- Brain Tumor Stem Cells (BTSCs)
- Immunotherapy
- Chemoresistance
- Gene Expression
- Epigenetics
- Signal Transduction Pathways
- Experimental Therapeutics
- Apoptosis or Programmed Cell Death
- Brain Tumor Cell Membrane Synthesis
- Mouse Models of Brain Tumors
- Brain Tumor Cell Migration
Brain Tumor Stem Cells (BTSCs)
Stem cells are a small population of cells within the body that have the ability to multiply, to self-renew, and to differentiate into a number of types of mature cells. Cancer stem cells in general, and BTSCs in particular, share these characteristics and have the ability to renew themselves and to differentiate into mature tumor cells. Therefore, BTSCs may be a continuous source of new mature brain tumor cells. Therapies that attack brain tumor cells but not BTSCs may not be able to prevent brain tumor recurrences. It may be critical to kill the BTSCs as well as the tumor cells themselves. Much research is focused on identifying which cells within a brain tumor are the actual BTSCs, and in determining their molecular and cellular characteristics. Understanding BTSCs may lead to approaches to kill them and prevent the re-growth or recurrence of brain tumors.
Immunotherapy
Cancer immunotherapy is an approach to stimulate the immune system to be able to better recognize, attack, and destroy tumors. The following approaches, individually or in combination, are being evaluated for their effectiveness in treating brain tumors. Protein factors that increase the activity of immune cells can be increased. A person’s immune T cells can be harvested, engineered to have a more robust reactivity to the tumor, and reintroduced into the patient. Therapeutic vaccines stimulate the body’s immune system to attack tumors. Immune system dendritic cells, which process tumor antigens, can be harvested from a patient, engineered to vigorously stimulate the attacking immune cells against the tumor, and returned to the patient. In brain tumor patients there is abnormally high number of active Tregs that dampen the immune response against the tumor. By inhibiting Tregs, the immune system can mount a stronger attack on tumors.
Chemoresistance
Both chemotherapy and radiation therapy (or radiotherapy) damage the DNA within tumor cells. When either chemotherapy or radiotherapy causes overwhelming DNA damage, cells are driven to initiate the process of programmed cell death, or apoptosis. Normally, cells are able to repair low levels of DNA damage, and many brain tumor stem cells exhibit chemoresistance and radioresistance by several mechanisms.
- They abnormally overexpress DNA repair and DNA damage response proteins that result in an increased capacity to repair DNA damage, thereby preventing the initiation of apoptosis.
- They overexpress anti-apoptotic proteins that directly inhibit apoptosis.
- They may express high levels of drug transporter molecules involved in actively transporting chemotherapeutics out of glioma and brain tumor stem cells.
A better understanding of the mechanisms involved in chemoresistance and radioresistance may lead to therapeutic interventions that increase the effectiveness of chemotherapy and radiotherapy treatments.
Gene Expression
Gene expression refers to the process by which DNA sequences are transcribed into RNA sequences that are subsequently translated into protein sequences. Proteins are the foundation of biological structures, enzyme activities, and myriad cellular processes, including the signal transduction pathways.
The regulation of gene expression is critical to normal development and the diversity of cellular types and activities. Different sets of genes are expressed in different cell types and under different conditions. Gene expression can be regulated at any of its biochemical steps.
The development of cancers, including brain tumors, involves abnormal alterations of the normal gene expression regulation patterns of cells. These may involve the abnormal transcription of sets of genes driven by transcription factors under the control of runaway signal transduction pathways.
MicroRNAs (miRNA) are a class of short RNA species that are involved in the normal regulation of gene expression. They bind to RNA that encodes proteins, and by doing so, inhibits their translation into protein. Evidence indicates that abnormal patterns of miRNAs results in alterations of gene expression patterns involved in brain tumor cell development and maintenance. The understanding of gene expression regulation alterations in brain tumors provides potential therapeutic approaches to killing these tumors.
Epigenetics
Epigenetics refers to a specific type of gene regulation that may be maintained through cell divisions and cell generations. Unlike mutations, in which the DNA sequence is altered, epigenetic changes do not involve DNA sequence alterations. Rather, the DNA (or proteins associated with the DNA) is chemically modified in such a way that the expression of the gene is altered. One way in which this occurs is through the methylation of specific DNA sequences.
When a methyl group (a small organic molecule) is added to part of the DNA sequence of a gene, the expression of the gene is turned off because the methylation interferes with the transcription of the gene. This process has been shown to be extremely important in the treatment of glioblastoma. If the MGMT gene is methylated, it will not be expressed, and the GBM will be sensitive to temozolomide treatment.
