaces, and to decrease the amount of uric acid in the cells, bringing it within the normal range.
‘Though there are many more lab tests needed before clinical trials can even be designed, our results represent an important step forward in both understanding how gout results from this mutation and finding a treatment,’ says Guggino.
John Hopkins Medicine
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Researchers at Lund University in Sweden have discovered a new protein that controls the presence of the Vel blood group antigen on our red blood cells. The discovery makes it possible to use simple DNA testing to find blood donors for patients who lack the Vel antigen and need a blood transfusion. Because there has not previously been any simple way to find these rare donors, there is a global shortage of Vel-negative blood. The largest known accumulation of this type of blood donor is found in the Swedish county of Västerbotten, which exports Vel-negative blood all over the world.
The Vel blood group was first described in 1952, when American doctors discovered a patient who developed serious complications from blood transfusions from normal donors. The patient lacked a previously unknown blood group antigen, which was named Vel. It has long been known that around one in 1 000 people lack the Vel antigen, but the molecule that carries it has been a mystery.
Lund University researchers Jill Storry, Magnus Jöud, Björn Nilsson and Martin L. Olsson and their colleagues have now discovered that the presence of the Vel antigen on our red blood cells is controlled by a previously unknown protein (SMIM1) that is not carried by those who lack the Vel antigen.
The findings have major clinical significance, according to Professor Martin L. Olsson, a consultant in transfusion medicine.
‘Until now there has not been a simple way to find these blood donors and there is therefore a major shortage of Vel-negative blood. Now we can identify these donors with simple DNA tests. From having previously only had access to one such donor in our region, there are now three and further screening is being carried out’, says Professor Olsson.
Two research groups with completely different focuses have collaborated to solve the 60-year-old riddle, explains Reader Björn Nilsson, who has led the work together with Reader Jill Storry and Professor Olsson.
‘Many researchers have tried to find the Vel molecule. We realised that it might be possible to find it using advanced DNA analysis techniques. Our idea proved to be correct and we found that the Vel blood group is inactivated in exactly the same way for all Vel-negative individuals’, says Björn Nilsson.
Another interesting aspect is that the new protein is unlike any previously known protein and appears to be present on the red blood cells of other species as well.
‘Interestingly, the new protein, SMIM1, is reminiscent of other molecules used by malaria parasites to infect humans. It is therefore possible that SMIM1 could be a long-sought malaria receptor on the red blood cells’, says Jill Storry.
Lund University
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Research from Western University and Lawson Health Research Institute sheds new light on a gene called ATRX and its function in the brain and pituitary. Children born with ATRX syndrome have cognitive defects and developmental abnormalities. ATRX mutations have also been linked to brain tumours.
Dr. Nathalie Bérubé, PhD, and her colleagues found mice developed without the ATRX gene had problems in the forebrain, the part of the brain associated with learning and memory, and in the anterior pituitary which has a direct effect on body growth and metabolism. The mice, unexpectedly, also displayed shortened lifespan, cataracts, heart enlargement, reduced bone density, hypoglycemia; in short, many of the symptoms associated with ageing.
Ashley Watson, a PhD candidate working in the Bérubé lab and the first author on the paper, discovered the loss of ATRX caused DNA damage especially at the ends of chromosomes which are called telomeres. She investigated further and discovered the damage is due to problems during DNA replication, which is required before the onset of cell division. Basically, the ATRX protein was needed to help replicate the telomere.
Working with Frank Beier of the Department of Physiology and Pharmacology at Western’s Schulich School of Medicine & Dentistry, the researchers made another discovery. ‘Mice that developed without ATRX were small at birth and failed to thrive, and when we looked at the skeleton of these mice, we found very low bone mineralisation. This is another feature found in mouse models of premature ageing,’ says Bérubé, an associate professor in the Departments of Biochemistry and Paediatrics at Schulich Medicine & Dentistry, and a scientist in the Molecular Genetics Program at the Children’s Health Research Institute within Lawson. ‘We found the loss of ATRX increases DNA damage locally in the forebrain and anterior pituitary, resulting in systemic defects similar to those seen in ageing.’
The researchers say the lack of ATRX in the anterior pituitary caused problems with the thyroid, resulting in low levels of a hormone called insulin-like growth factor-one (IGF-1) in the blood. There are theories that low IGF-1 can deplete stores of stem cells in the body, and Bérubé says that’s one of the explanations for the premature ageing.
University of Western Ontario
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Autophagy, the process by which cells that are starved for food resort to chewing up their own damaged proteins and membranes and recycling them into fuel, has emerged as a key pathway that cancer cells use to survive in the face of assault by chemotherapy and radiation. Using drugs to shut down that survival mechanism shows great promise, especially when combined with targeted agents and standard chemotherapies, but until recently, it has been unclear which patients’ cancers would respond to that combination therapy.
A team led by researchers from the Perelman School of Medicine at the University of Pennsylvania will present findings showing that colon cancer and lung cancer cell lines which expressed a gene known as helicase-like transcription factor (HLTF) tended to be impervious to the effects of the autophagy inhibition drug hydroxycholoroquine (HCQ). Cells where HLTF is silent, however, appeared to be sensitive to HCQ, which led the team to test HLTF expression in a group of colon cancer patients treated with two chemotherapies (the FOLFOX regimen plus bevacizumab) and HCQ. They found that low expression of HLTF predicted those who would respond to the combination therapy.
