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Pathology > Neoplasm 2 > Flashcards

Neoplasm 2 Flashcards

1
Q

Molecular Basis of Cancer

A

• Genetic Disease
– Acquired
– Inherited

• Non lethal genetic damage lies at the heart of carcinogenesis.
**( dead cells dont divide)

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2
Q

Genes Affected

A
  • Growth promoting proto-oncogenes
    • Growth inhibiting tumor suppressor genes
  • Genes that regulate apoptosis
    • Genes that repair DNA
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3
Q

Karyotypic Changes in Tumors

A
  • Point Mutations – ras
  • Translocations
    – Placement of the genes next to a strong promoter/enhancer
    – Fusion of the gene with new sequences

• Gene Amplifications

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4
Q

Karyotypic Changes in Tumors

A

• Deletions
• Aneuploidy
• microRNAs
• Epigenetic modifications

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5
Q

Deletions

A
  • Second most prevalent karyotypic abnormality in tumor cells
  • May result in the loss of a particular tumor suppressor gene
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6
Q

MicroRNAs

A
  • Non-coding single-stranded RNAs
  • Approximately 22 nucleotides in length

• Function as negative regulators of genes
– Inhibit gene expression posttranscriptionally
– Cause either repressed translation or mRNA cleavage

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7
Q

Epigenetic Modifications and Cancer

A

• Epigenetics:
– Reversible heritable changes in gene expression – Occurs without mutation
– Involve posttranslational modifications in histones and DNA methylation

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8
Q

Aneuploidy

A
  • A number of chromosomes that is not a multiple of the haploid state
  • Common in malignancies
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9
Q

Carcinogenesis

A

• Multi-step processes at both phenotypic and genetic levels
– Attributes of malignancy
• Invasiveness, metastatic potential
– Acquired in a stepwise fashion

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10
Q

Oncogenes and Cancer

Oncogenes

A
  • Genes that induce a transformed phenotype when expressed in cells
  • Mutated or overexpressed versions of normal cellular genes
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11
Q

Proto-oncogenes

A
  • Normal cellular genes
  • Control growth and differentiation

• Converted to oncogenes by:
– Changes in situ (mutations) that affect their expression and /or function
– Other (viral)

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12
Q

Tumor Suppressor Genes

A
  • Prevent uncontrolled growth
  • Usually both normal alleles must be mutated
  • In some cases, loss of a single allele of a tumor suppressor gene can promote transformation (haploinsufficiency)
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13
Q

Tumor Suppressor Genes

• Two general groups

– Governors
• Classic tumor suppressor genes
• Mutation of the gene causes

A

transformation by removing
a brake on cellular proliferation
• Example: Rb

– Guardians
• Sense genomic damage
• Can cause cessation of proliferation, initiate DNA repair,
induce apoptosis if DNA damage is too severe
• p53 (TP53)

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14
Q

Genes that Regulate Apoptosis and DNA Repair

A

• These genes may act like proto-oncogenes
– Loss of one copy sufficient for transformation)

• May act like tumor suppressor genes
– Loss of both copies

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15
Q

DNA Repair Genes

A

• Loss of function of these genes allows mutations in other genes during normal cell division to be passed on to the daughter cells

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16
Q

Cancer-related Genes

A

• It is best to consider these genes in the context of seven fundamental changes in cell physiology which dictate the malignant phenotype

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17
Q

Hallmarks of Cancer

Fundamental Changes Essential to Malignant Phenotype

A

Self-sufficiency in growth signals

– Growth factors
• Many tumors make growth factors
– Glioblastomas- PDGF
– Sarcomas- TGF-α

– Growth factor receptors and non-receptor tyrosine kinases

– Downstream signal transducing proteins
• ras

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18
Q

Fundamental Changes Essential to Malignant Phenotype

– Nuclear transcription factors

A

• These can regulate the expression of growth- promoting genes such as cyclins

– myc: can either activate or repress the transcription of other genes
» Activate cyclin-dependent kinases
» Repress CDK inhibitors

• Insensitivity to growth inhibitory signals

• Evasion of cell death

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19
Q

Fundamental Changes Essential to Malignant Phenotype

A
  • Autophagy
    • Limitless replicative potential
    • Development of sustained angiogenesis*
  • Ability to invade and metastasize*
    • Reprogramming energy metabolism
    – Glycolysis favored by tumors • *covered in Neoplasia I
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20
Q

Protein Products of Oncogenes Oncoproteins

Protein Products of Oncogenes

A
  • Growth factors
  • Growth factor receptors
  • Signal transducing proteins
    – protein products of the ras gene
    – non-receptor associated tyrosine kinases
  • Nuclear transcription factors
  • Cyclins and Cyclin-dependent kinases
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21
Q

Tumor Suppressor Genes

A

• Cancers may arise with the inactivation of genes which normally suppress cell proliferation

• Placed into two general groups
– Promoters

• Traditional tumor suppressor gene(p53,Rb)
– Caretakers

• Are responsible for processes which ensure the integrity of the genome
– DNA repair genes

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22
Q

Tumor Suppressor Genes

• Confusionoverterminology:

A

– Referred to as autosomal dominate but both genes must characteristically be homozygous for the mutant allele or inactivated by some other means for the effect to occur

– What is autosomal dominate is the increased risk of developing a malignancy with one mutated or otherwise inactivated gene

– The gene functions as an autosomal recessive, requiring loss of function of both normal copies.

