HD Exam3 Cancer.txt

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mmcmull1
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HD Exam3 Cancer.txt
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2011-04-11 00:41:24
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HD Exam3 Cancer
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HD Exam3 Cancer
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  1. Tumor Nomenclature
    • Tissue
    • of origin + suffix
  2. Benign => -oma
  3. Malignant => -sarcoma, -carcinoma, -blastoma
  4. Tumor progression overview
    Initiation -> promotion -> progression
  5. Initiating agents
    • (CURRV = curve)
    • Chemical carcinogens
    • Unknown factors
    • Radiation (UV Light)
    • Replication errors
    • Viruses
  6. Promoting agents
    • (Shin)
    • Specific promotors
    • Hormones
    • Inflammation
    • Normal growth promoters, etc.
  7. Growth inhibitors
    • Hormones - therapeutic or physiological
    • Age, surgery, radiation, etc
    • Normal growth inhibitors
  8. Initiation
    • –Initial permanent change, usually
    • in DNA
    • –Initiated cells are latent
    • -not yet a tumor
  9. Promotion
    • –Preferential growth stimulation
    • of initiated cell into clone of cells (clonal expansion)
    • –Can be reversed (i.e. loss of growth factors, stimulating agents, etc)
  10. Progression
    • –Tumors are heterogeneous
    • –Selection pressure generates
    • cells with increased malignant potential
  11. What is Cancer?
    Abnormal tissue mass whose growth exceeds and is uncoordinated with that of normal adjacent tissue (i.e. malignant tumors)


    • •Cancer is a group of diseases
    • characterized by
    • –disordered growth control
    • –acquisition of invasion and metastatic potential
  12. Implications
    of Definition of cancer
    • •Absent or minimal regulation of cell growth
    • –distinguishes cancer from other modulations of growth (i.e. may have high proliferation but regulated)
    • –difficult to establish cause and effect in carcinogenesis
    • –treatment cannot target the instigating agent but instead must target the mass of cells
  13. Genetic basis of cancer
    Cancer arises from the accumulation of genetic changes, not just a singular mutation
  14. Anaplasia
    • loss of differentiated features
    • Higher degree of anaplasia = Worse prognosis
  15. Criteria in determining benign vs. malignant tumors
    • (dig 'm)
    • Differentiation state
    • local Invasion
    • rate of Growth
    • Metastasis
  16. General features of benign tumors
    • •Slow growing
    • •Well differentiated (looks more like parenchymal cells)
    • •Localized
    • •Innocuous
    • •Capsulated (surrounded by fibrous membrane)
  17. General features of malignant tumors
    • •Rapid growth (increased metabolic activity)
    • •Wide range of differentiation
    • •Invades and metastasizes
    • •Distinct cellular phenotype
  18. Features
    of Cancer Cells
    • (SIT, LSE i.e. sit, Elsie)
    • •Self sufficiency in growth
    • signals

    • •Insensitivity to growth
    • inhibitory signals
    • •Tissue invasion and metastasis
    • •Limitless replicative potential
    • -Sustained angiogenesis

    •Evasion of apoptosis
  19. How does cancer kill?
    • •Organ Failure
    • –Tremendous reserve capacity
    • –Occurs only once tumor is far advanced
    • •Obstruction
    • –GI tract, hollow organs
    • Others like cachexia and
    • infection
    • –Wasting syndrome
    • –Impair immune defenses leading to pneumonia, septicemia, etc
    • -main cause of death
  20. Goals of epidemiology of cancer
    • –Identification of risk factors
    • –Development of prevention strategies
    • –Assessment of public health policies
    • (i.e. asbestos, sg warning of cigarettes)
  21. Cancer stats in the US: Most common and most deadly
    • Number of cases:
    • Men: Prostate, Lung
    • Women: Breast, Lung