Since previous studies have shown that HLTF gene silencing is common in 20 to 40 percent of many epithelial cancers, the Penn team is hopeful their findings could lead to the development of a predictive biomarker to identify patients with other cancers who are most likely to respond to drug therapies involving autophagy inhibitors.
Penn Medicine
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Men who develop prostate cancer after inheriting a faulty gene need immediate surgery or radiotherapy rather than being placed under surveillance, as their disease is more aggressive than other types, a new study has found.
A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust found prostate cancers spread more quickly and were more often fatal in men who had inherited a faulty BRCA2 gene than in men without the faulty gene.
The research, funded by the Ronald and Rita McAulay Foundation and Cancer Research UK, could challenge current NHS guidelines for prostate cancer, under which BRCA2 mutation carriers are offered the same treatment options as non-carriers.
It is often difficult to tell at diagnosis whether prostate cancer will be life-threatening or not, and while treatment options for early-stage disease include surgery and radiotherapy, many men instead receive active surveillance to see if the disease starts to progress.
The new study is the largest to compare prostate cancer patients with and without BRCA mutations, in order to tell whether gene testing should help to direct management options.
Senior author Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research (ICR) and Honorary Consultant in Clinical Oncology at The Royal Marsden, said: ‘It is clear from our study that prostate cancers linked to inheritance of the BRCA2 cancer gene are more deadly than other types. It must make sense to start offering affected men immediate surgery or radiotherapy, even for early-stage cases that would otherwise be classified as low-risk. We won’t be able to tell for certain that earlier treatment can benefit men with inherited cancer genes until we’ve tested it in a clinical trial, but the hope is that our study will ultimately save lives by directing treatment at those who most need it.’
The team from the ICR and The Royal Marsden, with collaborators across the UK, examined the medical records of 61 BRCA2-mutation carriers, 18 BRCA1-mutation carriers and 1,940 non-carriers.
They found BRCA1/2 mutation carriers were more likely to be diagnosed with advanced stage prostate cancers (37 per cent versus 28 per cent) or cancer that had already spread (18 per cent versus nine per cent) than non-carriers. Among those whose cancers had not spread out of the prostate at diagnosis, within five years more carriers than non-carriers had metastatic disease (23 per cent versus seven per cent).
Patients with BRCA2-mutations were also significantly less likely to survive the cancer, living an average of 6.5 years compared with 12.9 years for non-carriers. The team concluded that a BRCA2 test could be used in combination with other factors as a prognostic test. Men with a BRCA1 mutation also had a shorter average survival time of 10.5 years, but there was not a statistically significant difference with non-carriers.
ICR
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How do nerve cells — which can each be up to three feet long in humans — keep from rupturing or falling apart?
Axons, the long, cable-like projections on neurons, are made stronger by a unique modification of the common molecular building block of the cell skeleton. The finding, which may help guide the search for treatments for neurodegenerative diseases.
Microtubules are long, hollow cylinders that are a component of the cytoskeleton in all cells of the body. They also support transport of molecules within the cell and facilitate growth. They are made up of polymers of a building-block substance called tubulin.
‘Except for neurons, cells’ microtubules are in constant dynamic flux — being taking apart and rebuilt,’ says Scott Brady, professor and head of anatomy and cell biology at UIC and principal investigator on the study. But only neurons grow so long, he said, and once created they must endure throughout a person’s life, as much as 80 to 100 years. The microtubules of neurons are able to withstand laboratory conditions that cause other cells’ microtubules to break apart.
Brady had been able to show some time ago that the neuron’s stability depended on a modification of tubulin.
‘But when we tried to figure out what the modification was, we didn’t have the tools,’ he said.
Yuyu Song, a former graduate student in Brady’s lab and the first author of the study, took up the question. ‘It was like a detective story with many possibilities that had to be ruled out one by one,’ she said. Song, who is now a post-doctoral fellow at Howard Hughes Medical Institute at Yale School of Medicine, used a variety of methods to determine the nature of the modification and where it occurs.
She found that tubulin is modified by the chemical bonding of polyamines, positively charged molecules, at sites that might otherwise be chinks where tubulin could be broken down, causing the microtubules to fall apart. She was also able to show that the enzyme transglutaminase was responsible for adding the protective polyamines.
The blocking of a vulnerable site on tubulin would explain the extraordinary stability of neuron microtubules, said Brady. However, convincing others required the ‘thorough and elegant work’ that Song brought to it, he said. ‘It’s such a radical finding that we needed to show all the key steps along the way.’
The authors also note that increased microtubule stability correlates with decreased neuronal plasticity — and both occur in the process of ageing and in some neurodegenerative diseases. Continued research, they say, may help identify novel therapeutic approaches to prevent neurodegeneration or allow regeneration.
University of Illinois at Chicago College of Medicine
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Montréal scientists identified the DOCK1 protein as a potential target to reduce the progression of metastases in patients suffering from breast cancer, the most common type of cancer in women.
