Lecture Glossary 1&2 Flashcards
Oncogenes
Mutant alleles of proto-oncogenes; involves gain of function
TSG
Tumor Suppressor Genes
Tumor Suppressor Gene Types
1 - Promoters; 2 - Caretaker Genes; mutations involve loss of function
Promoter mutation
leads to transformation by directly releasing the brakes on cellular proliferation (ie traditional tumor suppressors p53 and pRb)
Caretaker mutation
no longer able to ensure the integrity of the genome ie those involved in DNA repair; said to have a mutator phenotype
Hallmark 1
Sustaining poliferative signalling; Therapeutic approach: EGFR inhibitors
Oncogene products for proliferative signalling (5)
Growth factors; growth factor receptors; signal transduction proteins; nuclear regulatory proteins; cell cycle regulators
Oncogenic Growth Factors (2 ie)
platelet-derived growth factor (PDGF); transforming growth factor alpha (TGF-a)
Oncogenic Growth Factor Receptors (3 Tyrosine Kinase Receptors ie)
ERythroBlastic oncogene B ERBB1 (Epithelial Growth Factor Receptor EGFR); ERBB2 (Human Epidermal gf Receptor 2 HER2); Anaplastic Lymphoma Kinase ALK
Common 2nd Messenger Oncoproteins
RAS; RAF; Pl3K; MYC; D cyclins
Hallmark 2
Evading Growth Suppressors; insensitivity to anti-growth signals; Therapeutic approach: Cyclin-dependant kinase inhibitors
p53
Guardian of the Genome; accumulates and binds to damaged DNA; alt senescence; G1 arrest and succesful repair else apoptosis
pRb (protein); RB (gene) RetinoBlastoma
Governor of Proliferation (cell cycle); hypophosphorylated pRb blocks transcription; subject to cyclin D (eg) phosphorylation; loss of gene RB = loss of pRb
Hallmark 3
resisting cell death; evading apoptosis; Therapeutic approach: proapoptotic BH3 mimetics
apoptosis
apo=from + ptosis=falling; programmed cell death
Loss of p53
mutagenic pathway (Hallmark 2); reduced function of pro-apoptotic factors such as BAX (Hallmark 3); NHEJ pathway (Hallmark 4); loss of synthesis of thrombospondin-1 leading to loss of inhibition of angiogenesis (Hallmark 5)
Reduced egress of cytochrome c from mitochondria
upregulation of anti-apoptotic factors such as BCL2 BCL-XL MCL-1; loss of Apoptotic Peptidase Activating Factor 1 (APAF-1) which activates caspase 9
Upregulation of Inhibitors of ApoPtosis (IAP)
inhibit Caspase 9
Reduced CD95
receptor for FasL enabling Fas-Associated via Death Domain (FADD) leads to Death-induced signalling complex
Inactivation of Death-induced signalling complex
DISC leads to caspase 8
Hallmark 4
Limitless replicative potential; Therapeutic approach: Telomerase inhibitors
Immortality
acquired lesions that inactivate senescence signals and reactivate telomerase which together convey limitless replicative potential
Evasion of mitotic crisis
Non-Homologous End Joining pathway (NHEJ) after loss of p53 (evasion of senscence) leads to dicentric chromosomes leads to double-stranded breaks (DSB) without telomerase ends in mitotic catastrophe but with telomerase yields cancer
Cancer Stem Cells (CSC)
cells within a tumor that can self-renew and drive tumorigenesis; each renewal one daughter remains stem cell
Hallmark 5
Sustained angiogenesis; Therapeutic approach: inhibitors of VEGF signalling
angiogenesis
the formation of new blood vessels from pre-existing vessels
Angiogenic activation
RAS MYC and MAPK signalling upregulate Vascular Endothelial Growth Factor (VEGF) expression and stimulate angiogenesis
Hallmark 6
Tissue invasion and metastasis; Therapeutic approach: inhibitors of HGF/c-Met
EMT-MET
Epithelial-mesenchymal transition & reverse
mesenchyme
from mesos=middle + enkhuma=infusion; undifferentiated mesodermal cells that give rise to such structures as connective tissues & blood & lymphatics & bone and cartilage
Tissue Invasion
Tumor moves to neighbouring differentiated cells ie from epithelial to basement membrane
Intravasation
down regulation of adhesion molecules like E-cadherin enables tumorous cells to detach from primary tumor and enter blood stream
Extravasation
Tumorous cells leave blood stream and attach to distant arteriole
Micrometastasis
Tumor cell division begins in new location
Metastasis
Occurs when colonization takes and tumor angiogenesis promotes growth
matrix metalloproteases
a group of enzymes that in concert are responsible for the degradation of most extracellularmatrixproteins during organogenesis growth and normal tissue turnover
chemotaxis
movement of a cell in response to chemical signals
Metastatic process
Tumor and recruited stromal cells secrete proteolytic enzymes (eg metalloproteases & cathepsins) that degrade basement membranes and ECM & release growth factors and generate chemotactic and angiogenic fragments from cleavage of ECM glycoproteins
