Week 7-8 Flashcards
CA + TSG
1
Q
Cancer (Overview)
A
- Loss of proliferation, differentiation; problems with signal transduction, cell cycle, DNA repair, GE; resembling tissues from malignant tumors (metastasis)
- Estimated: 1.73 mil diagnosis; 609K death)
2
Q
Benign vs Malignant (INVASIVENESS)
A
- Benign (Tumors): Innocuous, slow, well-organized+differentiated
- Malignant: loss of proliferation control –> tumor –> tissue damage and organ failure
3
Q
Cancer Causes (Enviornmental Carcinogen: DOSE-dependent)
A
- Pervical Pott: Chimney sweep + bath frq –> scrotum CA
2. Yamagiwa: coal tar chronic exposure –> benzo-a-pyrene –> mutation and CA
4
Q
Hallmarks
A
- Anti-Apoptosis and Pro-Proliferation
- Induced angiogenesis
- Replicative immortality
- Invasion + metastasis
- **Emerging: Deregulating cellular energetics/avoid immune destruction
- **Enabling: genome instability and tumor-promoting inflammation
5
Q
CA evolution: Multi-Step Tumorigenesis (Inherited, spontaneous and environmental mutations)
**REQUIRES DYSFUNCTION OF MULTIPLE PATHWAYS
A
- Proliferative cells: ESC, Tissue SC (HSC, crypt/skin SC); Transit amplifying cells (pluri without self-renewal); lymphocytes (mature B and T via antigen); melanocytes (UV)
- Ex. Germline mutation (APC @ 5q21)
> Methylation problems + APC B-catenin inactivation –> P-oncogene K-RAS mutation @ 12p12 –> homoz. loss of TSG and GoF of COX2 –> additional gross chromosomal alterations (telomerase)
6
Q
CA Evolution: Tumor Heterogeneity (Genetic and/or morphologic differentiation)
A
- Chemo doesn’t work on all; metastasis; selective growth advantage
- Darwinian Selection: Mal in heterogeneous population, and can be genetically identical
- IMPORTANT DUE TO:
> Inter-Tumor: dictates mis-regulated pathways –> therapeutic response
> Intra-Tumor: individual tumor response to therapy , resistance and relapse - **CAUSES:
Genetic diversity, epigenetic variation, Tumor microenvironment and identity of Cancer Initiating Cells
7
Q
Clonal Evolution of CA Cells (Genetic Variability)
A
- Succession = growth advantage
- Increased metastasis and chromosomal instability rates –> more clonal variability (parallel expansion, from any stem-like cells)
- Simple linear clonal succession and dynamic clonal diversification
8
Q
Oncogene (GoF)
A
- Over-expressed P-oncogene (extra copies of genetic material via chem/viral methods) –> mutations activated
>ex. Growth Factors (overproduction, no degradation; no signal transduction inhibitors like RAS/JAK2; TF overproduction like Myc; anti-apoptosis regulator overexpression like Bcl2; constantly activated tyrosine kinase likf ErbB)
9
Q
Tumor-Suppressor Gene (LoF of Rb and p53; Loss of heterozygosity)
A
- Genetic Ablation: KO via homologous recombo/CRISPR)
- RNAi to reduce abundance –> mutations inactivate
- Genetic and Epigenetic (DNA methylation): easier to correct
> Correction with Decitabine = inhibit DNA methyltransferase to reactivate GE of TSG - ex. BRCA for DNA repair and p53 for apoptosis signal
> p53 suppresses Bcl2 and activates pro-apoptotic proteins: AZACITIDINE (Decitabine as DNMT inhibitor) + Bcl2 inhibitor; VENTOCLAX (disrupt energy metabolism in leukemia SCs of AML)
10
Q
Proto-Oncogene: Retroviral hijacking and mutagenesis
A
- Retrovirus Transformation gets PO (C-ONC) in infection + PO mutations –> V-ONC integration repeats cycle
> ex. Activation of PO via Retrovirus LTR insertion (using active promoter/enhancer)
> ex. ALV provirus insertion near C-Myc (no transcriptional control –> Myc mRNA translation –> proliferation nonstop)
11
Q
PO Mutations
A
- Pancreatic K-RAS: Deletion; normal production of hyperactive protein
- Breast CA: Cyclin D1 (Regulatory mutation; overproduction)
- Similarly in bladder and colon CA
- Chromosomal Translocation –> strong enhancer to PO
> Myc in Burkitt’s Lymphoma t(8;14) via replacement of 5’ gene regulatory region of Myc with IgH for more transcription - Gene Amplification/Overproduction
> RAS (deregulated G-protein causes codon 12 point mutation from Gly to Val); Myc in 30% Neuroblastoma (Deregulated TF); ErbB2 in Breast CA (TK; ligand-indep)
> Trastuzumab (monoclonal Ab) against Her2/Neu/ErbB2 tyrosine kinase receptor –> blocks downstream signaling cascade
12
Q
*PO: oncogene generation via gene fusion (Chromosomal Translocation)
A
BCR-ABL in Chronic Myelogenous Leukemia (CML)
> Reciprocal: one with no consequence, other becomes Philadelphia/Hybrid
> Fusion to actively transcribed genes produces hyperactive ones –> 95% CML
> Treatment: Gleevec (Tyrosine Abl Kinase inhibitor) so no ATP to imatinib; side effects - oral sore/sensitivity, hair loss and anemia
13
Q
Extracellular Signal –> One Intracellular Signal Pathway
A
- Kinase-coupled receptors (transmembrane proteins; in cytosolic domain with intrinsic kinase activity)
- Phosphorylation activation (30% proteins, 520 kinases, 150 phosphatases)
> ex. Activated RTK phosphorylate themselves (cysteine-rich domain + EGF receptor; IG-like domain with PDGF and MCSF Receptors): ligand binding (independent firing) –> dimerization + kinase-domain cross-phosphorylation –> signaling complex along multiple pathways/mutated structures
> Overproduction of RTK: TK constantly active in mutant EGF receptor –> oncogene
14
Q
Knudson’s Two-Hit Hypothesis
A
- TSG may become non-functional only when BOTH ALLELES inactivated
> Overactivity: mutation enables oncogene –> cell transformation
> Underactivity: TSG and 2nd gene copy inactivation –> no TSG - ex. Retinoblastoma (Rb, Hereditary):
> Normal: no tumor
> a. Mutated (D): multiple tumors in both eyes (one inherited mutant and one good inactivated)
> b. Normal person with one tumor in one eye (one inactivation and one not)
15
Q
Loss of Heterozygosity (Both Inactivation)
A
- LOH/no expression of WT allele (pat/mat) and already-mutated other
- How to lose good copy of TSG:
> Nondisjunction (mitosis), chromosome loss + duplication (mit), mitotic recombination, gene conversion (HR), deletion and point mutation