Dr. Côté’s laboratory is interested in metastasis, which is the spread of cancer from an organ (or part of an organ) to another. Nearly 90 per cent of cancer patient deaths are attributable to metastasis, thus explaining the importance of understanding the underlying cellular and molecular mechanisms of this harmful process.
‘Despite important breakthroughs in breast cancer treatment, few mechanisms are known to explain the spread of metastases,’ says Dr. Côté, Director of the Cytoskeletal Organization and Cell Migration research unit at the IRCM. ‘We are looking to identify the proteins that regulate the metastatic process so that new agents can be developed and combined with current treatments.’
Two major breast cancer subtypes, HER2+ and Basal, have a tendency to be metastatic and recurrent, and are ultimately associated to a poor survival rate. Research at the IRCM was conducted on the HER2+ type (Human Epidermal growth factor Receptor 2), which represents approximately 25 per cent of breast cancer cases. HER2 positive tumours tend to develop and spread more quickly than other types of tumours.
‘By studying a genetic mouse model with HER2+ breast cancer, we identified the protein DOCK1 as an important regulator of metastasis,’ explains Mélanie Laurin, doctoral student in Dr. Côté’s laboratory and first author of the study. ‘When we eliminated this protein in mice, our results showed a significant decrease in lung metastases. We also discovered that the DOCK1 protein contributes to the growth of tumours.’
‘To show the correlation between the expression of DOCK1 and breast cancer prognosis, we performed an analysis of several databases of patient genic,’ adds Dr. Benjamin Haibe-Kains, researcher at the IRCM who collaborated with Dr. Côté’s team. ‘We did indeed discover that high levels of DOCK1 in HER2+ or Basal breast cancer patients are associated with a lower prognosis, or recurrence of the disease.’
‘Our work defined a new molecule required for the progression of breast cancer to the metastatic stage and allowed us to identify new markers that could become potential targets to stop the progression of metastases,’ concludes Dr. Côté. ‘We also showed that a chemical inhibitor of the DOCK1 protein, developed by Dr. Yoshinori Fukui, our collaborator in Japan, can stop the migration of cancerous cells. These results could eventually lead to the development of drugs that would limit the progression of metastatic breast cancer and could thereby improve patient prognosis.’
Institut de recherches cliniques de Montréal
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A team led by Massachusetts General Hospital (MGH) researchers has identified a genetic signature that appears to reflect the risk of tumour recurrence or spread in men surgically treated for prostate cancer. If confirmed in future studies, this finding not only may help determine which patients require additional treatment after the cancerous gland has been removed, it also may help address the most challenging problem in prostate cancer treatment – distinguishing tumours that require aggressive treatment from those that can safely be monitored.
‘Radical prostatectomy is the standard of care for men whose cancer is advanced but confined to the prostate gland, but we know that the factors we use to determine which patients need radiation therapy after surgery are inadequate,’ says W. Scott McDougal, MD, of the MGH Department of Urology, corresponding author of the report. ‘The treatments available to our patients can have significant impact on their quality of life, so a better way to know which patients with localised cancer need additional therapy after surgery and which require no additional treatment is a significant unmet need.’
Gene expression signatures indicating patient prognosis and sometimes the most appropriate treatment have been incorporated into care for breast cancer and other tumours. Studies looking for such markers in prostate cancer have had variable results, and their potential usefulness to guide treatment has not been determined. For the current study the research team – led by Chin-Lee Wu, MD, PhD, of the MGH Department of Pathology – examined samples of malignant tissue from around 200 prostate cancer patients who had radical prostatectomies at the MGH between 1993 and 1995, analyzing the expression patterns of more than 1,500 genes associated with prostate cancer in earlier studies. With the results of that analysis, they developed a 32-gene index to reflect the likelihood that a patient’s tumour would recur, signified by detectable levels of prostate-specific antigen (PSA) after the gland had been remove, or spread.
To validate the usefulness of the index, they used it to analyse tissue samples from a different group of almost 300 patients who had their prostates removed in 1996 and 1997, comparing the index with currently used prognostic factors – such as PSA levels, physical examination, and a tumour’s microscopic appearance – to see how accurately each predicted the actual incidence of tumour recurrence or metastasis during the 10 years after surgery. The expression-based index proved to be the most accurate method. Among those it designated as high-risk, the actual incidence of tumor recurrence was 47 percent and of metastasis, 14 percent. Among those classified as intermediate risk, actual recurrence was 22 percent, and metastasis occurred in 2 percent. No recurrence or metastasis were seen in patients classified as low-risk by the gene-expression index.
To get a sense of whether the index could help determine risk at the time of diagnosis, the researchers used it to assess pre-surgical needle biopsy samples from 79 patients in the validation group. The risk assignment based on biopsy results closely matched the assessment based on surgically removed tissue, and the prognostic ability of the index was better than that of other pathological information available at the time a biopsy was taken. Because the current report is based on study of patients treated at a single institution, the authors note, it requires confirmation in larger, multi-institutional studies.
‘A more accurate prognosis at the time of diagnosis could give patients and their physicians much more confidence in choosing a definitive therapy or pursuing active surveillance for those at low risk, which could reduce over-treatment, a critical issue in disease management,’ says lead author Wu, an associate professor of Pathology at Harvard Medical School. McDougal is the the Kerr Professor of Urology, at HMS.
