01.08.2016

Cancer stem cell metastasis

Tagged therapeutic stem cells (green) targeting breast cancer metastases (red) in the brain of a mouse model.
Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General Hospital (MGH) have developed an “imageable” mouse model of brain-metastatic breast cancer and shown the potential of a stem cell-based therapy to eliminate metastatic cells from the brain and prolong survival. In their search for novel, tumor-specific therapies that could target multiple brain metastases without damaging adjacent tissues, the research team first developed a mouse model that more closely mimicked what is seen in patients. To devise a potential new therapy, the investigators engineered a population of neural stem cells to express a potent version of a gene called TRAIL, which codes for a molecule that activates cell-death-inducing receptors found only on the surface of cancer cells.
The safe use of a stem cell-based therapy against brain metastasis would require preventing the engineered cells from persisting within the brain, where they could affect normal tissue and possibly give rise to new tumors. Shah and his team are currently developing similar animal models of brain metastasis from lung cancers and from melanoma. In addition to Shah, who also is an associate professor of radiology at Harvard Medical School, authors of the Brain report are co-lead authors Wanlu Du and Tugba Bagci-Onder, along with Jose-Luiz Figueiredo and Jordi Martinez-Quintanilla, all of the MGH Molecular Neurotherapy and Imaging Laboratory. The study was supported by National Institutes of Health grants and a grant from the James McDonald Foundation. Neuromas : emanate cells forming the sheath of nerves in the brain until their termination. Depending on the location and type of tumor, can be added: muscle weakness, paralysis and impaired hearing, vision, swallowing and speech.
Glioblastoma : this is a highly malignant tumor penetrates quickly into the surrounding tissues. Ependymoma and medulloblastoma : these are typical of brain tumors of childhood and adolescence. Meningioma : this is a benign tumor that can push the adjacent structures, however, if it grows quickly.
Neuroma : tumor that usually develops from cells of the sheath of the eighth cranial nerve (acoustic neuroma).
The difficulty lies in the distinction of tumor tissue compared to healthy tissue during surgery. Complications arise when the tumor still grows rapidly or when it enters the adjacent tissues. Copyright © 2012 Rayur, All trademarks are the property of the respective trademark owners. Patients with leukaemia were among the first to be given a treatment where transplants of blood stem cells made it possible to obtain cures. About leukaemiaLeukaemia is a term used to describe many different kinds of cancers of the blood. We've worked with scientists and doctors to answer some of your most frequently asked questions about stem cell science and potential therapies.
Using real time in vivo imaging and subsequent composite fluorescence imaging, they show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. The study, published online in the journal Brain, also describes a strategy for preventing the potential negative consequences of stem cell therapy. They found that injecting into the carotid artery breast cancer cells that express markers that allow them to enter the brain (cells labeled with bioluminescent and fluorescent markers to enable tracking by imaging technologies) resulted in the formation of many metastatic tumors throughout the brain, mimicking what is seen in advanced breast cancer patients.
Previous research by Shah and his colleagues had shown that two types of stem cells are naturally attracted toward tumors in the brain.
To facilitate removal of the therapeutic stem cells from the brain at the conclusion of therapy, the researchers created cells that, in addition to TRAIL, express a viral gene called HSV-TK, which renders them susceptible to the effects of the antiviral drug ganciclovir.


They also are working to improve understanding of the therapeutic efficacy of simultaneously targeting multiple tumor-specific molecules on the surface of metastatic cells within the brain and anticipate that their findings will make a major contribution toward developing novel targeted therapies for metastatic tumors in the brain. Indeed, the brain tumor is dangerous because it pushes the other surrounding structures and increased the pressure on vital brain centers, located around the bones can not sell when the internal volume increases. We distinguish glioblastomas, astrocytomas, ependymomas, medulloblastomas and oligodendrogliomas. Glioblastoma brain tumor is the most widespread and affects mainly those aged 40 to 60 years. Typical symptoms of pituitary tumors are primarily hormonal (growth disorders, fatigue, skin and fine wrinkles, erectile dysfunction). Typical symptoms are a gradual decrease in hearing, tinnitus, balance disorders and paralysis of the face. Benign tumors (meningiomas, neurinomas) can be resected surgically, usually inducing remission. Modern techniques, however, allow a minimum of damage healthy tissue surrounding the tumor (staining techniques, computer-assisted intervention, operation under local anesthesia). Radiotherapy is, or irradiating the tumor from the outside through the skin or to surgically inserting a small-ray source in order to destroy the tumor from the inside. However, in all of these, too many white blood cells (also called leukocytes) are produced and these leukemic cells do not mature abnormally.
Current therapeutic options for such patients are limited, particularly when there are many metastases.
After first verifying in their model that stem cells injected to the brain would travel to multiple metastatic sites and not to tumor-free areas, the team implanted into the brains of metastasis-bearing mice TRAIL-expressing stem cells, which reduced the growth of tumors. Several tests in cultured cells indicated that ganciclovir would cause the death of HSV-TK-expressing stem cells, and testing in the mouse model confirmed that administration of the drug after successful treatment of brain metastases successfully eliminated therapeutic stem cells that also expressed HSV-TK. For now, the influence of electromagnetic fields from mobile phones or power lines on the development of brain tumors has not been proven. Paralysis and slurred speech occur already a few weeks or months after the onset of the disease.
Intracranial pressure compresses the vital brain centers and nerve pathways of the brain, causing the patient to die without treatment.
Injecting the TRAIL-expressing stem cells into the carotid artery, a likely strategy for clinical application, led to significantly slower tumor growth and increased survival, compared with animals receiving unaltered stem cells or control injections. Only the origin of brain metastases is known: it is the spread of cancer cells from another malignant tumor that have spread into the body through the bloodstream. These leukaemic blasts are not able to perform the functions of normal mature blood cells which is to defend the body against infection and disease. In most forms of acute leukaemia, these leukaemic blasts accumulate in the bone marrow as well as in the blood and and suppress the formation of normal white blood cells. Leukaemia patients demonstrating chemotherapy procedures released into the public domain by Bill Branson.
They are usually sub-classified as acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) depending on the types of white blood cells that are affected.Chronic leukaemias are more slowly developing leukaemias that may escape diagnosis for several years before they are detected. Other known causes include accidental exposure to radiation and treatment with some types of anti-cancer drugs. However, in order for a full blown leukemia to develop, it is thought that several changes must be accumulated to alter the molecular programs that control cell behaviour. A large number of gene mutations have been linked to human leukaemias, and in some cases, the same mutation is consistently and uniquely associated with a particular type of leukaemia.


