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group_2_presentation_1_-_glioblastoma [2017/10/06 10:43] gaubaa |
group_2_presentation_1_-_glioblastoma [2018/01/25 15:19] (current) |
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| + | Link to ppt: https://docs.google.com/a/mcmaster.ca/presentation/d/1aPDGB9N-jfVw91J4yq4N44fnEg5pGluNftePloslFag/edit?usp=sharing | ||
| ====== Introduction ====== | ====== Introduction ====== | ||
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| - | ===== Etiology ===== | ||
| Glioblastomas (GBM) are the most common aggressive malignant tumors found in adults (Davis 2016). The onset tends to occur in glial tissue of the central nervous system, with most tumors found in the brain. Primary glioblastomas originate de novo, meaning they do not arise from previously present tumors or cancerous precursors in the central nervous system. In contrast, secondary tumors arise from previously existing low grade tumors that develop into GBM (Davis, 2016). Most cases of GBM tend to be sporadic and result from a complex mutation rather than a genetic predisposition. However, the cancer can result from the metastasis of peripheral cancer cells located commonly in the breast and lungs, effectively evading immunological responses upon penetrating the blood-brain barrier (Davis, 2016) Moreover, Gliomas could be astrocytic, oligodendrocytic, or a mix of both. Overall, there are few potential carcinogenic risk factors that can influence the onset of glioblastoma in the central nervous system. For instance, exposure to high doses of ionizing radiation is regarded as the only confirmed risk factor (Davis, 2016). | Glioblastomas (GBM) are the most common aggressive malignant tumors found in adults (Davis 2016). The onset tends to occur in glial tissue of the central nervous system, with most tumors found in the brain. Primary glioblastomas originate de novo, meaning they do not arise from previously present tumors or cancerous precursors in the central nervous system. In contrast, secondary tumors arise from previously existing low grade tumors that develop into GBM (Davis, 2016). Most cases of GBM tend to be sporadic and result from a complex mutation rather than a genetic predisposition. However, the cancer can result from the metastasis of peripheral cancer cells located commonly in the breast and lungs, effectively evading immunological responses upon penetrating the blood-brain barrier (Davis, 2016) Moreover, Gliomas could be astrocytic, oligodendrocytic, or a mix of both. Overall, there are few potential carcinogenic risk factors that can influence the onset of glioblastoma in the central nervous system. For instance, exposure to high doses of ionizing radiation is regarded as the only confirmed risk factor (Davis, 2016). | ||
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| ====== Brain Physiology ====== | ====== Brain Physiology ====== | ||
| - | The brain can be divided into two major components; white matter and grey matter. The grey matter consists of the cell bodies, axons and dendrites, it is where all the neuronal connections occur. The white matter consists of the glial cells and the myelinated axons that connect cell bodies to one another (Henson, 1999). Glioblastomas tend to occur in two subsets of the glial cells—astrocytes and oligodendrocytes. Astrocytes maintain the appropriate environment for neuronal signalling and are star-shaped cells that give the brain its shape. Astrocytes are the most common cell type to become tumours. Oligodendrocytes are responsible for forming myelin sheaths around axons. Tumours of oligodendrocytes are less common than astrocytomas. Many tumours contain a mixture of astrocytoma and oligodendroglioma cells. Tumours of other cell types in the brain are less common. For instance, tumours of neurons are very rare in adults (Henson, 1999). | + | The brain can be divided into two major components; white matter and grey matter (Figure 4). The grey matter consists of the cell bodies, axons and dendrites, it is where all the neuronal connections occur. The white matter consists of the glial cells and the myelinated axons that connect cell bodies to one another (Henson, 1999). Glioblastomas tend to occur in two subsets of the glial cells—astrocytes and oligodendrocytes. Astrocytes maintain the appropriate environment for neuronal signalling and are star-shaped cells that give the brain its shape. Astrocytes are the most common cell type to become tumours. Oligodendrocytes are responsible for forming myelin sheaths around axons. Tumours of oligodendrocytes are less common than astrocytomas. Many tumours contain a mixture of astrocytoma and oligodendroglioma cells. Tumours of other cell types in the brain are less common. For instance, tumours of neurons are very rare in adults (Henson, 1999). |
