Why Antiangiogenesis Fails
Harvard Medical School investigators at Massachusetts General Hospital have identified a potential mechanism behind the resistance that inevitably develops to cancer treatments which combine chemotherapy and antiangiogenic drugs.
In a paper published in Science Translational Medicine, the researchers report that treating metastatic colorectal cancer with antiangiogenesis drugs such as bevacizumab (Avastin) significantly increases several components of the extracellular matrix and also adds stiffness within liver metastases in both patients and mouse models.
“Systemic chemotherapy is a cornerstone of therapy for metastatic colorectal cancer, and the introduction of antiangiogenic drugs like bevacizumab has extended patients’ survival, although the tumors ultimately progress,” said Dai Fukumura, HMS associate professor of radiation oncology at Mass General and one of the study's co-senior authors. “Understanding how tumors become resistant to treatment could help us develop novel strategies to overcome those mechanisms of resistance.”
In a paper published in Science Translational Medicine, the researchers report that treating metastatic colorectal cancer with antiangiogenesis drugs such as bevacizumab (Avastin) significantly increases several components of the extracellular matrix and also adds stiffness within liver metastases in both patients and mouse models.
“Systemic chemotherapy is a cornerstone of therapy for metastatic colorectal cancer, and the introduction of antiangiogenic drugs like bevacizumab has extended patients’ survival, although the tumors ultimately progress,” said Dai Fukumura, HMS associate professor of radiation oncology at Mass General and one of the study's co-senior authors. “Understanding how tumors become resistant to treatment could help us develop novel strategies to overcome those mechanisms of resistance.”
Antiangiogenesis drugs were originally thought to improve cancer treatment by cutting off a tumor’s blood supply. However, Rakesh Jain, the A. Werk Cook Professor of Radiation Oncology (Tumor Biology) at HMS and Mass General and co-senior author of the current study, developed a different hypothesis for how they worked.
When given in judicious doses, Jain reasoned, the drugs acted by normalizing the abnormal vasculature within a tumor, thus improving the delivery of chemotherapy drugs and response to radiation treatment. This has been supported by many studies.
Another factor that can impede drug delivery within tumors is a buildup of compressive forces that squeeze blood vessels shut. In addition to the pressure exerted by proliferating tumor cells, the extracellular matrix surrounding the tumor cells also contributes to these forces.
Some recent studies have found that the hypoxia—reduction in oxygen supply—induced by antiangiogenic therapy increases the expression of collagen, a major component of the extracellular matrix, in primary tumors. The Mass General team set out to investigate whether other matrix components, specifically hyaluronic acid (HA) and sulfated glycosaminoglycans (sGAGs), were also affected by antiangiogenic therapy and if they contributed to treatment resistance.
The research team first studied samples of liver metastases from patients with colorectal cancer and found the HA expression was increased within tumors, compared with unaffected liver tissue, and was even higher in metastases from patients who had received antiangiogenic therapy. In two mouse models of metastatic colorectal cancer, they found that antiangiogenic treatment increased compressive forces within liver metastases by stiffening tissues.
Expression of both HA and sGAG was significantly higher after antiangiogenic treatment in the mouse models. In addition, antiangiogenic therapy appeared to cause an influx of suppressor immune cells that would reduce any immune response against the tumor.
Analysis of metastatic tissue from the mouse models revealed increased hypoxia and decreased density of microvessels after antiangiogenic therapy, which was followed by measurable increases in HA and sGAG. Inducing hypoxia in human liver stellate cells, the primary source of extracellular matrix, led to a more than fourfold increase in the expression of HA.
Adding an enzyme that targets HA to antiangiogenesis treatment in one of the mouse models caused a 74 percent reduction in HA levels and prolonged the animals’ survival, compared with combination chemotherapy and antiangiogenesis alone.
“Although various mechanisms of resistance to antiangiogenesis therapy have been suggested, our study is the first to propose a role for the extracellular matrix and alterations in the mechanical properties of tumors,” said Fukumura. “In addition to showing for the first time that antiangiogenesis therapy changes these properties within tumors, we also found that the hypoxia induced by extracellular matrix abnormalities attracts the immunosuppressive cells that help the tumor evade a systemic immune cell attack.”
The authors note that their findings in animal models need to be validated in controlled clinical trials in human patients.
“If these trials are successful, ‘normalizing’ the matrix may improve treatment outcomes in multiple cancers, since these tumors harbor an excessive quantity of abnormal extracellular matrix,” said Jain.
#Chemotherapy, #HavardMedicalSchool
Source: Harvard Medical School
Heart Repair Research Boosted by New Findings
Scientists trying to find ways to regenerate a damaged heart have shed more light on the molecular mechanisms that could one day make this a reality.
New findings from a study carried out by researchers at the University of Aberdeen and supported by the British Heart Foundation have been published today in Stem Cell Reports.
Whilst other organs such as the liver can regenerate, the heart muscle has very little ability to do so after suffering damage, such as a heart attack.
In the womb the body is able to produce heart muscle cells but soon after birth it effectively stops producing them.
Recent studies have suggested a few stem cells in the adult heart could still differentiate into heart muscle cells using similar mechanisms as those that happen in the embryonic heart.
