1. Tumorigenesis
    formation or production of tumors
  2. carcinogenesis
    the creation of cancer
  3. oncogenesis
    a tumor forming process
  4. carcinomas
    cancer derived from epithelial cells
  5. Sarcomas
    cancer arisen from connective tissue or muslce cells
  6. leukemia
    cancer derived from hemopoietic(blood) cells
  7. six ways for tumorigenesis
    • self-sufficiency in growth signals, increase in oncogene
    • insensitivity to antigrowth signals, decrease checkpoint control, decrease tumor supressor genes
    • evasion of apoptosis, decrease in apoptosis, increase in cell survival
    • limitless replicative potential, increase telomerase
    • tissue invasion and metastasis, decrease cell adhesion
    • sustained angiogenesis
  8. Ras
    • activated Ras can transform immortalized cell line but not primary cell cultures. co-transfection of Src and activated src can cause primary cells to adopt a transformed phenotype
    • cells grow up on top of each other, lost contact inhibition
  9. Colorectal cancer development
    • Loss of APC (adenomatous polyposis coli) - tumor-suppressor gene on chromosome 5
    • activation of K-ras - oncogene on chromosome 12, trigger activation of MAPK
    • loss of tumor suppressor gene in DCC (deleted in colon carcinoma) - chromosome 18, promote cell grwoth
    • loss of p53 - tumor suppressor gene - chromosome 17, no DNA damage checkpoint
  10. tumor progression
    • tumor begins as a single abnormal cell with multiple mutations/genetic changes
    • growth becomes mitogen dependent
    • unlimited replicative potential
    • becomes invasive
    • then start to metastasize to other tissues
    • Lack responses to antigrowth signals/apoptotic/death signals
    • also, loss of DNA repair mechanisms; cannot repair DNA damage due to DNA polymerase copy error or mutations
  11. Possible origins of cancer: stem cells
    • Stem cell niche: microenvironment, dependence of normal stem cells on the niche limit their expansion
    • Expansion of the normal stem cell niche permits the expansion of cancer stem cells that arose from normal stem cells: increase in number of niche = increase of stem cells
    • Cancer stem cells that arose from normal stem cells adapt to different niche along their expansion
    • Cancer stem cells that arose from normal stem cells become niche independent, and self-renewal is cell-autonomous
    • cancer stem cells arising from a progenitor cell - shift in the programmed deline in replication potential
  12. Intestinal stem cell
    • paneth cells on the bottom secret antimicrobial proteins defense, keep everything sealed
    • intestinal stem cell signaling: niche: stem cells on the bottom and mesenchymal cells
    • BMP on mesonchymal cells : a member of TGFbeta family protein
    • Noggin - a TGFbeta inhibitor
    • Dkk inhibits Wnt, Wnt from mesonchymal cells act on stem cell for proliferation
  13. Neoplasm/benign tumor
    • a tumor mass composed of cell whose growth regulation is out of control but remains clustered together and contained in a signle mass
    • do not metastasize and do not invade other cells
  14. Malignant tumor
    a tumor whose cells have acquired the ability to break away (by secreting proteases or protease activiators) from the original mass and invade surrounding tissue
  15. Metastasis tumor
    secondary tumor located at a site distant from the original tumor
  16. Metastasis
    • the process by which cells from a primary tumor break away from the original mass, enter thebloodstream, and travel to distant, secondary sites
    • loss of "warp" - fibrous connective tissue capsule of benign tumor
    • carcinoma cells secrete proteases and degrade basement membrane by invadopodia
    • EGF secreted from macrophages and diffused from blood vessels
    • Carcinoma cell migrating on EcM fiber
    • Tumro take advantage of EGF (growth fator that trigger growth of fiber) and grow within th efibers
    • Eventually get into blood stream and circulation in blood vessels, go to: lymphnode, liver, or bone marrow
    • second tumor - 1/100,000 escape
  17. angiogenesis
    • tormor growth requires formation of new blood vessels
    • in low O2, high HIF: hipoxia inducible factor and secreted VEGF: vascular endothelial growth factor
    • causes cipillary to grow out and form new capillary branch
    • inhibition of angiogenesis can be a caner treatment
  18. HIF
    hypoxia-inducible factor, transcription factor that respond to change in available oxygen in the cellular environment
  19. VEGF
    a chemical signal produced by cells that stimulates the growth of new blood vessels, part of the system that restores the oxygen supply to tissue when blood circulation is inadequate
  20. Transformation
    • the process by which cells in culture lose their "normal" characteristics and acquire many characteristics of cancer cells
    • have unlimited replication ability
    • anchorage indepedent - can grow in suspension, and can growth when removed from ECM (unlike normal cells)
    • do not exihibit contact inhibition, grow on top of each other
    • independent of growth factors
  21. Immortal cells
    • immortal cells have unlimited replication ability
    • immortal cells from after undergoing "crisis" in which a small % of cells survive and begin proliferating again
    • they are selected (acquire ability) to survive in culture
    • cells escape crisis after experiencing genetic mutations
    • telomerase is required for immortality
  22. NIH3T3 cells
    immortalized fibroblasts derived from mouse embryos that have survived crisis
  23. Cluster Analysis
    • Microarray analysis can identify different expression between normal vs cancer cells
    • Genes are grouped together according to some critera, possibly by their function or expression patter
    • red = overexpressed
    • green = underexpressed
  24. oncogenes
    • genes that cause cancer when activated or expressed at high levels