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| ===== Pathophysiology of Glioblastomas ===== | ===== Pathophysiology of Glioblastomas ===== | ||
| === Overview of Tumorigenesis === | === Overview of Tumorigenesis === | ||
| - | Six general intracellular events which lead to the development of glioblastoma. These steps do not occur in isolation, but the accumulation of these will lead to tumorigenesis. The first event is loss of cell cycle control. Normal cells have many checkpoints during the cell cycle to keep proliferation in control. However, in glioblastoma, genetic defects occur leading to uncontrolled regulation of the cell cycle causing proliferation. The second event that occurs is overexpression of growth factors and their receptors. This overexpression provides growth advantage to tumor cells, increasing their survivability. A third event that occurs in glioblastoma is angiogenesis. Glioblastoma is a vascular tumor, and thus needs angiogenesis to support itself. Another critical feature in glioblastoma is the mutation of stem cells into tumor cells*. Moreover, abnormal apoptosis is a significant feature in tumorigenesis. Genetic mutations, such as p53, disrupt normal apoptotic responses, and allow further progression of the cell cycle. Lastly, genetic instability allows for the accumulation of mutations. Some of these mutations will be advantageous since it will be a more malignant clone (Nakada et al. 2011). | + | Six general intracellular events which lead to the development of glioblastoma. These steps do not occur in isolation, but the accumulation of these will lead to tumorigenesis. The first event is loss of cell cycle control. Normal cells have many checkpoints during the cell cycle to keep proliferation in control. However, in glioblastoma, genetic defects occur leading to uncontrolled regulation of the cell cycle causing proliferation. The second event that occurs is overexpression of growth factors and their receptors. This overexpression provides a growth advantage to tumor cells, increasing their survivability. A third event that occurs in glioblastoma is angiogenesis. Glioblastoma is a vascular tumor, and thus needs angiogenesis to support itself. Another critical feature in glioblastoma is the mutation of stem cells into tumor cells. Moreover, abnormal apoptosis is a significant feature in tumorigenesis. Genetic mutations, such as p53, disrupt normal apoptotic responses, and allow further progression of the cell cycle. Lastly, genetic instability allows for the accumulation of mutations. Some of these mutations will be advantageous since it will be a more malignant clone (Nakada et al. 2011).These steps are outlined in Figure 5. |
| {{ :6image.png |}} | {{ :6image.png |}} | ||
| **Figure 5**: The six intracellular events that allow normal cells to be transformed to cancerous cells, through a process called tumorigenesis. | **Figure 5**: The six intracellular events that allow normal cells to be transformed to cancerous cells, through a process called tumorigenesis. | ||
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| === Angiogenesis === | === Angiogenesis === | ||
| - | Angiogenesis is initiated by angiogenic factor such as VEGF and FGF, which stimulate growth of endothelial cells. These are secreted in high concentrations from endothelial cells near the tumor, in a hypoxic microenvironment. The angiogenic factors bind to cognate receptors found on endothelial cells, leading to endothelial cell proliferation and migration. Then, there is a breakdown of local extracellular matrix, via MMPs, to provide room for new blood vessels to form. Next, angiopoietins (Ang-2) are secreted from the glioma cells to allow stability and maintenance of the new vasculature. Ang will bind to Tie-2 and destabilize vessels. After this breakdown and destabilization, endothelial cells gather into a tubular lumen. Individual sprouts are connected and form a vascular loop to allow for blood flow. Pericytes are then recruited and assemble on the outside off the new vasculature to allow maturation. Once a basement membrane is formed angiogenesis is complete (Nakada et al. 2011). | + | Angiogenesis is initiated by angiogenic factor such as VEGF and FGF, which stimulate growth of endothelial cells. These are secreted in high concentrations from endothelial cells near the tumor, in a hypoxic microenvironment. The angiogenic factors bind to cognate receptors found on endothelial cells, leading to endothelial cell proliferation and migration. Then, there is a breakdown of local extracellular matrix, via MMPs, to provide room for new blood vessels to form. Next, angiopoietins (Ang-2) are secreted from the glioma cells to allow stability and maintenance of the new vasculature. Ang will bind to Tie-2 and destabilize vessels. After this breakdown and destabilization, endothelial cells gather into a tubular lumen. Individual sprouts are connected and form a vascular loop to allow for blood flow. Pericytes are then recruited and assemble on the outside of the new vasculature to allow maturation. Once a basement membrane is formed angiogenesis is complete (Nakada et al. 2011). These steps are summarized in figure 9. |
