Brain Cancer

Primary brain cancer refers to malignant tumors that form either in the brain or in the nerves originating in the brain.Brain cancer does not frequently spread (metastasize) to outside of the central nervous system (CNS). The CNS is the part of the nervous system that includes the brain and spinal cord.Primary brain cancer makes up 2% to 3% of all new cancer cases in adults and is the second most common form of childhood cancer (after leukemia). Primary brain cancer is the leading cause of cancer deaths in children and is the third most common cause of cancer deaths in adults aged 15 to 34.

Secondary brain cancer refers to malignant tumors that originated elsewhere but have spread (metastasized) to the brain. Examples include, but are not limited to, breast cancer and lung cancer that have metastasized to the brain. Secondary brain cancer is more common than primary brain cancer.

Brain cancer rates are found to be higher in more developed countries than in less developed countries.9The American Cancer Society estimates that in 2016, in the U.S., about 23,770 individuals will be diagnosed with brain or spine cancer and about 16,050 individuals will die of brain or spinal cord tumors.

Brain Anatomy And Function

The brain and the spinal cord make up the central nervous system (CNS). The brain, an extremely complex organ, contains more than a trillion neurons. These neurons work together to give us the ability to understand, comprehend, reason, and remember. Since many regions of the brain intricately work together to accomplish certain tasks, it may be difficult to pinpoint a specific region that is solely responsible for a certain brain activity. 

The 3 main parts of the brain are the forebrain, the cerebellum, and the brain stem.  The forebrain includes the cerebrum and the diencephalon. The cerebrum is seperated into a left and a right hemisphere and is the most frontal part of the brain. The diencephalon includes parts of the brain such as the thalamus and hypothalamus, which are responsible for controling, emotion, pain, body temperature, and stress. More information on these parts are found below. The brain and spinal cord are protected by several layers of connective membrane tissue, collectively known as the meninges.The CNS is also protected by cerebrospinal fluid (CSF), a colorless fluid that is secreted by four hollow structures of the brain known as ventricles. The CSF helps absorb shocks or blows to the head and is responsible for regulating and maintaining the proper chemical environment necessary for optimal CNS function.

Some functions of the brain regions:

• Forebrain: The forebrain consists of the cerebrum and the diencephalon. This region is responsible for perception, learning, memory, skeletal-muscle coordination, awareness, regulation of behaviors (e.g. eating and drinking), control of body temperature, and the generation of emotions. 

• Cerebellum: The cerebellum is responsible for the coordination of movement and the control of posture and balance.

• Brain stem: The brain stem consists of the midbrain, pons, and medulla oblongata.The brainstem relays information between the spinal cord, forebrain, and cerebellum, and it has several important functions of its own. The brainstem controls movement, breathing, heart functions, and the regulation of sleep/conciousness.

Cells of the brain:

Like all other organs, the brain is also composed of many different types of cells. The cells that are most prevalent to brain cancer are:

• Nerve cells (neurons): Nerve cells are responsible for transmitting signals from the brain to the spinal cord and the body, and these cells are also responsible for bringing signals from the rest of the body back to the brain.

• Glial cells: Glial cells support neurons by insulating them, feeding them, and providing them with structural support. These cells are also responsible for getting rid of dead neurons. There are several different types of glial cells, each with its own function. Glial cell types include astrocytes, oligodendrocytes, and ependymal cells.

Types

There are over 100 types of cancer that can affect the central nervous system (CNS). As mentioned previously, cancers that arise in other locations (breast, lung, etc.) and spread (metastasize) to the brain are not considered brain cancer. They are still treated as the cancers of the original site. Here, we will only discuss primary brain cancers (those that originate in the brain).

