Cancer (Block 1) Flashcards
Cancer Cell Types
Carcinoma (80-90%)
- in situ/invasive
- epithelial cells (squamous cells and adenocarcinomas from secretory cells)
Sarcomas (1%)
- solid tumors of connective tissues
Leukemia/Lymphoma (7%)
- Leukemia - circulating cells
- lymphoma - solid mass
Neuroectodermal (1.3%)
- gliomas, blastomas, schwannomas
Tumor Suppressors
TP53 (p53) - inhibits G1 to S phase of cell cycle; promotes repair or apoptosis. Causes proliferation of damaged cells if mutated.
Rb - hyperphosphorylation inhibitis G1 to S phase of cell cycle. Can cause oncogenesis if mutated
Note: Both are phosphoproteins
Abnormal Cell Functions in Cancerous Cells
- Monoclonal tumor growth
- Genetic Instability
- Anchorage Independence
- Avoid Replicative Senescence
- Loss of Contact Inhibition
- Disregard signals for cell cycle control
- Avoid suicide by apoptosis
- Angiogenesis (Note VEGF role in this)
- Invasive
- Metastasis
Cancer Inheritance
Direct: Inherited mutation in oncogene or suppressor gene = increased susceptibility to certain type of cancer
EX: Breast Cancer (BRCA1 and 2)
Indirect: Defect DNA repair mechanism = increased susceptibility to cancer
EX: Xeroderma Pigmentosum
Three stage model of Chemical Carcinogenesis
- Initiation: change in DNA
- Promotion (of clonal expansion)
- Progression: changes cause/lead to metastasis
Direct vs. Indirect Carcinogens
Direct: Electrophilic compounds that react with DNA
Indirect: Metabolized before reacting with DNA
- Ex: Benzo-a-pyrene (tobacco smoke/coal tar): forms DNA adducts
Transforming Viruses cause Cancer
Viruses (10-20%)
Burkitt’s Lymphoma/EBV
Retroviruses (Viral Sarcoma)
- HIV indirectly causes Kaposi’s Sarcoma and Lymphoma
DNA Viruses
- HPV linked to cervical cancer
Bacterial Infections cause Cancer
Heliobacter pylori (Gram -, infects stomach and duodenum)
Oncogenesis Mechanism
Proto-oncogene activation/mutation
- Gain of function mutation
- Only 1 mutation needed
Tumor suppressor gene (caretaker) mutation
- Loss of Function
- 2 mutations needed on same chromosome
Activation of anti-apoptotic genes/loss of proapoptotic gene expression
Oncogene Activation Types
Deletion or Point mutation in coding sequence/Gene Sequence Mutation
- Hyperactive protein expressed/Constitutive Activation
Regulatory Sequence Mutation
- Increased Protein expression
Gene Amplification
- Increased protein expression
Chromosome Translocation
- Chimeric Gene product
- over-expression
Oncogenic Activation by chromosome Translocation
Translocation event leads to over-expression of proto-oncogene
- Burkitt Lymphoma = t(8;14)
- Follicular Lymphoma = t(14;18)
Translocation event creates fusion/chimeric gene
- Chronic Myeloid Leukemia (CML) = t(9;22) aka Philadelphia Chromosome
- Acute Promyelocytic Leukemia (APL) = t(15;17)
- Ewing Sarcoma = t(11;22)
Tumor Suppressor Genes
Gatekeepers (p53, Rb, Nf1)
- Cell Cycle control
- growth inhibition (contact inhibition)
- Pro-apoptotic factors
- Mutation = uncontrolled cell growth
Caretakers (BRCA1 and 2, Mismatch Repair Genes)
- DNA repair
- Genome Integrity
- Mutation = mutation accumulation
Knudson’s 2 Hit Hypothesis (Tumor suppressor genes)
If 2 mutated suppressor genes exist in a cell, tumor will begin
Somatic cells in a normal individual will be fine, while some rare cells will have one mutation.
A patient with an inherited susceptibility to cancer will have many/all somatic cells with one mutation; a second mutation will generate a tumor.
Sporadic vs. Inherited cancer (Knudson’s 2 hit model)
Inherited case: all cells carry one mutation, 2nd mutation from any of those cells will cause tumor
Sporadic case: all cells are normal, one cell must generate two mutations in order to cause tumor.
Mechanisms for “2nd Hit” (Knudson 2 hit model)
(Recheck/watch slide 99)
Genetic:
- gene inactivation due to accidental change of nuc sequence in DNA leads to many cells with inactivated gene
Epigenetic
- accident causes either packaging of DNA into heterochromatin or methylation of C nucleotides, which leads to many cells with inactivated gene
- accident can reduce chromatin condensation and activate genes that promote proliferation
miRNA in cancer
RNA-mediated inhibitition of target genes
- binds to a protein complex after being degraded, and will bind to any target mRNA with complementary sequence, preventing expression of that gene
Note: 100x expression of miR21 in glioblastoma
p53, Rb1, Nf1
p53
- DNA binding protein (TF)
- stop cell cycle and repair damage, or induce apoptosis
Rb1
- If Hypophosphorylated, cell cycle comes to a stop.
NF1 (RasGAP)
- Inactivates Ras proto-oncogene by increasing GTPase activity of Ras
Wnt signalling pathway (Effect on Beta Catenin)
- Wnt binds to Frizzled and activates Dishevelled
- Dishevelled inhibits gSK-3B/Axin/APC Complex (typically active except for in bottom of Colon Crypts)
- Beta Catenin nonphosphorylated, so not degraded (typically degraded because it is a proliferation promoting protein)
- Beta Catenin will then enter nucleus and bind to Tcf/Lef proteins, which in turn transcribe MYC and cyclin D genes
Telomeres
Specialized repetitive DNA sequences at ends of chromosomes: (TTAGGG)n
- protect ends of chromosomes and permit completion of chromosomal DNA replication (end replication problem solution)
- regulate integrity of chromosome during cell division as well as determine/enforce cell life span
- maintained by Telomerases (they renew the telomeres in germline, and cause immortalisation in cancer cells)
- grow shorter through life; if too short, cell death triggered
T-loop
Capping structure that protects the ends of chromosomes
- without T loop, p53 would observe ends of chromosomes as “breaks”, and would begin attempting repair or degradation of the chromosome.
Telomerase
Protein-mRNA complex that maintains telomeres.
- TERC: TElomerase RNA Component (mRNA template)
- TERT: TElomerase Reverse Transcriptase (protein)
(synthesizes telomere DNA from TERC)
Mechanism of Renewal
- Telomerase extends the existing parental telomere from its 3’ end (5’ to 3’)
- DNA polymerase elongates lagging strand (3’ to 5’)
Reactivation in Cancer (90%)
- Upregulates MYC (which upregulates telomerase)
Shortened/Lack of Telomeres
Shortening of Telomeres triggers cellular senescence (chromosomes become unstable if divided with too short telomeres); typically activates p53 cell-cycle arrest (which is usually followed by apoptosis)
- acts as a tumor suppressor mechanism
Lack of Telomeres
- end-capping structures absent leads to instability of chromosomes, which usually results in cell death but can also result in fusion events between chromosomes, which can also generate tumors.