    • Deaths:
    • Men: Lung, Prostate
    • Women: Lung, Breast
  22. Cancer causes
    Differs with cancers, but 65% from environmental factors (tobacco, diet), 35% from genetic factors
  23. Types of Epidemiological Studies
    • •Descriptive studies:
    • –data on incidence, mortality, risk
    • •Correlation studies:
    • –comparisons of populations with different exposures
    • •Special exposure groups:
    • –study of groups with unique exposures
    • •Migrant studies:
    • –cancer incidence in populations migrating between areas with different cancer rates
  24. Genetic basis of cancer
    • DNA damage
    • Acquired environmental factors = chemicals, radiation, viruses
  25. Carcinogen
    •any substance or agent which enhances tumor incidence
  26. Types of Carcinogenesis
    • –Chemical
    • –Radiation
    • –Endogenous
    • –Viral
  27. Chemical
    Carcinogens: overall mode of action
    • Procarcinogens in environment, become electrophiles, bind to DNA covalently
  28. Most carcinogens are metabolized...
    • Metabolism can activate or detoxify carcinogens. Electrophile can react w/ hydroxyl group or nigrogen group of DNA and form adducts
  29. Summary: Chemical Carcinogenesis
    • •Most chemical carcinogens induce DNA damage
    • •Chemical carcinogens usually require metabolism to be active (b/c reactive species. if they react w/ things in environment, no longer a carcinogen)
    • •Adduct formation requires electrophilic groups on the carcinogen and nucleophilic groups on the DNA
    • •Human exposure to carcinogens is ubiquitous (Can minimize but not totally get rid of)
  30. Radiation and Human Cancer
  31. Cellular Effects of Ionizing Radiation
    • Know direct and indirect effects lead to DNA damage.
    • Outcomes are: DNA repair, cell death, carcinogenesis
  32. Endogenously generated DNA damage
    • •Cellular generation of reactive oxygen species (ROS) - highly reactive, induce DNA
    • damage
    • •Contribute to natural (baseline) mutation rate
    • •Major source: by products of oxidative metabolism (electron transport)
  33. Summary-Mutations caused by DNA damage
  34. Consequences of DNA damage
    • •Repair and return to normality
    • •Extensive damage leading to cell death
    • •Misreading of modified bases at next round of proliferation

    Altered DNA sequence must be inherited by somatic daughter cells to be of functional significance
  35. Genotoxic Carcinogens alter DNA
    • •Single base changes, insertions, deletions
    • •Can either have no effect, or
    • –Change the KIND of protein produced (i.e.) gain/loss of function
    • –Change the AMOUNT of protein produced
    • •Targets are oncogenes and tumor suppressor genes
  36. Oncogene - Definition
    • •Altered form of normal cellular gene
    • •Cellular gene is the proto-oncogene (normal gene)
    • •Oncogenes encode regulatory proteins with dominant transforming properties - gain of function! (e.x. constitutively active kinases)
    • --single copy is sufficient for transformation
    • --presence of normal counterpart cannot block action of oncogene


    • code for:
    • •similar or identical mutated proteins
    • •function in growth regulatory pathways
    • •mutated forms generally hyperfunctional
    • •drive growth factor independent proliferation; suppress apoptosis; induce invasive /metastatic potential
  37. Classes of Oncogenes
    • •Growth factors and their receptors
    • --ex: EGF receptor mutions in squamous cells -> become ligand independent
    • •Non receptor tyrosine kinases
    • --c-ABL, v-Ras
    • •GTP binding proteins
    • --c-Ras (GDP -> GTP (active))
    • •Cytoplasmic serine/threonine kinases
    • --MAP Kinases
    • •Nuclear signaling
    • --estrogen receptors
    • •Transcription factors
    • --c-Myc, c-fos

  38. Know what tumor suppressor genes are and how
    they are different from oncogenes
    • •Code for proteins that inhibit trans-formation by variety of mechanisms
    • •Transformation involves loss of function of tumor suppressor genes (TSGs)
    • •Both alleles must be inactivated for an impact on cancer development
    • •Some DNA tumor viruses code for proteins that inactivate TSGs

    Tumor suppresor genes inhibit proliferation, promote apoptosis. Both copies of tumor suppressor gene have to be lost, vs. oncogenes.