ECM
Extra Cellular Matrix
Hallmark 7
Avoiding Immune destruction; Therapeutic approach: Immune activating anti-CTLA4 mAb
Immune surveillance
the normal function of the immune system is to constantly scan the body for emerging malignant cells and destroy them
Cancer Immunoediting
The ability of tumors to change the immunogenic properties of cells that ultimately leads to the darwenian selection of subclones that are best able to avoid immune deletion
immune evasion mechnism 1
selective outgrowth of antigen-negative variants
immune evasion mechnism 2
Secretion of immuno-suppressive factors (TGF-ß galectins; sugar-rich lectin-like factor IL-10; prostaglandin E2; metabolites derived from tryptophan; VEGF)
immune evasion mechnism 3
Engaging normal immune regulation pathways that serve as checkpoints in immune response (ie upregulating PD-L1&2 cell surface proteins that active the Programmed Death-1 (PD-1) receptor on effector T cells and inhibit T cell activiaton)
immune evasion mechnism 4
Induction of regulatory T cells
Hallmark 8
altered tumor metabolism; Therapeutic approach: aerobic glycolysis inhibitors
Warburg effect
aerobic glycolysis
aerobic glycolysis benefit
provides rapidly dividing tumor with metabolic intermediates required for synthesis of cellular components (through PI3K/Akt pathway) not available through mitochondrial oxidative phosphorylation
VEGF
Vascular Endothelial Growth Factor
Ras
small GTP-binding protein when activated proceeds to stimulate cascade of protein kinases important in a myriad of growth factor responses
Myc
transcripton regulator of genes responsible for cell growth and proliferation
PI3K
Phosphotidyl Inositol 3 Kinase
Akt
Protein Kinase B
Autophagy
From auto=self + phagos=eating; 4 steps—vesicle nucleation; vesicle elongation (becomes autophagosome); autophagosome & lysosome docking and fusion (becomes autolysosome); vesicle breakdown and degradation
Autophagy progression
In early stages inhibits tumor formation; in late stages promotes tumor formation
Hallmark 9
Cancer-enabling inflammation; Therapeutic approach: selective anti-inflammatory drugs
Hallmark 10
Genomic Instability; Therapeutic approach: PARP inhibitors
Causes of Genomic Damage (5)
inherited germline mutations; environmental factors; loss of function in genome maintenance/repair; infections; intracellular DNA damage
Inherited Germline Mutation predispositions
Rb; p53; APC; CDKN2A; BRCA1&2
Carcinogenic Environmental Factors
Carcinogens; UV & other irradiation; chemotherapeutic agents
Genome Maintenance LoF targets
BRCA; XRCC; MSH; p53
BRCA
BReast CAncer gene
APC
Adenomatous Polyposis Coli; the APC protein is a negative regulator of ß-catenin concentrations and interacts with E-cadherin in cell adhesion
CDKN2a
Cyclin Dependant Kinase iNhibitor 2A; gene encodes at least two proteins responsible for cell cycle regulation
XRCC
X-ray Repair Cross Complementing; protein involved in DNA SS break repair
MSH
MutS Homolog; protein involved in DNA repair complex
Infectious causes of cancer
Viral: HPV–cervical cancer; Bacterial: H Pylori–stomach cancer
Carcinogenic Intracellular DNA damage
Spontaneous de-amination; Reactive Oxygen Species (ROS); replicative accidents (ie anaphase bridges)
Heriditary Cancers
Genomic instability and mutation primary event
Sporadic Cancers
Genetic instability and mutation secondary to sustained proliferative signalling OR evading growth suppressors; followed by resisting cell death
PARP
Poly (Adp-Ribose) Polymerase; a family of proteins involvedin DNA repair & genomic stability and programmed cell death
BH3
One of the members of the Bcl-2 Homology domain which only has an apoptotic role
CTLA4
Cytotoxic T-lymphocyte-Associated protein 4; a protein receptor functioning as immune checkpoint downregulating immune response
TNM
Tumor (0-4) indicates primary size; Nodes (lymph) (0-3) degree of spread to lymph nodes; Metastasis (0-1) has cancer spread to distant site
anaplasia
ana=backward + plasis= formation; cells with a loss of morphological characteristics and orientation
hyperplasia
hyper=over + plasis=formation; cell overgrowth
dysplasia
dys=bad + plasis=formation; abnormal growth or development ie enlarged nucleus; cytologically different
metaplasia
meta=beyond + plasis=formation; one type of normal cell is replaced by a cell of another type not normally present at the site; ‘invaders’ appear normal; ie squamous cells replaced by secretory cells
adenomas
pedunculated polyps (pre-invsive stalk like growths) in the colon
Tumor progression
Normal –> hyperplastic –> dysplastic –> neoplastic –>