Massachusetts General Hospital
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Researchers at the University of North Carolina have discovered that transcription factors regulating the levels of oxygen in the blood also play a role in the spread of the skin cancer melanoma.
A research team led by William Kim, MD, member of the UNC Lineberger Comprehensive Cancer Center, and graduate student and first author Sara Hanna, linked melanoma metastases to a pair of transcription factors known as HIF1 and HIF2.
Researchers found that HIF1 and HIF2 are over-expressed in melanoma tumours. In healthy cells, HIF1 and HIF2 assist in regulating hypoxia, the state caused by low levels of oxygen in the blood. Hypoxia has been linked to metastases in several solid tumours, and the UNC team has found that it promotes the spread of melanoma from the skin to other sites in the body through the lymphatic system.
Patients who are diagnosed with early stage melanomas have a high rate of survival, but the prognosis worsens significantly once the tumours spread to other sites throughout the body. Using in vitro systems and mouse models, researchers suppressed the expression of HIF1 and HIF2 in the melanoma tumours. While the inactivation of the transcription factors did not reduce the growth of the initial tumours, it did reduce the rate at which the melanoma spread to other sites in the body.
Both HIF1 and HIF2 independently activate the protein kinase SRC using different signalling pathways. The SRC protein has been linked to several different cancers, and the identification of its role in melanoma suggests that existing therapies targeting SRC may prove to be a viable target for therapies aimed at reducing the spread and ultimate lethality of the cancer.
‘What we are trying to do now is inhibit these pathways with drugs in the mice to see if we see a decrease of metastasis,’ said Hanna.
University of North Carolina
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Sampling of embryonic DNA after IVF without biopsy
, /in E-News /by 3wmediaPre-implantation genetic diagnosis (PGD) technologies allow identification of genetic disorders in human pre-implantation embryos after in vitro fertilisation (IVF) and before the embryo is transferred back to the patient. This technique allows couples with a high-risk of passing on inherited diseases, to increase their chances of having a healthy baby. Despite the theoretical benefits of PGD, clinical outcomes using these technologies vary, possibly because of the need to remove one or more cells from the embryo using biopsy.
In a recent study a group of researchers from Italy and the United Kingdom sought to achieve diagnose of genetic disease in embryonic DNA without the use of a biopsy. By extracting fluid from human embryos at the blastocyst stage they found that it contains DNA from the embryo. Blastocysts are 5 or 6 day old embryos and are at the last free-living stage that can be studied in the laboratory prior to transfer into the uterus. They contain between 50 and 300 cells that surround a fluid-filled cavity called the blastocoels. The researchers carefully removed fluid from the blastocoel, leaving the cells intact; the sampled blastocysts were subsequently cryopreserved. Analysis of this fluid showed that it contained cell-free DNA in a state good enough to determine several known genes of the sex chromosomes by polymerase chain reaction (PCR); whole genome amplification and followed by analysis using a specialized tool for genetic testing called a DNA microarray were also used and revealed whether the embryos had a normal number of chromosomes – chromosome abnormalities are one of the main causes of miscarriage and failure of embryos to form pregnancies during IVF treatments.
‘This is the first time that embryonic DNA has been detected in the human blastocyst without the use of biopsy,’ explained lead researchers Dr. Simone Palini Ph.D., from the IVF Unit at Cervesi Hospital in Cattolica, Italy and Dr. Galluzzi from University of Urbino in Italy and Dr. Dagan Wells from University of Oxford, United Kingdom.
‘This is a technique that most embryologists can easily master,’ Dr. Buletti who directs the IVF team at Cervesi Hospital Cattolica and Prof. Magnani, Chairman of the Department of Biomolecular Sciences of the University of Urbino, added. ‘More work needs to be done to confirm our results, but we hope that this approach will ultimately help infertile couples achieve their dream of having a family. It may also improve the options for families affected by severe inherited conditions, helping them to have healthy babies.’
‘Even though it is only a preliminary finding, this approach may allow for genetic testing of the embryo without the complexity of cell sampling,’ Dr. Joe Leigh Simpson MD, Senior Vice President for Research Programs, March of Dimes Foundation and President, International Federation of Fertility Societies (IFFS), a pioneer in reproductive medicine and genetics, commented on the research. EurekAlert
A protein’s well-known cousin sheds light on its gout-linked relative
, /in E-News /by 3wmediaJohns Hopkins scientists have found out how a gout-linked genetic mutation contributes to the disease: by causing a breakdown in a cellular pump that clears an acidic waste product from the bloodstream. By comparing this protein pump to a related protein involved in cystic fibrosis, the researchers also identified a compound that partially repairs the pump in laboratory tests.
The mutation in question, known as Q141K, results from the simple exchange of one amino acid for another, but it prevents the protein ABCG2 from pumping uric acid waste out of the bloodstream and into urine. A build-up of uric acid in the blood can lead to its crystallisation in joints, especially in the foot, causing excruciatingly painful gout.
‘The protein where the mutation occurs, ABCG2, is best known for its counterproductive activity in breast cancer patients, where it pumps anti-cancer drugs out of the tumour cells we are trying to kill,’ says William Guggino, Ph.D., professor and director of the Department of Physiology at the Johns Hopkins University School of Medicine. ‘In kidney cells, though, ABCG2 is crucial for getting uric acid out of the body. What we figured out is exactly how a gout-causing genetic mutation inhibits ABCG2 function.’