| {{ :angio13.png |}} | {{ :angio13.png |}} | ||
| **Figure 9**: Steps for glioblastoma to undergo angiogenesis. Angiogenesis is a necessary process that allows glioma cells to survive and continue to proliferate. | **Figure 9**: Steps for glioblastoma to undergo angiogenesis. Angiogenesis is a necessary process that allows glioma cells to survive and continue to proliferate. | ||
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| === Genetic Instability === | === Genetic Instability === | ||
| - | Normal cells have tight regulations during the cell cycle to prevent mutations from occuring. However, when this tight regulation of the cell cycle is lost there will be an accumulation of genomic mutations during a series of cell divisions. These alterations will transform normal cells into precancerous cells. These cells would not be classified or diagnosed as cancer cells, however, these cells have a higher potential to be cancerous. The adition of more mutations that lead to increased growth trasform these cells into cancerous cells, and thus can be diagnsed as cancer. Furthermore, the cancer cells will continue to alter these cancer cells to be more malignant. Thus, genetic instability not only leads to tumorigenesis, but maintains the survivability of these cancer cells (Shen. 2011) | + | Normal cells have tight regulations during the cell cycle to prevent mutations from occuring. However, when this tight regulation of the cell cycle is lost there will be an accumulation of genomic mutations during a series of cell divisions. These alterations will transform normal cells into precancerous cells. These cells would not be classified or diagnosed as cancer cells, however, these cells have a higher potential to be cancerous. The addition of more mutations that lead to increased growth transform these cells into cancerous cells, and thus can be diagnosed as cancer. Furthermore, the cancer cells will continue to alter these cancer cells to be more malignant. Thus, genetic instability not only leads to tumorigenesis, but maintains the survivability of these cancer cells (Shen. 2011). The progression of normal cells to cancerous cells is outlined in figure 11. |
| {{ :gene_insta.png |}} | {{ :gene_insta.png |}} | ||
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| **Bevacizumab (Avastin®)** | **Bevacizumab (Avastin®)** | ||
| - | Bevacizumab (Avastin®) is a monoclonal antibody implemented in GBM chemotherapeutic regiments to target vascular endothelial growth factor (VEGF) and was approved by the FDA in 2009 after clinical trials had demonstrated excellent performance. The VEGF protein is needed for angiogenesis, a process that involves the synthesis of new vasculature from pre-existing vessels and occurs during wound healing and when cells are deficient in oxygen levels. The synthesis of new blood vessels among tumor cells mediated by VEGF leads to a greater blood and oxygen supply necessary for the proliferation of GBM cells (Gil-Gil et al. 2013). Avastin works to reduce vascular permeability and edema, enhancing delivery of oxygen to brain cells and reducing necrosis in the tumor core when administered in conjunction with radiation therapy (Davis 2016). According to Gil-Gil et al. 2013, GBM cells generate the proangiogenic factor called VEGF which binds with its tyrosine kinase receptor on the surface of endothelial cells, initiating a signal cascade resulting in angiogenesis. Figure 7 demonstrates that Bevacizumab is easily able to penetrate the selectively permeable blood-brain barrier with a molecular weight of 149 kDa and binds with a high affinity to VEGF, sterically inhibiting the factor from binding to its receptors on endothelial cells and effectively reducing angiogenesis, inhibiting tumor growth, and reducing edema in the brain. | + | Bevacizumab (Avastin®) is a monoclonal antibody implemented in GBM chemotherapeutic regiments to target vascular endothelial growth factor (VEGF) and was approved by the FDA in 2009 after clinical trials had demonstrated excellent performance. The VEGF protein is needed for angiogenesis, a process that involves the synthesis of new vasculature from pre-existing vessels and occurs during wound healing and when cells are deficient in oxygen levels. The synthesis of new blood vessels among tumor cells mediated by VEGF leads to a greater blood and oxygen supply necessary for the proliferation of GBM cells (Gil-Gil et al. 2013). Avastin works to reduce vascular permeability and edema, enhancing delivery of oxygen to brain cells and reducing necrosis in the tumor core when administered in conjunction with radiation therapy (Davis 2016). According to Gil-Gil et al. 2013, GBM cells generate the proangiogenic factor called VEGF which binds with its tyrosine kinase receptor on the surface of endothelial cells, initiating a signal cascade resulting in angiogenesis. Figure 12 demonstrates that Bevacizumab is easily able to penetrate the selectively permeable blood-brain barrier with a molecular weight of 149 kDa and binds with a high affinity to VEGF, sterically inhibiting the factor from binding to its receptors on endothelial cells and effectively reducing angiogenesis, inhibiting tumor growth, and reducing edema in the brain. |
