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Flashcards in Exam #4: Cancer Deck (40)
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What are the six acquired capabilities of cancer cells?

1) Self-sufficiency in growth signals (oncogenes)
2) Insensitivity to antigrowth signals (tumor suppressors)
3) Evading apoptosis (mutation apoptotic pathway)
4) Limitless Replicative Potential (Telomerase)
5) Sustained Angiogenesis
6) Tissue invasion & metastasis


Proto-oncogene vs. Oncogene

- Proto-oncogenes are genes associated with the control of cell division-- they promote growth
- A mutated proto-oncogene is an oncogene causing excessive growth
- Gain of function mutation
- Dominant
- Analogous to gas pedal stuck on


Tumor Suppressor Gene & Mutation

- Tumor suppressor genes normally inhibit growth
- Mutations inactivate the genes
- Recessive i.e. needs mutation in BOTH alleles
- Analogous to break failure


Caretaker Gene & Mutation

- Function to protect the integrity of the genome e.g. DNA repair enzymes
- Mutation causes increased accumulation of DNA damage



- Family of Epidermal Growth Factor Receptors (tyrosine kinase)
- Mutations convert into oncogene form
- Point mutation allows activation of receptor without ligand
- Generates Neu Oncoprotein
- Implicated in breast cancer



- Family of Epidermal Growth Factor Receptors (tyrosine kinase)
- Mutations convert into oncogene form
- Specifically, mutation deletes ligand binding domain
- Receptor is constitutively active without ligand
- Generates Erb1 Oncoprotein


Ras Mutations

- G-protein that is normally activated by Sos in the MAP kinase signaling cascade
- Mutations generate a form of Ras that is constitutively active
- Specifically, mutations occur at amino acid positions 12, 13, or 16 & favor GTP binding
- Dominant
- Cancers include pancreas, large intestine, biliary tract, & skin


Burkitt's Lymphoma

- B-cell cancer
- Caused by c-Myc rearrangement from chromosome 8 to 14
- c-Myc now near control elements for antibody heavy chain
- Continual production of high levels of Myc in B-cells


Two Hit Model

- 2 mutations required for tumorigenesis
- 1st mutation in germline (tumor suppressor) is inherited form parents & gives predisposition to cancer
- 2nd somatic mutation is spontaneously & necessary for tumorigenesis



- Malignancy of the retina seen in childhood
- Gene RB1 encodes Retinoblastoma protein, Rb, that normally inhibits cell cycle progression by binding E2F
- Hereditary vs. Sporadic
- Involved in numerous other cancers



- Normally unstable, stability increased by ATM/ATR phosphorylation
- Normal instability comes from association with Mdm2, which targets p53 for degradation
- Functions as homotetramer
- Encoded by TP53, most commonly mutated gene in cancer
- dominant negative mutations


Li-Fraumeni Syndrome

- Heritable condition conferring susceptibility to many forms of cancer
- Dominant inheritance
- Caused by mutant TP53 allele i.e. disabled p53 tetramer
- DNA Damage Repair severely limited
- Early onset tumors, many family members w/ tumors, multiple tumors in individual


HPV protein E6

- HPV is the most common cause of cervical cancer
- Viral protein E6 inhibits p53 by targeting for ubiquitination


HPV protein E7

- HPV is the most common cause of cervical cancer
- Viral protein E7 inhibits p53 by targeting for ubiquitination


Neurofibromatosis 1

- Characterized by cafe au lait spots i.e. multiple non-malignant peripheral nerve tumors
- Caused by a loss of function mutation of NF1 gene, which encodes for the protein, neurofibromin


NF1 gene & neurofibromin: normal function

- NF1 encodes for the protein neurofibromin
- Neurofibromin accelerated GTP hydrolysis by Ras
- Lack of NF1 gene prolongs Ras signaling



- Function in DNA repair by repairing ds-DNA breaks
- Also contribute to homologous recombination


Epigenetic Change

- any process that alters gene activity without changing the DNA sequence AND leads to modifications that can be transmitted to the cell's progeny


Breakage/Fusion/Bridge Cycle

- Loss of p53 function prevents cell cycle arrest & initiate cycle
- Lack of telomeres allows fusion of sister chromatids at mitosis
- Resulting chromosome doesn't separate at mitosis; rather, it breaks
- Cycle continues
- Ultimately cell should experience mitotic catastrophe and die



- Oxygen sensitive transcription factor
- Regulates the expression of VEGF, vascular endothelial growth factor


HIF-1aB Regulation

- Oxygen mediated
- Normoxia= HIF-1a is hydroxylated, ubiquitinated, & destoryed i.e. NO HIF-1B
- Hypoxia= HIF-1a not hydroxylated, pairs with HIF-1B, activates transcription factors for angiogenesis (VEGF)


Outline the steps of Metastasis

1) Invasion of Basement Membrane (E-Cadherin breakdown & Secretion of MMPs)
2) Passage through ECM (breakdown of collagen IV & laminin)
3) Intravasation & Immune System Avoidance
4) Adhesion to basement membrane
5) Extravastion
6) Metastatic Deposit
7) Angiogenesis
8) Growth


Familial Adenomatous Polyposis (FAP)

- Inherited condition where patients develop adenomatous polyps in colon (benign)
- Develops into colorectal adenocarcinoma without prophylactic colectomy
- Due to mutation of APC gene


APC & WNT signaling in FAP

- APC gene normally encodes tumor suppressor, APC, which also ensures correct attachment of microtubules to kinetochore
- APC down-regulates WNT
- Without APC, WNT simulates expression of cyclin D, Myc, & other growth promoting genes through B-Catenin


Familial Nonpolyposis colorectal carcinoma (HNPCC)

- Hereditary susceptibility to colon cancer
- Defective DNA mismatch repair from mutations in MSH2 or MLH1 genes
- Patient's inherit one defective allele, and get second later


Philadelphia Chromosome

- Reciprocal translocation between chromosomes 9 & 22
- Fuses BCR & ABL genes together
- ABL normally endcodes tyrosine kinase
- BCR-ABL tyrosine kinase is constitutively active
- Characteristic of Chronic Myelogenous Leukemia


Chronic Myeloid Leukemia

- Caused by BCR-ABL kinase action in hematopoietic cells of the bone marrow, causing expansion of white blood cells


Imatinib Mesylate

- Specific BCR-ABL kinase inhibitor
- Treatment for CML



- Monoclonal antibody that binds extracellular domain of HER2/Neu
- HER2/Neu expression is prominent in some breast cancers
- Trastuzumab has potent anti-tumor effects


Why do normal cells divide a certain number of times and then enter senescence?

- In somatic cells, telomerase (extends telomere) is not expressed in high quantity
- Therefore, with each division, the telomere shortens
- After ~70 divisions short telomeres are recognized as ds-DNA breaks, and p53 mediates cell cycle arrest