Gout affects 2 to 3 percent of Americans, approximately 6 million people. It usually involves sudden attacks of severe pain, often in the joint at the base of the big toe and frequently in the wee hours of the morning, when body temperature is lowest. It has been nicknamed the ‘disease of kings,’ because it usually results from high-purine diets, food that only kings and other noblemen could afford in large quantities in bygone years: red meat, organ meats, oily fishes and some vegetables like asparagus and mushrooms.
Guggino notes that the ABCG2 Q141K mutation was first connected with gout in 2008 through a large genomic study directed, in part, by Josef Coresh, M.D., a biostatistician and epidemiologist at the Johns Hopkins University School of Public Health. At the time, Guggino’s laboratory was studying a protein frequently found mutated in cystic fibrosis patients: cystic fibrosis transmembrane conductance regulator, or CFTR. The structure of ABCG2 is quite similar to CFTR’s, so Coresh suggested that Guggino’s team apply their knowledge of CFTR to characterise ABCG2.
The team first genetically engineered several standard mammalian cell types to make regular or mutant versions of ABCG2. Cells with the mutated ABCG2 gene contained much less of the ABCG2 protein than cells making the regular form. Additionally, the researchers found that the mutation made it difficult for ABCG2 molecules to get to their proper place on the cell surface. Since ABCG2 pumps molecules from the inside of the cell to the outside, it is not functional anywhere but the cell surface.
The team then lowered the temperature at which the ABCG2-making cells were growing, and found more mutant ABCG2 at the cell surface. Guggino says this finding suggested that the lower temperature had stabilised ABCG2 and helped it achieve its proper 3-D conformation, because proteins that don’t assume the right shape are likely to be broken into pieces for reuse, preventing them from reaching their final destinations.
When ABCG2 and CFTR are lined up, their structures are very similar. In fact, one of the most common cystic fibrosis mutations, a CFTR deletion of amino acid F508, lines up next to the Q141K mutation in ABCG2 and causes similar results in the protein’s location and processing.
Knowing that the F508 deletion in CFTR creates instability in a certain part of the protein, the researchers introduced additional mutations intended to stabilise the wobbly region of the Q141K mutant ABCG2. As predicted, they found that this stabilisation increased the amount of ABCG2 on the cell surface, suggesting again that ABCG2 had been saved from the recycling bin.
To confirm the involvement of the recycling process, the team fed the cells several small molecules known to help malformed proteins avoid degradation. One molecule, VRT-325, partially restores CFTR’s activity. The same molecule was also able to increase the amount of mutant ABCG2 found in the cells and on their surfaces, and to decrease the amount of uric acid in the cells, bringing it within the normal range.
‘Though there are many more lab tests needed before clinical trials can even be designed, our results represent an important step forward in both understanding how gout results from this mutation and finding a treatment,’ says Guggino. John Hopkins Medicine
Newly discovered blood protein solves 60-year-old riddle
, /in E-News /by 3wmediaResearchers at Lund University in Sweden have discovered a new protein that controls the presence of the Vel blood group antigen on our red blood cells. The discovery makes it possible to use simple DNA testing to find blood donors for patients who lack the Vel antigen and need a blood transfusion. Because there has not previously been any simple way to find these rare donors, there is a global shortage of Vel-negative blood. The largest known accumulation of this type of blood donor is found in the Swedish county of Västerbotten, which exports Vel-negative blood all over the world.
The Vel blood group was first described in 1952, when American doctors discovered a patient who developed serious complications from blood transfusions from normal donors. The patient lacked a previously unknown blood group antigen, which was named Vel. It has long been known that around one in 1 000 people lack the Vel antigen, but the molecule that carries it has been a mystery.
Lund University researchers Jill Storry, Magnus Jöud, Björn Nilsson and Martin L. Olsson and their colleagues have now discovered that the presence of the Vel antigen on our red blood cells is controlled by a previously unknown protein (SMIM1) that is not carried by those who lack the Vel antigen.
The findings have major clinical significance, according to Professor Martin L. Olsson, a consultant in transfusion medicine.
‘Until now there has not been a simple way to find these blood donors and there is therefore a major shortage of Vel-negative blood. Now we can identify these donors with simple DNA tests. From having previously only had access to one such donor in our region, there are now three and further screening is being carried out’, says Professor Olsson.
Two research groups with completely different focuses have collaborated to solve the 60-year-old riddle, explains Reader Björn Nilsson, who has led the work together with Reader Jill Storry and Professor Olsson.
‘Many researchers have tried to find the Vel molecule. We realised that it might be possible to find it using advanced DNA analysis techniques. Our idea proved to be correct and we found that the Vel blood group is inactivated in exactly the same way for all Vel-negative individuals’, says Björn Nilsson.
Another interesting aspect is that the new protein is unlike any previously known protein and appears to be present on the red blood cells of other species as well.