Chronic myeloid leukaemia (CML) is an example of such a leukaemia where knowledge of a shared driver mutation led to the development of a drug (Gleevec) that is very successful in killing the leukemic cells in CML patients.
However, in most patients with leukaemia, it is not yet known which mutation or group of mutations are actually driving their disease.Because many types of leukaemia are thought to require several rare mutations in order to develop, the first change is assumed to occur in a cell that will remain in the body for a long time. If a stem cell is affected by a genetic change, all the cells it produces will inherit the same mutation. However, cells go through a number of steps to develop from HSCs into specialised cells such as white blood cells.
For many leukaemias, a complex series of events is probably involved and it is not yet clear where the first important mutation occurs.How are healthy blood stem cells used to treat leukaemia?Acute leukaemia usually requires immediate and intensive treatment. Depending on the particular type of leukaemia and many other things about the individual patient, treatment options might include chemotherapy, steroids or a more intensive procedure such as a haematopoietic stem cell transplant combined with high-dose chemotherapy followed by a transplant of healthy haematopoietic stem cells.High-dose chemotherapy is the most effective currently established method to kill leukaemic cells and can cure some patients.
However, it also severely damages the remaining normal blood-forming cells in the bone marrow. The cells for the transplant can be collected from the blood or bone marrow of a healthy donor. In fact, such transplants are effective because they contain important immune cells that help to kill the leukaemic cells in addition to HSCs that rescue blood production. A patient’s own cells can sometimes be used for the transplant, if it is possible to collect enough healthy cells before the treatment is performed. Otherwise the transplanted donor cells can be attacked by the patient’s residual immune system and rejected.Intensive chemotherapy followed by a HSC transplant is very effective for treating many types of acute leukaemia.
Careful observation, restricted access to other people and preventative treatment with antibiotics are used to reduce infection risks.Graft-versus-host disease (GvHD) – This complication occurs when donor blood cells attack the patient’s own normal tissues. Other strategies to prevent GvHD include suppressing the immune system with drugs and removing a specific type of white blood cells (lymphocytes) from the transplant.Researchers and doctors are investigating ways to improve current transplantation approaches in order to address these limitations. Newer forms of transplantation called mini-allografts or reduced-intensity allografts have been developed to reduce the risk. These procedures allow lower doses of chemotherapy to be used, which helps reduce the extent of damage to the bone marrow. Instead, donor immune cells are transplanted with and after the donor HSCs to attack and eliminate any remaining leukaemic cells. Alternatively, attempts are being made to selectively remove the immune cells that cause GvHD from the transplant.Scientists and doctors are also currently investigating treatments that might reduce the time it takes for the patient’s immune system to recover after a HSC transplant. One option is to treat the patient with selected proteins called growth factors, which can enhance the production of the particular immune cells needed to fight infections. This can help reduce the risk of infection while the patient recovers.The future of haematopoietic stem cell treatments for leukaemiaStem cell research is a rapidly developing field. New technologies such as induced pluripotent stem cells are already being used to study leukaemia in the lab. Researchers can then study the cells to learn more about how the disease arises and is maintained, and to design and test new, potentially more effective and less toxic therapies.
In the future, new methods for the lab-based production of HSCs that can be used in transplant patients may also be developed.
This could revolutionize many of the current shortcoming of current transplants and lack of matched donors.



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