Gliomas
Malignant gliomas are the most common and deadly brain cancers. They originate in the glial cells of the central nervous system (CNS). Gliomas can be divided into 3 main types: astrocytomas, oligodendrogliomas, and ependymomas.The median survival of patients with glioma has improved over the past few years but is still only 15 months, with few patients living more than two years.Research indicates that this type of brain cancer may resist treatment because it contains stem cells that are responsible for driving the formation of blood vessels (angiogenesis), spread of the tumor (metastasis), and resistance to treatments. 

• Astrocytomas: Astrocytomas are tumors that develop in astrocytes and are found in the cerebrum and the cerebellum. Astrocytomas make up approximately 50% of all primary brain tumors. Glioblastoma multiforme, an astryocytoma subtype, is the most aggressive form of brain cancer and is associated with poor prognosis.21

• Oligodendrogliomas: Oligodendrogliomas are tumors that develop in oligodendrocytes, and more often in the oligodendrocytes that are found in the cerebral hemispheres.  Oligodendrocytes are glial cells that produce myelin, a component of the brain that increases impulse speed. 22Oligodendrogliomas make up approximately 4% of primary brain tumors. Approximately 55% of all cases of oligodendrogliomas appear in people between the ages of 40 and 64. 

• Ependymomas: Ependymomas are tumors that develop in the ependymal cells. Ependymal cells are the cells in the brain and where ceribrospinal fluid (CSF) is created and stored. Ependymomas account for only 2% to 3% of all primary brain tumors but account for 8% to 10% of brain tumors in children. Ependymoma tumors are usually found in ventricle linings, the spinal cord, or the regions near the cerebellum.

Nongliomas
Nongliomas are tumors that do not arise from glial cells. More prevalent examples of nongliomas include meningiomas and medulloblastomas. Less prevalent examples include medullpituitary adenomas, primary CNS lymphomas, and CNS germ cell tumors. 

• Meningiomas: Meningiomas are tumors that develop in the meninges, membranes covering the brain and spinal cord. Meningioma tumors are frequently formed from arachnoid cells. These cells are responsible for the absorption of the cerebrospinal fluid (CSF). Meningioma tumors are responsible for 13% to 30% of all tumors arising within the cranium - the bony case surrounding the brain. Tumor arising within the cranium are also called intracranial tumors. Most meningiomas are benign. Malignant meningiomas are extremely rare, with an incidence rate of approximately two out of every million people, per year. The risk for developing meningiomas increases with age and is more prevalent in women. 

• Medulloblastomas: Medulloblastomas are the most common brain malignancies in children. These cancers arise in the posterior fossa - a specific region of the space inside the skull (intracranial cavity) that contains the brainstem and the cerebellum. The fourth ventricle region is involved in the development of approximately 80% of childhood cases. 

Symptoms And Detection

Brain tumor symptoms depend on the tumor's size, location, type and if/how much the tumor has invaded other areas of the body. The most common symptom is headaches, which occurs in 35% of patients and can appear along with nausea, vomiting, and problems with a variety of  specific nerve functions, called focal neurological deficits. Headaches may be a warning sign, especially in patients who normally do not suffer from headaches. Localized (focal) problems vary depending on the tumor’s location. It is also important to inform the patient's doctor if headaches become increasingly frequent or severe.

Several medical tests can be used to detect or rule out a brain tumor:

• Neurological exam: The neurological exam refers to a preliminary set of tests performed on a patient in order to gather information on his/her mental state, sensory system, nervous system, and motor functions. Based on the neurological exam results, the physician will then decide if additional tests are necessary.