‘Interestingly, the new protein, SMIM1, is reminiscent of other molecules used by malaria parasites to infect humans. It is therefore possible that SMIM1 could be a long-sought malaria receptor on the red blood cells’, says Jill Storry. Lund University
Shedding light on a gene mutation that causes signs of premature ageing
, /in E-News /by 3wmediaResearch from Western University and Lawson Health Research Institute sheds new light on a gene called ATRX and its function in the brain and pituitary. Children born with ATRX syndrome have cognitive defects and developmental abnormalities. ATRX mutations have also been linked to brain tumours.
Dr. Nathalie Bérubé, PhD, and her colleagues found mice developed without the ATRX gene had problems in the forebrain, the part of the brain associated with learning and memory, and in the anterior pituitary which has a direct effect on body growth and metabolism. The mice, unexpectedly, also displayed shortened lifespan, cataracts, heart enlargement, reduced bone density, hypoglycemia; in short, many of the symptoms associated with ageing.
Ashley Watson, a PhD candidate working in the Bérubé lab and the first author on the paper, discovered the loss of ATRX caused DNA damage especially at the ends of chromosomes which are called telomeres. She investigated further and discovered the damage is due to problems during DNA replication, which is required before the onset of cell division. Basically, the ATRX protein was needed to help replicate the telomere.
Working with Frank Beier of the Department of Physiology and Pharmacology at Western’s Schulich School of Medicine & Dentistry, the researchers made another discovery. ‘Mice that developed without ATRX were small at birth and failed to thrive, and when we looked at the skeleton of these mice, we found very low bone mineralisation. This is another feature found in mouse models of premature ageing,’ says Bérubé, an associate professor in the Departments of Biochemistry and Paediatrics at Schulich Medicine & Dentistry, and a scientist in the Molecular Genetics Program at the Children’s Health Research Institute within Lawson. ‘We found the loss of ATRX increases DNA damage locally in the forebrain and anterior pituitary, resulting in systemic defects similar to those seen in ageing.’
The researchers say the lack of ATRX in the anterior pituitary caused problems with the thyroid, resulting in low levels of a hormone called insulin-like growth factor-one (IGF-1) in the blood. There are theories that low IGF-1 can deplete stores of stem cells in the body, and Bérubé says that’s one of the explanations for the premature ageing. University of Western Ontario
Possible predictive biomarker for identifying patients who may respond to autophagy inhibitors
, /in E-News /by 3wmediaAutophagy, the process by which cells that are starved for food resort to chewing up their own damaged proteins and membranes and recycling them into fuel, has emerged as a key pathway that cancer cells use to survive in the face of assault by chemotherapy and radiation. Using drugs to shut down that survival mechanism shows great promise, especially when combined with targeted agents and standard chemotherapies, but until recently, it has been unclear which patients’ cancers would respond to that combination therapy.
A team led by researchers from the Perelman School of Medicine at the University of Pennsylvania will present findings showing that colon cancer and lung cancer cell lines which expressed a gene known as helicase-like transcription factor (HLTF) tended to be impervious to the effects of the autophagy inhibition drug hydroxycholoroquine (HCQ). Cells where HLTF is silent, however, appeared to be sensitive to HCQ, which led the team to test HLTF expression in a group of colon cancer patients treated with two chemotherapies (the FOLFOX regimen plus bevacizumab) and HCQ. They found that low expression of HLTF predicted those who would respond to the combination therapy.
Since previous studies have shown that HLTF gene silencing is common in 20 to 40 percent of many epithelial cancers, the Penn team is hopeful their findings could lead to the development of a predictive biomarker to identify patients with other cancers who are most likely to respond to drug therapies involving autophagy inhibitors. Penn Medicine
Scientists find that prostate cancer patients with BRCA2 mutations require urgent treatment
, /in E-News /by 3wmediaMen who develop prostate cancer after inheriting a faulty gene need immediate surgery or radiotherapy rather than being placed under surveillance, as their disease is more aggressive than other types, a new study has found.
A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust found prostate cancers spread more quickly and were more often fatal in men who had inherited a faulty BRCA2 gene than in men without the faulty gene.
The research, funded by the Ronald and Rita McAulay Foundation and Cancer Research UK, could challenge current NHS guidelines for prostate cancer, under which BRCA2 mutation carriers are offered the same treatment options as non-carriers.
It is often difficult to tell at diagnosis whether prostate cancer will be life-threatening or not, and while treatment options for early-stage disease include surgery and radiotherapy, many men instead receive active surveillance to see if the disease starts to progress.
The new study is the largest to compare prostate cancer patients with and without BRCA mutations, in order to tell whether gene testing should help to direct management options.
Senior author Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research (ICR) and Honorary Consultant in Clinical Oncology at The Royal Marsden, said: ‘It is clear from our study that prostate cancers linked to inheritance of the BRCA2 cancer gene are more deadly than other types. It must make sense to start offering affected men immediate surgery or radiotherapy, even for early-stage cases that would otherwise be classified as low-risk. We won’t be able to tell for certain that earlier treatment can benefit men with inherited cancer genes until we’ve tested it in a clinical trial, but the hope is that our study will ultimately save lives by directing treatment at those who most need it.’
The team from the ICR and The Royal Marsden, with collaborators across the UK, examined the medical records of 61 BRCA2-mutation carriers, 18 BRCA1-mutation carriers and 1,940 non-carriers.