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23
Q

Rb gene

A
  • Best know cancer suppressor gene
  • Childhood tumor: retinoblastoma
  • Both normal alleles of Rb locus must be inactivated
  • Associated with increased risk of other tumors
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24
Q

Molecular Basis of Cancer

A
  • Tumor mass results from the clonal expansion of a single progenitor cell that has incurred genetic damage
  • Monoclonal Theory of Cancer
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25
Q

Protein Products of Tumor Suppressor Genes

A

Growth Inhibitory Factors

Molecules That Regulate Adhesion

Signal Transduction

Regulation of Nuclear Transcription and the Cell Cycle

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26
Q

Other Genes That Function as Tumor Suppressors

• The TGF-β pathway

A

– The gene encoding the type II TGF-β receptor is inactivated in 70% or more of colon cancers

27
Q

Growth Inhibitory Factors

A

• Bind to cell membrane and inhibit growth
• Example:
– BRCA-1
– Normal function: protein product inhibits cell
growth after binding to surface receptors (if it doesnt bind….)
– Mutations greatly increase risk of cancer

28
Q

Molecules that Regulate Cell Adhesion

• DCC (deleted in colon cancer)

A

– Inactivated in most colon cancers and in cancers of breast, prostate, pancreas, and endometrium

– Loss of this gene presumably interferes with communication between cells and their environment

– Altered differentiation or proliferation

29
Q

Signal Transduction

A

• Down regulation of growth promoting signals

• NF-1
– Intimately related to signal transduction via ras
– Codes a GTPase activating protein (GAP)

30
Q

Molecules that Regulate Nuclear
Transcription and the Cell Cycle

A

• Rb **
• TP53 (p53) ***

31
Q

Protein Products of Rb gene

A

• In hypophosphorylated form, bind to transcription factors, preventing DNA synthesis -> transcription block

32
Q

Protein Products of TP53 (p53)

A
  • Found in many types of cancers
  • Rarely familial, usually sporadic
  • When DNA is damaged, levels of TP53 protein product increase, arresting the cell in G1
  • Allows time for DNA repair
33
Q

PPTP53

A
  • When DNA repair is complete, the cell cycle continues

* If repair mechanisms fail, it
– Stops the cell from dividing
– Ultimately activated cell suicide genes: Apoptosis

34
Q

Genes that Regulate Apoptosis

Evasion of Cell Death

A
  • The apoptotic pathway can be divided into upstream regulators and downstream effectors
  • Regulators are divided into two major pathways
    – One interpreting extra-cellular or extrinsic signals
    – The other interpreting intra-cellular signals
35
Q

Evasion of Cell Death

A

• Stimulation of either pathway results in activation of a normally inactive protease
– Caspase-8 or caspase-9
– Initiates a proteolytic cascade involving “executioner” caspases which disassemble the cell in an orderly fashion

36
Q

Extrinsic Pathway

• Initiated when a TNF receptor such as CD95 (Fas) is bound to its ligand

A
  • This results in triplication of the receptor and its death domains
  • This attracts the intracellular adaptor protein FADD.
    – This protein recruits procaspase-8 to form the death-inducing signaling complex
37
Q

Intrinsic Pathway

• The intrinsic (mitochondrial) pathway is triggered by a variety of stimuli
– Withdrawal of survival factors
– Stress
– Injury

A
  • Activation of this pathway leads to permeabilization of the mitochondrial outer membrane
  • Results in the release of molecules (cytochome c) which initiate apoptosis
38
Q

Intrinsic Pathway

•Theintegrityofthemitochondrialoutermembrane is regulated by pro- and anti-apoptotic members of the BCL-2 family

A
  • Pro-apoptotic
    – BAX and BAK
  • Anti-apoptotic
    – BCL2 and BCL-X
  • Athirdsetofproteins(BH-3onlyproteins) regulates the balance between them
    – BAD, BID, and PUMA
39
Q

BCL2

• Anti apoptosis gene
• Prevents release of cytochrome c from mitochondria

A
  • Activated by translocation to the IgG heavy chain locus on Chromosome 14 (80% of B cell lymphomas)
  • Protects cell from apoptosis, decreasing cell death
40
Q

BAX

A
  • Promotes apoptosis by promoting the release of cytochrome c from mitochondria
  • Up regulated by TP53
41
Q

Limitless Replicative Potential

• Most normal human cells have a capacity of 60 – 70 doublings

A

• After this—enter a non-replicative senescence
– Felt to be due to shortening of telomeres. **
– Short telomeres recognized as DNA breaks and the cell cycle is arrested

• Tumors avoid this by activation of the enzyme,
telomerase
– Maintains normal telomere length ***

42
Q

Molecular Basis of Multistep Carcinogenesis

• Non-random chromosomal abnormalities

A
  • No single oncogene can fully transform cells *****

* Every human cancer has multiple genetic alterations: *****
– Several oncogenes
– Loss of 2 or more suppressor genes

