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2014-09-26 23:11:44
Foundations fnd1 cancer tubberly

I don't even want to make a silly description. This is just sad
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  1. Intercellular communication
    • Endocrine (distant)
    • Paracrine (near)
    • Juxtacrine (touching)
    • Autocrine (self)
  2. Intermolecular communication
    • 2nd messenger (between proteins)
    • Phosphorylatin (kinase or auto)
    • Direct contact (association)
  3. Signal transduction switch
    Phosphorylation is most common example
  4. Signal transduction timer
    GTP binding and hydrolysis of G proteins is common example
  5. Nuclear receptors
    Ligand has an intracellular carrier molecule or is small and hydrophilic and can enter nucleus
  6. Cytokine/hematopoietic growth factor receptor
    • Dimer receptor comes together when ligand binds (cytokine)
    • JAK recruited phosphorylates intracellular region of receptor which binds STAT gene regulatory protein
    • STAT enters nucleus and binds other gene regulatory proteins and they activate transcription of growth factors
  7. T or B cell receptors
    Multimeric (many receptors interact)
  8. Notch signalling
    • Juxtacrine between delta jagged and notch
    • Errors in this receptor cause T cell acute lymphoid luekemia
  9. Beta adrenergic recptor
    Conformational change to expose hydrophib region acts as signal
  10. PIP2
    • Secondary messenger multiple cleavage sites
    • phospholipase A2 results in arachidonic acid (AA)
    • phospholipase C results in diacyl glycerol (DAG/DG) and inositol 1,4,5 triphosphate (IP3)
    • phospholipase D results in phosphatidic acid (PA)
  11. Signal termination
    • Receptor can be endocytosed and recylced to membrane or degraded
    • Receptor desensitization
    • Begins with aggonist binding to receptor. G protein receptor kinase (GRK) phosphorylates 7Tm so that beta arrestin (betaArr) can bind, inhibiting G protein binding and promoting endocytosis (degrade or recylce)
  12. Uses of 7Tm G protein coupled
    • Fight or flight
    • Sight, smell, taste
  13. Heterotrimeric G protein
    • Three subunit alpha(membrane bound), beta(covalent)gamma(membrane bound)
    • Signal molecule to receptor recruits G protein
    • GDP to GTP releases beta and gamma until it hydrolyzes
    • Specific to certain pathway (many types!)
  14. Phosphatidylinositol signaling
    • alpha subunit of activated G protein activates phospholipase C to cleave PIP2
    • diacyl glycerol in membrane goes to activate protein kinase C (PKC)
    • inostol 1,4,5 triphosphate (IP3) in cytosol opens ER Ca channel
    • Ca also activates protein kinase C (PKC)
  15. Cyclic AMP signalling
    • alpha subunit of activated G protein activates adenylyl cyclase to make ATP to cAMP
    • cAMP activate protein kinase A (PKA)
    • Protein kinase A phosphorylates a gene regulatory protein in the nucleus to activate target genes
  16. Cholera
    • GTP hydrolysis inhibition causing over production of cAMP
    • Decreases Na absorption and increases Cl secretion
    • Dehydration through rice water stool
  17. Pertussis
    • Gi (inhibitory G protein) is deactivated so that it cannot inhibit adenylyl cyclase
    • cAMP depresses immune system leukocytes
  18. Ras
    • Localized to membrane via acylation by farnesyl transferase (remember FTI from metabolism?) or via geranylgeranyl transferase depending on tissue
    • mSOS (activated by Grb2 associated with receptor tyrosine kinase) changes GDP to GTP in Ras
    • Ras activates Raf, which activates Mek (kinase) actiavtes Erk (Map kinases)
    • GTPase (hydrolysis) in Ras is performed by Gap upon receiving a signal
    • Gef does nucleotide exchange to activate Ras
    • Loss of Gap leaves Ras always on and leads to neurofibromatosis
  19. Tyrosine kinase family
    • Bind ligand
    • Receptor and non-receptor (JAK)
    • Commonly involved in cancer
  20. Src kinase
    • Phosphorylate SH2
    • Opens up proline rich domain when activated, which autophosphorylates
    • Then does kinase activity
    • Dephosphorylate SH2 to inactivate
    • Related to 1st tumor virus, 1st oncogene, 1st tyrosine kinase, 1st to have signaling motifs for protein-protein complexes
  21. Signal transduction molecules
    • Adaptors and scaffolds
    • Often related to tyrosine kinase
    • The target of specific signal transduction therapies (imatinib)