They found BRCA1/2 mutation carriers were more likely to be diagnosed with advanced stage prostate cancers (37 per cent versus 28 per cent) or cancer that had already spread (18 per cent versus nine per cent) than non-carriers. Among those whose cancers had not spread out of the prostate at diagnosis, within five years more carriers than non-carriers had metastatic disease (23 per cent versus seven per cent).
Patients with BRCA2-mutations were also significantly less likely to survive the cancer, living an average of 6.5 years compared with 12.9 years for non-carriers. The team concluded that a BRCA2 test could be used in combination with other factors as a prognostic test. Men with a BRCA1 mutation also had a shorter average survival time of 10.5 years, but there was not a statistically significant difference with non-carriers. ICR
Scientists learn what makes nerve cells so strong
, /in E-News /by 3wmediaHow do nerve cells — which can each be up to three feet long in humans — keep from rupturing or falling apart?
Axons, the long, cable-like projections on neurons, are made stronger by a unique modification of the common molecular building block of the cell skeleton. The finding, which may help guide the search for treatments for neurodegenerative diseases.
Microtubules are long, hollow cylinders that are a component of the cytoskeleton in all cells of the body. They also support transport of molecules within the cell and facilitate growth. They are made up of polymers of a building-block substance called tubulin.
‘Except for neurons, cells’ microtubules are in constant dynamic flux — being taking apart and rebuilt,’ says Scott Brady, professor and head of anatomy and cell biology at UIC and principal investigator on the study. But only neurons grow so long, he said, and once created they must endure throughout a person’s life, as much as 80 to 100 years. The microtubules of neurons are able to withstand laboratory conditions that cause other cells’ microtubules to break apart.
Brady had been able to show some time ago that the neuron’s stability depended on a modification of tubulin.
‘But when we tried to figure out what the modification was, we didn’t have the tools,’ he said.
Yuyu Song, a former graduate student in Brady’s lab and the first author of the study, took up the question. ‘It was like a detective story with many possibilities that had to be ruled out one by one,’ she said. Song, who is now a post-doctoral fellow at Howard Hughes Medical Institute at Yale School of Medicine, used a variety of methods to determine the nature of the modification and where it occurs.
She found that tubulin is modified by the chemical bonding of polyamines, positively charged molecules, at sites that might otherwise be chinks where tubulin could be broken down, causing the microtubules to fall apart. She was also able to show that the enzyme transglutaminase was responsible for adding the protective polyamines.
The blocking of a vulnerable site on tubulin would explain the extraordinary stability of neuron microtubules, said Brady. However, convincing others required the ‘thorough and elegant work’ that Song brought to it, he said. ‘It’s such a radical finding that we needed to show all the key steps along the way.’
The authors also note that increased microtubule stability correlates with decreased neuronal plasticity — and both occur in the process of ageing and in some neurodegenerative diseases. Continued research, they say, may help identify novel therapeutic approaches to prevent neurodegeneration or allow regeneration. University of Illinois at Chicago College of Medicine
Scientists identify a potential target to reduce the progression of metastases, the main cause of death for breast cancer patients
, /in E-News /by 3wmediaMontréal scientists identified the DOCK1 protein as a potential target to reduce the progression of metastases in patients suffering from breast cancer, the most common type of cancer in women.
Dr. Côté’s laboratory is interested in metastasis, which is the spread of cancer from an organ (or part of an organ) to another. Nearly 90 per cent of cancer patient deaths are attributable to metastasis, thus explaining the importance of understanding the underlying cellular and molecular mechanisms of this harmful process.
‘Despite important breakthroughs in breast cancer treatment, few mechanisms are known to explain the spread of metastases,’ says Dr. Côté, Director of the Cytoskeletal Organization and Cell Migration research unit at the IRCM. ‘We are looking to identify the proteins that regulate the metastatic process so that new agents can be developed and combined with current treatments.’
Two major breast cancer subtypes, HER2+ and Basal, have a tendency to be metastatic and recurrent, and are ultimately associated to a poor survival rate. Research at the IRCM was conducted on the HER2+ type (Human Epidermal growth factor Receptor 2), which represents approximately 25 per cent of breast cancer cases. HER2 positive tumours tend to develop and spread more quickly than other types of tumours.
‘By studying a genetic mouse model with HER2+ breast cancer, we identified the protein DOCK1 as an important regulator of metastasis,’ explains Mélanie Laurin, doctoral student in Dr. Côté’s laboratory and first author of the study. ‘When we eliminated this protein in mice, our results showed a significant decrease in lung metastases. We also discovered that the DOCK1 protein contributes to the growth of tumours.’
‘To show the correlation between the expression of DOCK1 and breast cancer prognosis, we performed an analysis of several databases of patient genic,’ adds Dr. Benjamin Haibe-Kains, researcher at the IRCM who collaborated with Dr. Côté’s team. ‘We did indeed discover that high levels of DOCK1 in HER2+ or Basal breast cancer patients are associated with a lower prognosis, or recurrence of the disease.’
