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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
Protein Products of Tumor Suppressor Genes
Growth Inhibitory Factors Molecules That Regulate Adhesion Signal Transduction Regulation of Nuclear Transcription and the Cell Cycle
26
Other Genes That Function as Tumor Suppressors • The TGF-β pathway
– The gene encoding the type II TGF-β receptor is inactivated in 70% or more of colon cancers
27
Growth Inhibitory Factors
• 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
Molecules that Regulate Cell Adhesion | • DCC (deleted in colon cancer)
– 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
Signal Transduction
• Down regulation of growth promoting signals • NF-1 – Intimately related to signal transduction via ras – Codes a GTPase activating protein (GAP)
30
Molecules that Regulate Nuclear Transcription and the Cell Cycle
• Rb **** • TP53 (p53) *****
31
Protein Products of Rb gene
• In hypophosphorylated form, bind to transcription factors, preventing DNA synthesis -> transcription block
32
Protein Products of TP53 (p53)
* 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
PPTP53
* 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
Genes that Regulate Apoptosis Evasion of Cell Death
* 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
Evasion of Cell Death
• 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
Extrinsic Pathway • Initiated when a TNF receptor such as CD95 (Fas) is bound to its ligand
* 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
Intrinsic Pathway • The intrinsic (mitochondrial) pathway is triggered by a variety of stimuli – Withdrawal of survival factors – Stress – Injury
* Activation of this pathway leads to permeabilization of the mitochondrial outer membrane * Results in the release of molecules (cytochome c) which initiate apoptosis
38
Intrinsic Pathway | •Theintegrityofthemitochondrialoutermembrane is regulated by pro- and anti-apoptotic members of the BCL-2 family
* Pro-apoptotic – BAX and BAK * Anti-apoptotic – BCL2 and BCL-X * Athirdsetofproteins(BH-3onlyproteins) regulates the balance between them – BAD, BID, and PUMA
39
BCL2 | • Anti apoptosis gene • Prevents release of cytochrome c from mitochondria
* 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
BAX
* Promotes apoptosis by promoting the release of cytochrome c from mitochondria * Up regulated by TP53
41
Limitless Replicative Potential | • Most normal human cells have a capacity of 60 – 70 doublings
• 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
Molecular Basis of Multistep Carcinogenesis | • Non-random chromosomal abnormalities
* No single oncogene can fully transform cells ***** | * Every human cancer has multiple genetic alterations: ***** – Several oncogenes – Loss of 2 or more suppressor genes
43
Karyotypic Changes in Tumors | • Balanced translocations
* Deletions | * Cytogenetic manifestations of gene amplification
44
Carcinogens
Chemical Radiation Oncogenic Viruses
45
Chemical Carcinogens | • Both man-made and natural products
* Initiation (mutagenesis) – Direct acting – Indirect acting: require metabolic activation * Promotion – Reversible – Not tumorogenic by themselves
46
Steps in Chemical Carcinogenesis | • Initiation results from exposure of cells to chemical carcinogen
* Mutations * Promoters induce tumors in initiated cells but are non-tumorogenic by themselves * Promoters have a reversible effect
47
Chemical Carcinogens | • All direct and ultimate carcinogens contain highly reactive electrophile groups
• Although any gene may be targeted, proto- oncogenes and tumor suppressor genes are frequently mutated by the carcinogen(s)
48
Carcinogenic Chemicals • Alkylating agents – Anticancer drugs
``` • Aromatic amines and azo dyes – β naphthylamine • Polycyclic and heterocyclic aromatic hydrocarbons – benzopyrene • Natural plant and microbial products – Aflatoxin B1 ```
49
Radiation
• UV radiation – Damages DNA by the formation of pyrimidine dimers • Ionizing radiation – Direct - generation of free radicals
50
Repair Mechanisms | • Degradation of the DNA damage to an innocuous form
• Cut and patch repair
51
Ionizing Radiation
* 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
Oncogenic Viruses
• 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
DNA Oncogenic Viruses
• 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
DNA Oncogenic Viruses
• HPV (human papilloma virus). ****** • Epstein-Barr virus (EBV) • Hepatitis B virus (HBV) • Hepatitis C virus (HCV) • Kaposi sarcoma herpesvirus (KSHV. HHV8)
55
Epstien-Barr Virus First virus linked to a human tumor – Burkitt lymphoma
• 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
HPV
• 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
HBV and HCV
* 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
HBV
* 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
HCV
* 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
RNA Oncogenic Viruses
• 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
Bacteria and Carcinogenesis | • Heliobacter pylori
– 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
H. pylori
• 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
CONCLUSIONS ******
* 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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