    • gain of mutations: often dominant that cuase or increase chane of cancer
  25. proto-oncogenes
    genes which when mutated become oncogenes
  26. tumor suppressors
    • genes that cause cancer when loss of function occurs (by mutation or abnormal inactviation)
    • mutation usually recessive
  27. 4 ways to convert a proto-oncogene into an oncogene
    • hyperactive protein made in normal amounts - deletion or point mutation in coding sequence
    • normal protein greatly overproduced - gene amplification
    • nearby regulatory DNA sequence cause normal protein to be overproduced - chromosome rearrangement
    • fusion to actively transcribed gene greatly overproduces fusion protein; or fusion protein is hyperactive - chromsome rearrangement
  28. APC loss of function
    • adenomatous polyposis coli, a major gene that is invovled in causing colorectal cancer, functions in the wnt-signaling pathway
    • APC usually bins axin and occupy beta catenin (inhibited)
    • mutant apc - beta catenin is released and lead to gene transcription of cmyc gene
  29. Ras-MAPK pathway
    • ras mutation found in many human cancers, MAPK is phosphorylated on both Y185 and T183
    • leads to c-fos gene transcription
  30. src tyrosine kinase
    • can be activated by mutation
    • normal cellular: Tyr527 phosphorylation at the C terminus by csk inactivates c-Src; losing phosphorylation would be constutitively active
    • viral: lacks the C terminis, v-src is constitutively active
  31. Burkitt's lymphoma
    • c myc is constitutively activated by a chromosomal transloation that palce it next to the imunoglobulin heavy chain promoter, cmyc moved from chromosome 8 to 14
    • myc regulates cell cycles through Rb proteins
  32. Proto-oncogene receptor proteins: Her2 receptor
    • mutated by point mutation - Valine -> Glutamine
    • Neu oncoprotein
    • does not need ligand, always dimerized and always active
    • antibodies against Her2 are used to treat human breast cancer - causes Her2 to get degraded
  33. Endostatin
    • inhibition of angiogenesis - cancer treatment
    • a naturally occuring 20kDa C-terminal fragment derived from type XVIII collagen
  34. Proto-oncogene receptor proteins: EGF receptor
    • truncation of the EGF receptor causing constitutive dimerization
    • ErbB oncoprotein - constitutively active protein-tyrosine kinase
    • ligand independent
  35. Generation of tropomyosin-Trk chimera
    • chromosome translocation
    • fusing the coil coil region of tropomyosin to the intracellular domain of the Trk receptor - found in colon carcinomas
    • chimeric Trk oncoprotein is constitutively active
  36. EpoR activation by a viral oncoprotein
    • Spleen focus-forming virus
    • FFV induces oncogenesis by producing a ligand that dimerized Epo receptor
    • gp55 - a viral protein mimics a ligand and activates receptor
  37. Activation of Abl in chronic myelogenous leukemia
    • chromosomal translocation causing a fusion protein between Abl and Bcr, 9 and 22
    • causes constitutive activation of the kinase, makes Bcr-Abl fusion protein
    • fusion protein can bind JAK2, STAT5 - substrate activated by phosphoyrlation, overactive but nonspecific
    • substrate can be inhibited with Imatinib
  38. Gleevec/Imatinib/STI-571
    • 1st cancer drug targetd to signal-transduction protein unique to tumor cells
    • Imatinib binds to Abl in CML active site and inhibits substrate binding
  39. six broad classes of tumor suppressors
    • intracellular proteins that regulate or inhibit progression through a specific stage of the cell cycle, p16 and Rb(inhibit G1 - S)
    • receptors or signaling proteins that inhibit cell proliferation, TGF-beta pathway
    • negative regulators of pathways that promote proliferation, APC
    • checkoint control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal, p53
    • proteins that promote apoptosis, Bax or Fas
    • enzymes that participate in DNA repair, cells that lack such factors accumulate in many gene,s some of which will promote tumor formation
  40. ATM
    • the kinase that activates p53
    • p-p53 no longer bindsn to Mdm2 (ub ligase), disasscoation
    • lead to stable, active p-p53 and bind to regulatory region of p21
    • transcription of p21 gene - tranlades into p21 Cdk inhibitor protein
    • CIP - cells arrest in G1 and G2
  41. p53 activation
    • ATM phosphorylation of p53
    • Chk2 phospphorylate p53 (chk2 also phosphorylates cdc25A, leads to proteasomal degradation (decrease of cdk2) rapid G1/S block)
    • ATM phosphorylation of Mdm2, since Mdm2 is the ub ligase that induces the degradation of p53, phosphorylation leads to inactive Mdm2 and stabilized p53
    • Mdm2 bidning to pArf14 -inactive, more p53 activity
  42. TGFbeta signaling pathway
    • receptors/signaling proteins inhbit cell proliferaion (transcription of p15 encoding cell-cycle inhibitor, Pal-1 encodes inhibitor of protease that degrades extracellular matrix proteins)
    • loss of function mutants promote cell growth
    • decreased produciton of p15 increases proliferation
    • decreased production of Pal-1 allows increased extracellular matrix
    • degradation and metastasis
  43. p16
    • tumor suppressor, binds and inhibits cyc3 and CDK4
    • once removes, active kinse which will phosphorylate Rb
    • phosphorylated Rb releases E2F - activator of transcription fo proteins needed for DNA synthesis
  44. telomerase
    • Telomerase is an enzyme that adds DNA sequence repeats ("TTAGGG" in all vertebrates) to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. The telomeres contain condensed DNA material, giving stability to the chromosomes.
    • loss of telomerase limits the number of cell civision - at the tip of linear dNA molecules, usually hard to replicate, are usually tandem repeats of short sequences
    • recognizes telomere DNA - telomerase extends the 3'end, elongates 5 to 3, 3 is slightly longer than 5, protected from degradation
    • ecah time a cell divides it loses 50-100 nucleotides
Card Set