  22. Insulin related substrate (IRS)
    Docking protein scaffold that is phosphorylated by receptor tyrosine kinase when insulin binds
  23. Imatinib (disease mechanism)
    • Chronic myeloid leukemia
    • Translocation of 9;22 at breakpoint (Bcr) of 22 adds Abl gene of 9 to make bcr/abl
    • Bcr/Abl has tyrosine kinase activity and acts as a signal transduction scaffold molecule
    • Activates Ras pathway (MAPK pathway), JAK/STAT
  24. Essential alterations for malignant transformation
    • Self sufficiency in growth signals
    • Insensitivity to growth inhibitory signals
    • Apoptosis evasion
    • DNA repair defects
    • Telomerase activity
    • Sustained angiogenesis
    • Metastatic capability
  25. Oncogenes
    • Promote cell growth in tumors
    • Can be inserted by virus insertional mutagenesis near protooncogene
    • Dominant
    • EGFR overexpression in lung tumors, gliblastomas and head and neck
    • ERB-B2 (HER2/neu) in breast cancer
    • Ras (carcinoma kras, bladder hras, hematopoietic nras)
    • Myc (Burkitt lymphoma by ebstein barr virus, amplification in breast, colon, lung, N-Myc amplification in neuroblastoma)
  26. Targeted therapies
    • Imatinib targets Bcr/Abl in chronic myeloid leukemia
    • Herceptin targets HER-2/neu in breast cancer
    • c-kit targeted in GI stromal tumors
  27. Tumor suprressor genes
    • Recessive
    • WT-1 in Wilms tumor
    • vonHippel Lindau (VHL) gene in clear cell renal carcinoma
    • Regulators of the cell cycle (cyclin D, CDK4, Rb, p16INK4a)
  28. p53
    • Can predict chemo responsiveness of tumor
    • >50% of tumors
    • Cell cycle arrest and apoptosis
  29. APC/beta catenin
    • Mutated APC allele causes thousand of colon polyps that can become malignant
    • Beta Catenin also causes colon tumors
  30. BCL-2
    • Prototypic anti-apoptotic gene
    • B-cell follicular lymphomas
  31. Angiogenesis
    • Essential to supply nutrients and growth factors like PDGF
    • Tortuous and leaky
    • Endostatin inhibits angiogenesis
  32. Metastatic cascade
    • Invasion of extracellular matrix by
    • detachment of self, attachment of matrix, proteases, tumor platelet aggregates
    • Homing of tumor cells by
    • readherance to endothelium, protease through basement membrane, favorable soil and classic locations, uses many cytokines and chemokines
  33. DNA repair in cancer
    • Defects in repair genes leads to genomic instability syndromes with mutator phenotypes
    • BRCA1/2 homologous recombination
  34. Adenoma-Carcinoma sequence of colorectal cancers
    First hit, 2nd hit, non aggresive, further mutation makes it carcinoma
  35. Gatekeeper genes
    • Oncogenes and tumor suppressor
    • High risk for malignancy development
  36. Caretaker genes
    • Affect genomic stability
    • DNA repair genes
    • Lower risk for malignancy development
  37. Multistage carcinogens
    • Initiation and promotion then progression (accumulation of genetic mutations causes invasive and metastatic tumor)
    • Adenoma-carcinoma sequence of colorectal
    • Requires initiator
    • Requires high promoter frequency (not spread out over time)
  38. Chemical carcinogens
    • Electrophilic to bind nucleophilic DNA and create adducts
    • Indirect (metabolism required)
    • Direct are electrophilic
    • Initators must be strong electrophiles
    • Use Ames test (direct and indirect) sensitivity of 50-70%
  39. Nitrogen mustards
    • Direct chemical carcinogen
    • Chlorambucil, melphalan, cyclophosphamide
    • Secondary cancers (leukemias) post treatment
    • Can attack crosslinked gene to fix...or cause cancer
  40. Lung cancer
    • Smoking (90%)
    • Squamous cell carcinoma in the dysplastic epithelium of bronchial lining
    • DNA adduct formed by benzo[a]pyrene metabolized by cyt p450
  41. Aspergillus mycotoxins
    • Grains and yellow mold of peanuts
    • Common in asia and africa where it synergizes with hepatitis A B C
    • Aflatoxin B1 forms DNA adducts, mutating p53 at codon 249 in high aflatoxin regions
  42. DNA photoducts
    Thymine dimers fixed by nucleotide excision repair
  43. UV and skin
    • Basal and squamous are associated with total sun exposure
    • Melanoma is with heavy sun exposure like tanning
  44. Sunscreen
    • Inorganic scatters (zinc oxide)
    • Organic absorbs and disperses as IR heat
    • Need UVA/B (broadspectrum), SPF30 and water resistant
    • Especially during childhood!