• Cerebral angiography: A cerebral angiography is a procedure performed on a patient to visualize the blood flow through the blood vessels in the patient’s brain. This procedure is done to identify possible blood clots and blood vessel problems in the brain, such as aneurysms, arterial blockages, and vasculitis. This procedure may also be used to confirm the presence of a brain tumor. 
  How it works
  Cerebral angiography is typically done in the hospital or in a radiology center. The patient may be told not to consume solid foods or liquids for a certain period of time leading up to the test. For the procedure, the patient will be lying on an x-ray table with his/her head immobilized by a strap, tape, etc. This is to prevent any possible movement that may disrupt the exam. An electrocardiogram (ECG) will be used to monitor the patient’s heart activity during the cerebral angiography. Right before the start of the procedure, a local numbing shot (anesthetic) will be administered in the region of the patient's body (usually the groin) where a thin tube (catheter) will subsequently be inserted. The catheter will go into an artery and will be carefully manuevered upwards, through the abdominal area, towards an artery in the patient's neck. Once the catheter is in its intended position, a special dye will be injected into it, and x-ray scans will be taken as a method of tracking the dye’s movement through the arteries and blood vessels in the brain. These x-ray scans will allow the doctor to identify the location of any arterial and vascular blockages and locate any possible abnormal vascular and arterial structural defects in the patient’s brain.

• CT scan
• MRI scan
• Surgical biopsy

Tumor Biology

In recent years, studies have suggested that cancer stem cells, or more specifically, glioma stem cells, may have an important role in brain cancer development and tumor relapse. CD133 is a protein found on the surface of cells. It is a stem cell marker that is commonly used to identify brain tumor stem cells (BTSCs). BTSCs have been found in types of brain cancer such as glioblastoma multiforme, ependymomas, astrocytomas, medulloblastomas, and other glioma and nongliomas. BTSCs may be resistant to treatment with chemotherapy and/or radiation due to a variety of factors, including the overexpression of anti-cell death (antiapoptotic) factors, activation of DNA repair checkpoints, and increased blood vessel development (angiogenesis). 

There are many genes that have been linked to the development and spread of brain cancer, with some more prevalent than others. Some of the genes involved in brain cancer are:

• TP53: This gene is a tumor suppressor gene that is in charge of regulating cell division and cell death (apoptosis). About half of all human tumors have a mutation in the TP53 tumor suppressor gene. Studies have shown that approximately 40% of astrocytomas have a mutated or deleted TP53 gene. 

• NF1: This gene encodes for the production of neurofibromin. The neurofibromin protein acts as a tumor suppressor by regulating the expression of Ras, another protein involved in cancer development. 

• NF2: This gene encodes for the merlin protein, which regulates cell shape, cell movement, and cell-to-cell communication. The merlin protein also acts as a tumor suppressor in the cells of the nervous system. Studies show that the NF2 gene is deleted or mutated in approximately 40% to 50% of patients with meningioma or schwannoma. 

• Bcl2: This gene encodes for the Bcl2 protein, which inhibits cell death. Studies suggest that overexpression of the Bcl2 protein significantly increases tumor resistance to cytotoxic drugs. 

• Myc: This family of genes encodes for the Myc transcription factor proteins, which are involved in tumorigenesis and cell cycle regulation. The Myc proteins are overexpressed in many types of gliomas, including medulloblastoma, astrocytomas, and glioblastoma multiforme. 

• EGFR: This gene encodes for the epidermal growth factor receptor (EGFR). EGFR belongs to the family of receptor tyrosine kinases (RTK), which are cell surface receptors that bind to cell signaling factors such as growth factors and cytokines. Increased RTK signaling through two oncogenic pathways called the  PI3K-AKT-mTOR pathway and the Ras-MAPK pathway have been linked to cases of malignant gliomas. Studies show that approximately 40% of gioblastomas and anaplastic astrocytomas have too many copies of the EGFR gene (gene amplification) and/or changes (mutations) in the EGFR gene. 

• VEGF: This gene encodes for the vascular endothelial growth factor (VEGF), which is a key protein involved in blood vessel formation (angiogenesis) and vascular permeability. Its receptor, vascular endothelial growth factor receptor (VEGFR), also belongs to the family of receptor tyrosine kinases (RTK). Studies show that VEGF is commonly overexpressed in meningiomas, as well as in malignant gliomas, such as pilocytic astrocytomas and glioblastomas.

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