Introduction to Cancer Biology (Part 1): Abnormal Signal Transduction

an introduction to cancer biology in this presentation we will discuss selected characteristics common to many cancers abnormal signal transduction resulting in uncontrolled cell proliferation loss of apoptosis or programmed cell death tissue invasion and metastasis permitting spread of the cancer and angiogenesis leading to enhanced blood supply of tumors normal cells require signals usually delivered by ligands to stimulate their growth and to tell them when to stop growing these signals or ligands can be in the form of growth factors and inhibitors extracellular matrix components or cell adhesion molecules these signals are transmitted into the cell through proteins found on the surface of cells called receptors each ligand binds to its own specific receptor receptors often consist of three domains an extracellular ligand binding domain a transmembrane domain and an intracellular domain binding of a ligand to the extracellular domain activates the receptor tyrosine kinase which activates other proteins by phosphorylation of adding a phosphate to the amino acid tyrosine on a protein inside the cell when a ligand binds to the receptor a signal goes to the intracellular domain activating the Associated enzyme and initiating a cascade of signals to the nucleus that tell the cell to grow and divide or to stop growing malignant cells generate many of their own growth signals which allows them to divide with reduced external growth stimulation some cells are able to produce their own growth factors and stimulate their own growth this is called autocrine stimulation for example glioblastoma is express platelet derived growth factor or PDGF sarcomas express tumor growth factor alpha or TGF alpha as well as epidermal growth factor receptor or EGFR in normal cells the production of cell surface receptors is limited by cellular restraints on gene expression and protein translation in tumour cells however mutations in the genes encoding for the receptors disrupts this finely tuned regulation and too many copies of the gene are produced a phenomenon called gene amplification this in turn leads to excessive transcription and production of receptors the end result is a higher than normal number of copies known as over expression of the receptor on the tumor cell surface this gives the tumor cell increased potential to be triggered into a growth phase by the binding of ligands to the excess receptors the more receptors expressed the more binding sites are available for the ligands gross over expression of growth factor receptors can result in ligand independent signaling where receptors are active in the absence of stimulating molecules structural changes to a receptor can also lead to ligand independent activation for example truncated versions of the epidermal growth factor receptor where much of the intracellular domain is missing are constituent 'iv EGF receptor also known as her 1 or herb 1 is a member of a subfamily of type 1 receptor tyrosine kinases these receptors are found primarily in the membranes of normal epithelial cells from skin breast colon and lung amongst others EGF receptor and its ligands play an essential role in the regulation of cell proliferation differentiation and survival EGFR is overexpressed in tumors arising from the colon rectum and had a neck to name a few when a specific ligand binds to its receptor this leads to changes in the receptor that transmit a specific signal into the cell for example the receptor tyrosine kinase is activated and initiates a signaling pathway specific to that receptor this phenomenon is called signal transduction activation of a signal transduction pathway creates a complex chain of events in the cytoplasm or fluid intracellular space that eventually leads into the cell nucleus where the transcription of genes regulating cell cycle progression are stimulated resulting in cell proliferation one of the major Cascades implicated in cancers is the rats raff mitogen-activated protein or map kinase pathway another interesting pathway is the phosphors Anozie tied 3 kinase or pi3k a kt mammalian target of rapamycin or mTOR pathway these pathways are linked to each other and other signal transduction pathways in the cell deregulation or loss of normal controls in any of these pathways is thought to be present in all human tumors once the signal reaches the nucleus transcription factors are activated these factors transcribe the genes that are translated into the proteins such as growth factors that are necessary to allow the cell to continue to proliferate the end result of any growth factor receptor signal transduction pathway is tumor DNA replication and cell division one tumor cell becomes 2 if mitosis continues to tumor cells become 4 with exponential growth potential on the tissue level this leads to increased tumor growth and increase tumor size many of the components of these signal transduction pathways are potential targets of anti-cancer therapies therapies can target the ligands receptors intracellular second messengers and nuclear transcription factors responsible for tumor growth ligands can be neutralized before they bind to the receptors an example of this is bevacizumab or Avastin which is a humanized monoclonal antibody that targets circulating vascular endothelial growth factor or vag F platelet derived growth factor or PDGF and fibroblast growth factor or fgf are other examples of ligands that can be targeted for different cells in the body the receptors on the surface of normal and tumor cells can be inhibited directly Sutekh Samad or Erbitux is an example of this it is a chimeric antibody that binds directly to the epidermal growth factor receptor and competitively inhibits the binding of EGF and other ligands such as TGF alpha another way to block the receptors function is through small molecule inhibitors of receptor phosphorylation associated with them for example EGF receptors have a tyrosine kinase that can be blocked by the molecules gefitinib or ERISA and erlotinib or Tarceva

Channel: Mechanisms in Medicine

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Keywords: mTOR, tyrosine kinase, Biology, EGFR, tumorigenesis, proliferation, animation, Cancer, PI3K, receptor, targeted therapy, VEGF

Id: jjfYQMW_nek

Length: 7min 46sec (466 seconds)

Published: Fri Oct 26 2012