| {{ :avastin.png?500 |}} | {{ :avastin.png?500 |}} | ||
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| **Radiation Therapy and Temozolomide** | **Radiation Therapy and Temozolomide** | ||
| - | Following the surgical removal of the tumour, patients undergo various forms of radiation therapy (RT), most commonly RT is externally delivered in which ionizing radiation is targeted at cancer cells left in the brain following resection, damaging DNA and resulting in apoptosis (Davis, 2016). One the most effective forms of RT is brachytherapy, particularly the use of a new device approved in 2002 called GliaSite. This involves the administration of 125I solution which is filled into a closed catheter ballon and inflated to fill the resection cavity (Chan et al., 2005). Following and often times concurrently with RT, patients are put on a 4-6 week chemotherapeutic regime, they are administered a drug called temozolomide (TMZ) (Davis, 2016). Temozolomide is a small (194 Da) lipophilic molecule that is available as an orally administered chemotherapeutic pill. Due to TMZ’s small size and lipophilic character, it readily crosses the blood-brain barrier (Agarwalla & Kirkwood, 2000). Once TMZ is in the body it is rapidly metabolized into MTIC, which is an alkylating agent that adds a methyl group to the O6 position of guanine in DNA, this results in the incorporation of a thymine residue instead of a cytosine residue across the methylated guanine (Zhang, Stevens & Bradshaw, 2012). The abnormal thymine-guanine pair leads to DNA mismatch repair activation, in which the mispaired thymine is excised but the the methylated guanine is left, eventually, cycles of this leads to breaks in the DNA and apoptosis. It is important to note that there can be resistance to TMZ and its alkylating activity, specifically via a protein known as O6-methylguanine methyltransferase (MGMT). MGMT protects cells from carcinogens and consequently, it can also protect and resist chemotherapeutic agents like TMZ. MGMT is able to transfer the O6-alkyl group on guanine, to its active site (cysteine 145), effectively repairing DNA and therefore evading apoptosis (Zhang, Stevens & Bradshaw, 2012). | + | Following the surgical removal of the tumour, patients undergo various forms of radiation therapy (RT), most commonly RT is externally delivered in which ionizing radiation is targeted at cancer cells left in the brain following resection, damaging DNA and resulting in apoptosis (Davis, 2016). One the most effective forms of RT is brachytherapy, particularly the use of a new device approved in 2002 called GliaSite. This involves the administration of 125I solution which is filled into a closed catheter ballon and inflated to fill the resection cavity (Chan et al., 2005). Following and often times concurrently with RT, patients are put on a 4-6 week chemotherapeutic regime, they are administered a drug called temozolomide (TMZ) (Davis, 2016). Temozolomide is a small (194 Da) lipophilic molecule that is available as an orally administered chemotherapeutic pill. Due to TMZ’s small size and lipophilic character, it readily crosses the blood-brain barrier (Agarwalla & Kirkwood, 2000). Once TMZ is in the body it is rapidly metabolized into MTIC, which is an alkylating agent that adds a methyl group to the O6 position of guanine in DNA, this results in the incorporation of a thymine residue instead of a cytosine residue across the methylated guanine (Zhang, Stevens & Bradshaw, 2012). The abnormal thymine-guanine pair leads to DNA mismatch repair activation, in which the mispaired thymine is excised but the the methylated guanine is left, eventually, cycles of this leads to breaks in the DNA and apoptosis. It is important to note that there can be resistance to TMZ and its alkylating activity, specifically via a protein known as O6-methylguanine methyltransferase (MGMT). MGMT protects cells from carcinogens and consequently, it can also protect and resist chemotherapeutic agents like TMZ. MGMT is able to transfer the O6-alkyl group on guanine (Figure 13), to its active site (cysteine 145), effectively repairing DNA and therefore evading apoptosis (Zhang, Stevens & Bradshaw, 2012). |
| {{ :tmzz.png |}} | {{ :tmzz.png |}} | ||
