Tumors of the Nervous System: General Considerations
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The clinical signs always depend on the location of the tumor and include elevated intracranial pressure (ICP), focal neurologic deficit, and seizures (focal and/or secondarily generalized).
Definitions of tumor, neoplasia, brain tumor, malignant versus benign are given. Various modalities of brain tumor therapy include chemotherapy, radiation therapy, targeted therapy, biological therapy, concomitant therapy, and adjuvant therapy. Endpoints on clinical trials include complete remission (CR), partial remission (PR), stable disease, progressive disease (PD), overall survival (OS), event-free survival (EFS), progression-free survival (PFS), disease-free survival (DFS), and relapse-free survival (RFS).
Tumors are histologically characterized by cellularity, anaplasia, metaplasia, pleomorphism, mitoses and atypical mitoses, reactive versus neoplastic changes, endothelial proliferation and neovascularity, necrosis without or with pseudopalisading, encapsulation and invasion, rosette formation, palisades and pseudopalisades, desmoplasia, reactive astrogliosis, microglial activation, and perivascular lymphocytic cuffing.
The updated new edition of the WHO Classification of Tumors of the Central Nervous System is presented and the tumor entities with the WHO grades listed. The various grading systems as proposed during the last 70 years are described which include the actual WHO grading system (2016), Kernohan et al. (Proc Staff Meet Mayo Clin 24(3):71–75, 1949), Ringertz (Acta Pathol Microbiol Scand 27(1):51–64, 1950), St. Anne/Mayo (1988), and the Smith grading for oligodendroglioma (Cancer 52(11):2107–2114, 1983).
The hallmarks of cancer include growth signal autonomy, evasion of growth inhibitory signals, avoiding immune destruction, unlimited replicative potential, tumor-promoting inflammation, invasion and metastasis, angiogenesis (formation of new blood vessels), genome instability and mutation, evasion of cell death, and reprogramming energy metabolism.
The cell cycle in normal cells is considered and consists of a series of highly ordered molecular events that are required for a cell to grow and replicate. The cell cycle progresses through several well-defined phases each of which must properly be completed before the next one initiates. The molecular events underlying the management of damaged DNA are detailed later in the chapter DNA damage response. At the molecular level, checkpoint activities are executed via protein complex formations involving cyclins and cyclin-dependent kinases (CDKs; the most important are CDK1, CDK2, CDK4, and CDK6). CDK inhibitors (CKIs) bind to cyclin/CDK complexes, thereby blocking CDK activity. To a large extent, dysregulation of the cell cycle in cancer cells can be attributed to genetic alterations in proto-oncogenes and/or tumor suppressor genes. Aberrations in the affected genes include somatic or germline mutations, under-/overexpression, and chromosomal instability such as amplifications/deletions.
Damage to DNA can be inflicted through several mechanisms which includes DNA replication errors (mismatched bases) or exposure to reactive oxygen species (ROS) which affects mainly mitochondrial DNA. Exogenous damage is caused by external factors such as UV irradiation or mutagenic chemicals. The types of aberrations range from mutations/base modifications to major structural damage of the double helix. Frequently encountered chemical modifications of nucleobases are depurination, depyrimidination, methylation, and oxidation.
Mechanisms of DNA damage repair include double-strand break repair (DSBR), single-strand break repair (SSBR), nucleotide excision repair (NER), and mismatch repair (MMR).
An oncogene is a gene that is a mutated (changed) form of a gene involved in normal cell growth. It may cause the growth of cancer cells. Oncogenes include growth factors, receptors for growth factors, signal transducers, and transcription factors.
A tumor suppressor gene is a type of gene that makes a protein called a tumor suppressor protein that helps control cell growth, stimulates cell death, and triggers the induction of permanent cell cycle arrest. Mutations in tumor suppressor genes may lead to cancer. The “two-hit hypothesis” states that firstly a germline mutation predisposes the individual to cancer and secondly mutations in both alleles are necessary for tumor initiation.
The many ways cells undergo death include apoptosis, autophagy, necroptosis, ferroptosis, pyroptosis, parthanatos, cyclophilin D (CypD) necrosis, and NETosis. Cell death models lead to passive necrosis by damage or toxins or cellular suicide and cellular sabotage.
Genomic instability is the result of shortcomings in DNA damage responses (DDR) that greatly increase the rate at which chromosomes and DNA are damaged and that allow cells with such damage to survive and to replicate.
Signal transduction is the process by which a cell responds to substances in its environment. The binding of a substance to a molecule on the surface of a cell causes signals to be passed from one molecule to another inside the cell. These signals can affect many functions of the cell, including cell division and cell death. A multitude of signaling pathways are distinguished including growth factors, protein kinases, receptor protein tyrosine kinases, mitogen-activated protein kinase (MAPK), PI3K-AKT-mTOR signaling (phosphatidylinositol-4,5-biphosphate 3 kinase)-AKT-(mechanistic target of rapamycin), hypoxia-inducible factor (HIF), NF-κB pathways, Wnt signaling, Notch signaling, Hedgehog signaling, and TGFß signaling.
Epigenetic changes result from age and exposure to environmental factors (diet, exercise, drugs, and chemicals) and change the way genes are switched on and off without changing the actual DNA sequence. Epigenetic regulation of transcription includes histone modifications and DNA methylation.
Telomeres make up the ends of a chromosome. Each time a cell divides, the telomeres lose a small amount of DNA and become shorter. In cancer cells the telomeres do not get shorter, and may become longer, as the cells divide. Telomerase is an enzyme that helps keep cells alive by adding DNA to telomeres.
Vessels are created through vasculogenesis or angiogenesis. The tumor angiogenesis hypothesis states that virtually all tumors would be restricted to a microscopic size in the absence of angiogenesis. Antiangiogenesis means the prevention of new capillary sprouts from being recruited into an early tumor implant.
Glioma invasion and microenvironment might play major roles. Invasion includes local spread of a malignant neoplasm by infiltration or destruction of adjacent tissue; for epithelial neoplasms, invasion signifies infiltration beneath the epithelial basement membrane. The microenvironment might be promoting or suppressive. Molecular mechanisms include players like the extracellular matrix (ECM), matrix metalloproteinases, integrins, chondroitin sulfate proteoglycans, glycoproteins, galectins, small GTPases, axonal guidance molecules, ephrins, netrins, semaphorins, TWIST, SNAIL, SLUG, ZEB, and cadherins.
MicroRNAs (miRNAs) are small cellular non-coding RNAs of approximately 20 nucleotides in length which bind to 3′ untranslated regions (UTRs) of target mRNAs and thereby block translation. Cancer cells frequently express upregulated miRNAs with oncogenic activity (termed oncomiRs) and downregulated miRNAs with tumor suppressor properties.
A stem cell (SC) is a cell from which other types of cells develop and which may remain dormant until a physiological signal is received. Cancer stem cells (CSC) are subpopulations of cells with stem cell properties that initiate and maintain the cancer phenotype. Brain cancer stem cells display normal neural stem cell markers. The proportion of brain CSCs correlates with prognosis, and fast-growing tumors (GBM) have more brain CSCs than slow-growing tumors.
Carcinogens are responsible for cancer-causing mutations and include radiation, chemicals, infectious pathogens, and particular endogenous reactions.
Frequently encountered molecular changes, epigenetic and chromosomal aberrations in brain tumors are listed followed by a description of predictive molecular biomarkers relevant to gliomas. Treatment recommendations and agents used for brain tumors are provided.
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