Scientists are already able to manipulate cultured embryonic stem cells in a petri dish to become heart muscle cells (cardiac myocytes) that visually ‘beat’. This process allows experts to study the molecular mechanisms driving stem cell differentiation into heart muscle cells.
The tissues and organs of developing embryos are organised by a process called cell-to-cell signalling – effectively cells ‘talking’ to each other. These interactions are controlled by signalling molecules. A particularly important class of these molecules are called Wnt signals.
Previous studies had shown that ‘artificial’ activation and inhibition of Wnt signalling can induce the production of heart muscle cells. New research carried out at the University of Aberdeen has carefully monitored Wnt signalling activity and where and when Wnt signals normally occur, which now lends further evidence that Wnt signals naturally regulate heart muscle differentiation.
New findings from a study carried out by researchers at the University of Aberdeen and supported by the British Heart Foundation have been published today in Stem Cell Reports.
Whilst other organs such as the liver can regenerate, the heart muscle has very little ability to do so after suffering damage, such as a heart attack.
In the womb the body is able to produce heart muscle cells but soon after birth it effectively stops producing them.
Recent studies have suggested a few stem cells in the adult heart could still differentiate into heart muscle cells using similar mechanisms as those that happen in the embryonic heart.
Scientists are already able to manipulate cultured embryonic stem cells in a petri dish to become heart muscle cells (cardiac myocytes) that visually ‘beat’. This process allows experts to study the molecular mechanisms driving stem cell differentiation into heart muscle cells.
The tissues and organs of developing embryos are organised by a process called cell-to-cell signalling – effectively cells ‘talking’ to each other. These interactions are controlled by signalling molecules. A particularly important class of these molecules are called Wnt signals.
Previous studies had shown that ‘artificial’ activation and inhibition of Wnt signalling can induce the production of heart muscle cells. New research carried out at the University of Aberdeen has carefully monitored Wnt signalling activity and where and when Wnt signals normally occur, which now lends further evidence that Wnt signals naturally regulate heart muscle differentiation.
The hope is that if we understand the molecular mechanisms surrounding how this works we may in the future contribute to new therapeutic strategies to encourage heart regeneration."
Silvia Mazzotta
It is hoped that by understanding the molecular mechanisms involved in heart muscle cell development, scientists will be able to contribute to new therapeutic strategies that could, in the future, encourage heart regeneration.
First author of the paper, Silvia Mazzotta, who is a PhD student at the University of Aberdeen said: “During embryonic life we can make heart muscle cells but if an adult suffers from heart infarction in later life the heart muscle can’t regenerate sufficiently to repair itself.
“The hope is that if we understand the molecular mechanisms surrounding how this works we may in the future contribute to new therapeutic strategies to encourage heart regeneration."
Professor Stefan Hoppler added: “What this research shows is that flicking the switch to turn Wnt signalling on or off is not just an experimental trick, but recapitulates normal heart muscle cell formation.
“This is potentially extremely important considering the huge impact that cardiovascular disease has on modern society.”
Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which funded the research, said: “Heart failure, often caused by the irreparable damage inflicted by a heart attack, affects over half a million people in the UK. Treatments to prevent people developing heart failure, or that can reverse this disabling condition, are urgently needed – research like this offers hope.
“This study offers clues that may help to switch on the repair of heart cells after a heart attack. This is the major goal of the BHF’s Mending Broken Hearts Appeal, which was launched to help reduce the burden of heart failure by funding pioneering regenerative medicine research.”
#HeartRepair, #StemCell
Source: The University of Aberdeen
New Technology Improves Vision for brain injury patients
The computer-delivered therapy is designed to improve speed and effectiveness of eye movements to better compensate for visual field loss.
The program called NeuroEyeCoach™can be considered to be the first evidence based registered medical device accessible to patients at home or in clinical settings.
The program called NeuroEyeCoach™can be considered to be the first evidence based registered medical device accessible to patients at home or in clinical settings.
Published in academic journal Biomed Research International, is a report of a collaborative study between researchers in Aberdeen, LMU University of Munich and University of Verona showing that NeuroEyeCoach is an effective compensatory approach for those with visual field loss after stroke.
Loss of sight due to brain injury, usually from stroke, affects approximately a third of stroke survivors. In these types of brain injury, partial blindness in the visual field occurs due to a disruption in the connections between the eyes and the visual processing areas of the brain.
Professor Arash Sahraie Head of the School of Psychology at the University of Aberdeen who led the study said: “This type of sight deficit can be massively debilitating for those affected by it. Patients report a loss of confidence in their own ability to navigate the environment that can then manifest itself in the form of withdrawal from daily life.
We have developed the research into an accessible treatment that can help patients achieve major improvements in their vision within about 2-3 weeks."
Professor Arash Sahraie, Head of the School of Psychology
"This is why it’s important to develop techniques to help patients to improve as much as they can and this compensatory technique is yet another step forward in providing help and therapy for these patients.
"We have developed the research into an accessible treatment that can help patients achieve major improvements in their vision within about 2-3 weeks. The therapy is adaptive and we can tailor the treatment programme according to the needs of the individual.
"Our study found that this treatment can improve what remains of the partially sighted patients’ vision by training them to better detect objects in their visual field.”
#NewTechnology #BrainInjury
Source: The University of Aberdeen