    Oncogenes = specific mutation to make it active

    tumor suppressor = any mutation that makes it not functional
  39. describe p53 and how it functions as a tumor suppressor
    • p53 is a transcription factor, promotes apoptosis and inhibit cell proliferation, genes turned on during DNA damage, leading to apoptosis
  40. know why multiple cellular mutations are required before a cell can become cancerous and the colon cancer example given in class
    • homozygous loss of APC [tumor suppresor gene, binds to beta catenin, prevents transcription, 50% of colon cancers have this mutation] -> mutation of Ras -> formation of adenoma -> Homozygous loss of DCC [70% of colon cancers]-> Homozygous loss of p53
  41. Know what angiogenesis is and why it is important for tumor development and metastasis
    • Angiogenesis = sprouting of new vessels from
    • existing vessels
    • •Growth of blood vessels into tumor (neovascularization)
    • •Essential for tumor growth > 2mm
    • •Supply of oxygen, nutrients, growth factors
    • •Initiated by proliferative signals
    • -Vascular endothelial growth factor (VEGF)
    • -Angiopoeitins
    • -Basic fibroblast growth factor (bFGF)
  42. Inhibitors of angiogenesis
    • Angiostatin
    • –Most potent anti-angiogenic factor known
    • –Specific inhibitor of endothelial cell proliferation
    • –Cleavage fragment of plasminogen
    • Endostatin
    • -Cleavage fragment of collagen XIII
    • Thrombospondin-1
  43. Be able to describe how you could block angiogenesis
    • •Block angiogenic factors
    • -VEGF antibodies
    • -inhibitors of receptor kinases

    • •Induce or apply anti-angiogenic factors
    • -Endostatin

    • •Interfere with matrix proteases
    • -MMP9
  44. why blocking angiogenesis may be a useful anti-cancer treatment
    • •Tumors are dormant without angiogenesis
    • •Tumor progression requires switching on angiogenesis
    • –Imbalance between inhibitors and activators
    • –Oncogenes, TSGs contribute to angiogenic switch
    • •Control of angiogenesis = control of cancer?
  45. Know how angiogenesis promotes metastasis
    • • allows for tumor growth
    • • provides an exit portal for metastatic tumor cell
  46. Know the definition of metastasis and the general concepts associated with it
    • Metastasis = Escape of cancer cells from a
    • primary tumor and re-establishment of growth at distant, secondary sites
    • •Late event in cancer process, but underlying genetic changes required for metastasis may occur early
    • •50% of patients present with metastases
    • •Size of primary? -Often but not always predictive
    • •Efficiency of metastasis? - Not very - 1/10,000 cells. However, most human cancers successfully metastasize
  47. Metastasis - routes of transport
    • •Shedding into body cavities
    • –Peritoneum
    • –Pleural cavity
    • •Blood vessels

    • –Capillaries
    • –Hepatic portal vein
    • •Lymphatics
    • –Drain into lymph nodes
    • –Empty into venous system
  48. Know what the seed and soil hypothesis is
    • •Homing mechanisms attract cancer
    • cells to specific sites
    • •Successful metastasis requires
    • –viable seed (cancer cells)
    • –appropriate soil (host organ)
    • •growth factors, ECM, etc.
    • Cells need to be able to proliferate at the new site
  49. Metastatic cascade
    • •Series of sequential, interrelated steps
    • •Failure in any one step prevents metastasis
    • •Outcome depends on interactions between tumor cell and host factors
  50. Metastatic Tumors Requirements
    • •Motility
    • •Reduced cohesiveness
    • •Proteolytic activity
    • •Suppression of apoptosis
  51. Metastatic tumors: motility
    Cancer cells in circulation:

    • •Single cells or emboli - clusters with platelets, lymphocytes
    • •Hostile environment - blood pressure, turbulence, immune attack
    • •99% cell death rate
  52. Metastatic tumors: reduced cohesiveness
    • –E-Cadherin downregulated
    • •Ca++ dependent cell adhesion molecule
    • •frequently lost in metastatic cells
  53. Metastatic tumors: proteolytic activity
    • –Collagenase
    • •Degrades ECM
  54. Extravasation
    • Extravasation = Exit of tumor cells at secondary site
  55. Proliferation at Secondary Site
    • •Cells may remain dormant
    • •Specific growth factors, ECM required for proliferation
    • •Cells with low growth factor requirements generally more metastatic
    • •Metastases can also metastasize

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