Chapter 3 Notes

• Signal Transduction Pathway - Reception

  Receptor proteins and their activation in cancer
• Signal Transduction Pathway - Transduction

  Signal transducer proteins and their activation in cancer
• Signal Transduction Pathway - Response


  Response proteins and their activation in cancer
• Signaling Pathway: Group of proteins in a cell that work together to control one or more cell functions, such as cell division or cell death
• Signaling Transduction: Transmission of molecular signals from a cell’s exterior to its interior, which ultimately results in a cellular response
• Cell communication is crucial in maintenance of the tissue architecture
• Cells communicate via chemical signals
• Principles of Signal Transduction: Reception, Transduction, Response
• Cascade of signals. Phosphorylation drives signal transduction. Phosphorylation is the addition of phosphate group to one or more sites on the protein. Amino acids: Tyrosine (Tyr, Y), Serine (Ser, S), Threonine (Thr,T). ATP = adenosine triphosphate
• Kinases catalyze phosphorylation
• Ligands fit into a specific pocket, resulting in the activation of other responses. Ligand proteins as growth factors: Growth-stimulating factors or mitogens induce cells to proliferate. Examples: Epidermal growth factor (EGF) - Stimulates growth of epithelial cells (EGF receptors or EGF-R), Platelet-derived growth factor (PDGF) - Stimulates growth of fibroblasts, adipocytes
• Ligand proteins as growth factors

  • Growth-stimulating factors or mitogens induce cells to proliferate
  • Epidermal growth factor (EGF) stimulates growth of epithelial cells
  • Platelet-derived growth factor (PDGF) stimulates growth of fibroblasts, adipocytes, and smooth muscle cells
• Wound Scratch assay


  • Measures the ability of cells to move to the wound site
• Some growth factors act as oncogenes if produced in abnormal amounts
• Autocrine tumours produce multiple autocrine mitogens at the same time


  • Small cell lung carcinoma (TGF, IGF-1, SCF)
  • Kaposi sarcoma (PDGF, TGF, IGF-1, Ang2, CXCL22)
• RTK activation mechanism


  1. Monomers can diffuse laterally across the plasma membrane

  2. Can spontaneously dimerize with ligands

  3. Conformational change in the ecto domain results following binding

  4. Signaling activity cascades following transphosphorylation
• Activation of RTKs in cancer can be due to gain-of-function mutations, protein overexpression, autocrine ligand production, release, and fusion proteins
• Loss of domain (required for activation) can lead to pumps out ligand and chromosomal translocation as contributors
• GAIN-OF-FUNCTION MUTATIONS AND/OR OVEREXPRESSION ACTIVATE RTKs in CANCER
• Inscriptional activation


  1. Autocrine (from within) ligand production and release

  2. Fusion proteins
• Loss of domelin is required for activation
• Autocrine ligand expression and release activates RTKs in cancer
• Fusion proteins can cause constitutively activated dimerized receptors
• Fusion proteins drive dimerizations; ligand not required
• Non-RTK receptors with roles in cancer

  • Cytokine receptors
  • TGF-β receptors
  • Notch receptors
  • Patched-Smoothened receptors
  • Frizzled receptors
  • Integrin receptors
• Cytokine receptor molecules will dimerize in response to ligand binding, then the Jaks will phosphorylate and activate each other. The activated Jaks will phosphorylate the C-terminal tails of the receptor molecules, thereby creating receptors that will emit signals
• TGF-β receptors have an extracellular binding domain, a transmembrane domain, and a cytoplasmic kinase domain. CIS will proceed to phosphorylate heterodimers, cytosolic proteins that migrate to the nucleus
• Notch receptor tries to engulf the delta ligand. Protein cleavage is critical for signaling to occur on site. No longer transmembrane domain tethered to plasma membrane
• Patched-Smoothened Receptor System: Drosophila genetics led to these types of names: Patched, Hedgehog, etc. It keeps it away from the primary. Cilic binds to patched and relieves Smoothened. Translocates to the nucleus. Active repressor. Transcriptional promoter
• Wnt/Frizzled Receptor System: Related to wingless. Needs to be present to bind to WNT (Kinase). Mutated APC can be passed on to offspring. Becomes stabilized and accumulates as B-catenin is not being phosphorylated. B-catenin can drive cancer if it's related
• Key points: Deregulation of cell signaling is central to the formation of cancer. Tyrosine phosphorylation is key in transduction of mitogenic signaling. RTKs are activated by transphosphorylation. Many non-RTK receptors are involved in the formation of cancer: Frizzled, Patched-Smoothened, TGF-β, etc.
• Last lecture key points

  • Cancer significantly impacts our society
  • Cancer is a collection of diseases
  • Cancer begins when normal cells undergo genetic changes and start growing uncontrollably
  • Cancer is detected using imaging techniques
  • Cancer is diagnosed using histopathology techniques
  • Cancer develops in stages over a long period of time
  • Cancer is caused by exposure to risk factors
  • Carcinogens are directly involved in causing cancer
  • All mutagens are carcinogens
  • Majority of cancers are due to lifestyle and are preventable
• Tumour markers


  • Molecules considered as signals of tumour cells and altered in cancerous conditions
  • Proteins, DNA, gene expression patterns
  • One specific kind of cancer is normally characterized by one or more tumour markers
  • Used for tumour subtyping
  • Expression of tumour specific markers is used for cancer diagnosis, prognosis and guiding treatment
• Immunohistochemistry (IHC)


  A histopathological technique that uses specific antibodies to detect specific tumour markers on tissue sections
• Immunohistochemistry principle


  • Labeling reaction
  • Detecting signal (chromogen staining)
• Tumour Grade


  • The description of a tumour based on how abnormal the tumour tissue looks under a microscope
  • Tumour grade is an indicator of tumour aggressiveness
  • Grading systems differ depending on the type of cancer
  • Generalized grading: 1, 2, 3, 4 depending on the level of abnormality
  • Some cancers have their own grading systems
• Breast Cancer Scoring system

  • Features: Tubule Formation, Nuclear grade, Mitotic rate
  • Scoring: G1 (Low grade/Well Differentiated), G2 (Intermediate grade/Moderately Differentiated), G3 (High grade/Poorly Differentiated)
• Factors for Tumour Grading

  • Nuclear grade
  • Mitotic rate
• Scoring for Tumour Grading

  • G1: (Low grade/Well Differentiated)
  • G2: (Intermediate grade/Moderately Differentiated)
  • G3: (High grade/Poorly Differentiated)
• Cancer Staging describes how large a tumour has grown and how far it has spread