43
Q

Karyotypic Changes in Tumors

• Balanced translocations

A
  • Deletions

* Cytogenetic manifestations of gene amplification

44
Q

Carcinogens

A

Chemical

Radiation

Oncogenic Viruses

45
Q

Chemical Carcinogens

• Both man-made and natural products

A
  • Initiation (mutagenesis)
    – Direct acting
    – Indirect acting: require metabolic activation
  • Promotion
    – Reversible
    – Not tumorogenic by themselves
46
Q

Steps in Chemical Carcinogenesis

• Initiation results from exposure of cells to chemical carcinogen

A
  • Mutations
  • Promoters induce tumors in initiated cells but are non-tumorogenic by themselves
  • Promoters have a reversible effect
47
Q

Chemical Carcinogens

• All direct and ultimate carcinogens contain highly reactive electrophile groups

A

• Although any gene may be targeted, proto- oncogenes and tumor suppressor genes are frequently mutated by the carcinogen(s)

48
Q

Carcinogenic Chemicals

• Alkylating agents
– Anticancer drugs

A 
• Aromatic amines and azo dyes 
– β naphthylamine

• Polycyclic and heterocyclic aromatic hydrocarbons
– benzopyrene

• Natural plant and microbial products
 – Aflatoxin B1
49
Q

Radiation

A

• UV radiation
– Damages DNA by the formation of pyrimidine dimers

• Ionizing radiation
– Direct
- generation of free radicals

50
Q

Repair Mechanisms

• Degradation of the DNA damage to an innocuous form

A

• Cut and patch repair

51
Q

Ionizing Radiation

A
  • X-rays, gamma rays, alpha particles, beta particles, protons, neutrons, are all carcinogenic
  • Survivors of the atomic bombs at Hiroshima and Nagasaki demonstrated a markedly high occurrence of leukemia, as well as cancers of the thyroid, breast, colon and lung
52
Q

Oncogenic Viruses

A

• Any virus which can produce benign or malignant neoplasia in a susceptible mammal or any virus capable of transforming a cell in tissue culture

53
Q

DNA Oncogenic Viruses

A

• Transforming DNA viruses form stable associations with host cell genome

• Integrated virus unable to complete replicative cycle because essential genes are interrupted during integration of viral DNA

• Viral genes transcribed early—important
– Expressed in transformed cells

54
Q

DNA Oncogenic Viruses

A

• HPV (human papilloma virus). ****
• Epstein-Barr virus (EBV)
• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Kaposi sarcoma herpesvirus (KSHV. HHV8)

55
Q

Epstien-Barr Virus

First virus linked to a human tumor – Burkitt lymphoma

A

• Hassincebeenfoundin:
– B cell lymphomas in patients with defective T cell immunity
– A subset of Hodgkin lymphoma
– Nasopharyngeal carcinoma
– A subset of T cell lymphoma
– Gastric carcinomas
– NK cell lymphomas

56
Q

HPV

A

• Scores of genetically distinct types of HPV have been identified
• Some cause benign squamous papillomas (warts)
• Some have a high-risk of developing into a malignancy
• Covered in depth in Female Genitourinary Disease

57
Q

HBV and HCV

A
  • Strong evidence linking chronic HBV and HCV infection with hepatocellular carcinoma
  • Mode of action in tumorigenesis not fully understood
  • These viruses’ genomes do not encode viral oncoproteins
58
Q

HBV

A
  • No consistent pattern of integration of HBV DNA in liver cells
  • The oncogenic effects of these viruses are multifactorial
  • In cases of unresolved chronic inflammation, the immune response may become maladaptive, promoting tumorigenesis
59
Q

HCV

A
  • Although not a DNA virus, it is strongly linked to the development of hepatocellular carcinoma
  • The HCV core protein may have a direct effect on tumorigenesis
  • Chronic liver cell injury, regeneration, and inflammation may also play a role
60
Q

RNA Oncogenic Viruses

A

• HTLV-1 (human t-cell leukemia virus-1)

– Associated with a form of T cell leukemia/lymphoma endemic in certain parts of the world
– Leukemia develops in only 1% of infected individuals after a latent period of 20 – 30 yrs.

61
Q

Bacteria and Carcinogenesis

• Heliobacter pylori

A

– Linked to gastric lymphomas and gastric carcinomas

– Scenario for the development of malignancy involves increased epithelial cell proliferation in a background of chronic inflammation or gastritis

– Strains associated with the development of
adenocarcinoma contain CagA gene (cytotoxin- associated A)

62
Q

H. pylori

A

• Lymphoma

– Increased risk of developing a B cell gastric lymphoma

  • Pathogenesis seems to involve both strain- specific H. pylori factors, as well as host factors
63
Q

CONCLUSIONS ****

A
  • Effects of carcinogens is dose-dependent and additive over time
  • Effects of carcinogens requires a lag period characterized by pre-malignant changes which may span a latent period of years
  • Cellular changes resulting from a carcinogen are transmitted to daughter cells

Pathology (15 decks)

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