‘Our work defined a new molecule required for the progression of breast cancer to the metastatic stage and allowed us to identify new markers that could become potential targets to stop the progression of metastases,’ concludes Dr. Côté. ‘We also showed that a chemical inhibitor of the DOCK1 protein, developed by Dr. Yoshinori Fukui, our collaborator in Japan, can stop the migration of cancerous cells. These results could eventually lead to the development of drugs that would limit the progression of metastatic breast cancer and could thereby improve patient prognosis.’ Institut de recherches cliniques de Montréal
Gene-expression signature may signify risk for recurrence, metastasis in prostate cancer
, /in E-News /by 3wmediaA team led by Massachusetts General Hospital (MGH) researchers has identified a genetic signature that appears to reflect the risk of tumour recurrence or spread in men surgically treated for prostate cancer. If confirmed in future studies, this finding not only may help determine which patients require additional treatment after the cancerous gland has been removed, it also may help address the most challenging problem in prostate cancer treatment – distinguishing tumours that require aggressive treatment from those that can safely be monitored.
‘Radical prostatectomy is the standard of care for men whose cancer is advanced but confined to the prostate gland, but we know that the factors we use to determine which patients need radiation therapy after surgery are inadequate,’ says W. Scott McDougal, MD, of the MGH Department of Urology, corresponding author of the report. ‘The treatments available to our patients can have significant impact on their quality of life, so a better way to know which patients with localised cancer need additional therapy after surgery and which require no additional treatment is a significant unmet need.’
Gene expression signatures indicating patient prognosis and sometimes the most appropriate treatment have been incorporated into care for breast cancer and other tumours. Studies looking for such markers in prostate cancer have had variable results, and their potential usefulness to guide treatment has not been determined. For the current study the research team – led by Chin-Lee Wu, MD, PhD, of the MGH Department of Pathology – examined samples of malignant tissue from around 200 prostate cancer patients who had radical prostatectomies at the MGH between 1993 and 1995, analyzing the expression patterns of more than 1,500 genes associated with prostate cancer in earlier studies. With the results of that analysis, they developed a 32-gene index to reflect the likelihood that a patient’s tumour would recur, signified by detectable levels of prostate-specific antigen (PSA) after the gland had been remove, or spread.
To validate the usefulness of the index, they used it to analyse tissue samples from a different group of almost 300 patients who had their prostates removed in 1996 and 1997, comparing the index with currently used prognostic factors – such as PSA levels, physical examination, and a tumour’s microscopic appearance – to see how accurately each predicted the actual incidence of tumour recurrence or metastasis during the 10 years after surgery. The expression-based index proved to be the most accurate method. Among those it designated as high-risk, the actual incidence of tumor recurrence was 47 percent and of metastasis, 14 percent. Among those classified as intermediate risk, actual recurrence was 22 percent, and metastasis occurred in 2 percent. No recurrence or metastasis were seen in patients classified as low-risk by the gene-expression index.
To get a sense of whether the index could help determine risk at the time of diagnosis, the researchers used it to assess pre-surgical needle biopsy samples from 79 patients in the validation group. The risk assignment based on biopsy results closely matched the assessment based on surgically removed tissue, and the prognostic ability of the index was better than that of other pathological information available at the time a biopsy was taken. Because the current report is based on study of patients treated at a single institution, the authors note, it requires confirmation in larger, multi-institutional studies.
‘A more accurate prognosis at the time of diagnosis could give patients and their physicians much more confidence in choosing a definitive therapy or pursuing active surveillance for those at low risk, which could reduce over-treatment, a critical issue in disease management,’ says lead author Wu, an associate professor of Pathology at Harvard Medical School. McDougal is the the Kerr Professor of Urology, at HMS. Massachusetts General Hospital
Transcription factors regulating blood oxygen linked to melanoma metastases
, /in E-News /by 3wmediaResearchers at the University of North Carolina have discovered that transcription factors regulating the levels of oxygen in the blood also play a role in the spread of the skin cancer melanoma.
A research team led by William Kim, MD, member of the UNC Lineberger Comprehensive Cancer Center, and graduate student and first author Sara Hanna, linked melanoma metastases to a pair of transcription factors known as HIF1 and HIF2.
Researchers found that HIF1 and HIF2 are over-expressed in melanoma tumours. In healthy cells, HIF1 and HIF2 assist in regulating hypoxia, the state caused by low levels of oxygen in the blood. Hypoxia has been linked to metastases in several solid tumours, and the UNC team has found that it promotes the spread of melanoma from the skin to other sites in the body through the lymphatic system.
Patients who are diagnosed with early stage melanomas have a high rate of survival, but the prognosis worsens significantly once the tumours spread to other sites throughout the body. Using in vitro systems and mouse models, researchers suppressed the expression of HIF1 and HIF2 in the melanoma tumours. While the inactivation of the transcription factors did not reduce the growth of the initial tumours, it did reduce the rate at which the melanoma spread to other sites in the body.
Both HIF1 and HIF2 independently activate the protein kinase SRC using different signalling pathways. The SRC protein has been linked to several different cancers, and the identification of its role in melanoma suggests that existing therapies targeting SRC may prove to be a viable target for therapies aimed at reducing the spread and ultimate lethality of the cancer.
‘What we are trying to do now is inhibit these pathways with drugs in the mice to see if we see a decrease of metastasis,’ said Hanna. University of North Carolina