On the other hand, if the MGMT gene is not methylated, the gene will be expressed, and temozolomide treatment will not be effective. In addition, reducing the overall methylation of DNA in glioblastoma may result in the expression of genes (not normally expressed due to methylation) involved in an increased proliferation of the tumor cells. This opens the possibility that a therapeutic approach that increases DNA methylation in these tumor cells might be effective at slowing their growth.
Signal Transduction Pathways
The ability of cells within the body to respond to different molecular signals in their environment is central to their diverse biological activities. This ability is also critical for the coordinated actions of cells in development, growth, tissue repair, immunity, and other processes required for normal tissue function. Signal transduction is the process by which an extracellular molecular signal binds to a cell surface receptor, thereby initiating a sequence of biochemical events within the cell, resulting in changes in biological activities (directly or through the alteration of the expression of genes).
Different classes of receptors bind different types of molecular signals and activate different signal transduction pathways. There is great complexity in the number of types of receptors in each class as well as the interactions between signal transduction pathways. Cancers, including brain tumors, are driven by abnormally controlled signal transduction pathways. For example, abnormally high levels or activity of the EGF receptor, and downstream signal transduction pathways, drive malignant gliomas. A completely different class of receptors is involved in the development of medulloblastoma through the hedgehog signal transduction pathway.
Knowing which signal transduction pathways are involved in different brain tumors allows for the development of drugs that target specific components of these pathways and potentially kill tumors. Unfortunately, several abnormal pathways are involved in malignant brain tumors, so targeting an individual pathway may not be sufficient to kill the tumors. A great deal of research is currently revealing, for example, the multiple abnormally controlled pathways within malignant gliomas, providing targets for combination therapies.
Experimental Therapeutics
In addition to chemotherapy and radiotherapy, there are a number of experimental therapeutic approaches being evaluated to treat brain tumors. Small molecule drugs that inhibit specific components of the signal transduction pathways involved in brain tumor genesis and maintenance are being evaluated in clinical trial as single agents and in combinations of agents that target two or more pathway components. Antibodies directed against the extracellular portions of signal receptors are being evaluated or used in clinical applications. A significant amount of clinical evaluation using immunotherapy approaches are in progress.
Other experimental therapeutic approaches being evaluated include gene therapy, oncolytic viruses, and nanotechnology. Gene therapy involves introducing genes into tumor cells that may kill cells directly, stop cell growth, or make tumor cells more susceptible to chemotherapy or immunotherapy. Oncolytic viruses are viruses that have been specifically modified in order for them to infect and kill brain tumor cells without harming normal cells. Nanotechnology utilizes small particles (nanometer scale) that are engineered to recognize brain tumor cells and to deliver therapeutics directly to them. Solid tumors, including many brain tumors, require the growth of new blood vessels into them in order to supply them with oxygen and nutrients. Angiogenesis inhibitors that inhibit the growth of new blood vessel are currently being evaluated in clinical trials and used in the treatment glioblastoma (bevacizumab: Avastin). The development of these approaches may lead to effective brain tumor therapies.
Apoptosis or Programmed Cell Death
Apoptosis is a normal process in which cells go through an ordered series of programmed biochemical events resulting in their death. Apoptosis is necessary for normal development, growth, and the elimination of unneeded cells. Apoptosis also plays a role in preventing the development of tumors by eliminating abnormal cells that can progress into tumors. Tumors overcome this due to mutations or biochemical processes that block apoptosis and prevent apoptosis from eliminating the abnormal tumor cells. Approaches that stimulate apoptosis in brain tumor cells would be therapeutic in eradicating tumors.
Brain Tumor Cell Membrane Synthesis
Making cell membranes is part of natural cell growth activity. The tumor cells within brain tumors that are rapidly growing synthesize cell membranes at a much higher rate than do normal cells. Research in this area looks at how blocking this process in tumor cells could inhibit tumor growth.
Mouse Models of Brain Tumors
In genetic mouse models, genetic engineering is used to create strains of mice that develop human-like brain tumors. In xenograft mouse models, human brain tumor tissue or cell lines are implanted into the cranium of mice. These models are used to study the basic biology of how tumors form and behave, as well as for testing of potential therapeutic approaches.
Brain Tumor Cell Migration
Brain tumor cell migration is the ability of brain tumor cells to infiltrate into surrounding brain tissue.