  45. Ionizing radiation
    Atomic blast, x rays for techs and patients, radium dial painters
  46. Chernobyl 1986
    Thyroid cancer in children increased from 1989 to 2000s
  47. Abestos
    • Chrysolite (serpintine flexible) more common
    • Crocidolite (amphibole rigid rod) travels deeper
    • Intersitial fibrosis, carcinoma, mesothelioma
    • Macrophages digest and cause chronic inflammation
    • 20 year latency
  48. HPV
    • Creates E6 and E7 (usually repressed by E1 and E2
    • Both inhibit p53
    • E7 inhibits p21 and Rb-E2F
  49. Heliobacter pylori
    • Makes proteins that interfere with signaling pathways to increase cytokines/chemokines
    • Inflammatory modulators and growth factors
    • All that causes inflamation
  50. Inflamation and cancer
    • Hemochromatosis (hepatic cancer), acid reflux (esophageal), viral hepatitis B and C(hepatic), asbestos (mesothelioma), heliobacter pylori (gastric), inflammatory bowel disease (colon)
    • Affects epithelium to lead to cancer
    • Affects stroma to lead to metastasis by landscape effects
  51. Heterogeneitiy of cancer
    There are many different types
  52. Terminology, benign or malignant
    • oma-benign
    • sarcoma-malignant mesenchymal
    • carcinoma-malignant epithelial
    • lymphoma-malignant lympocytic
    • melanoma-malignant melanocytic
  53. Benign v malignant
    • Benign
    • Well differentiated, slow growth rate, non invasive, circumscribed (fibrous capsule/expansile nodule)
    • Malignant, anaplasitc (poorly differentiated), pleomorphic, fast rate of growth, invasive, metastatic capability
  54. Growth rate determinant factors
    • What proportion divide
    • How frequently they divide
    • Ratio of division to death
  55. Metastatic routes
    • Lymphatic (goes to lymph nodes)
    • Hematogenous through small veins to other organs
    • Seeding of body cavities (like peritoneum)
  56. TNM and overall staging
    • T (tissues) size and adjacent tissues involved
    • N (nodes) how many, how far, what kind
    • M (metastatic spread) distant metasteses
    • Overall staging based off of certain TNM score, cancer specific
  57. Direct tumor effect
    Destruction or invasion of adjacent tissues (bowel obstruction or seizure etc)
  58. Cachexia
    • Linked to cytokines and host response
    • Wasting, loss of appetite, lethargy
    • Also due to chemo
  59. Paraneoplastic Syndromes
    • Remote effects due to local primary tumor effects
    • Ectopic hormone production (can cause hypercalcemia for example)
    • Autoimmune antibodies against host
  60. Hematologic effects of cancer
    • High cytokine levels can lead to immunosupression leading to infection (also chemo)
    • Inflammatory reponse activates platelets
    • Decreased platelets due to chemo and cancer
    • Anemia from inflammation and cancer
  61. Cancer rates (temporal and regional)
    • In US over time are driven by society, screening and nonmedical technology
    • Most geographical risks are environmental, not racial like HBV and diet