Neoplasia Part 2 Flashcards
what are the hallmarks of cancer? (8)
-Self-sufficiency in growth signals
-Insensitivity to growth inhibition
-Altered cellular metabolism
-Evasion of apoptosis
-Limitless replicative potential
-Sustained angiogenesis
-Ability to invade and metastasize
-Evasion of the immune system
what are the 2 enabling factors of cancer?
-Cancer-promoting inflammation
-Genomic instability resulting from defects in DNA repair
how are Oncogenes involved in cancer’s self-sufficient growth?
promote autonomous growth
how are Oncoproteins involved in cancer’s self-sufficient growth?
lack regulatory elements and don’t depend on external growth
what are the steps in normal cell proliferation, where if one is altered, irregular growth can be promoted? (5)
- Binding of growth factor to receptor
- Transient receptor activation leading to activation of signal transducing proteins on the inside of the membrane
- Transmission of the signal via 2nd messengers or signal transduction molecules to the nucleus
- Activation of nuclear regulatory factors that then initiate DNA transcription
- Progression in the cell cycle culminating in cell division
how does the signaling of growth factors normally act?
paracrine fashion
in cancer, how is growth factor signaling altered?
autocrine growth loop established
what growth factor is affected in glioblastomas?
PDGF
(platelet derived growth factor)
what growth factor is affected in sarcomas?
TGF-α
Tumor cells can activate ______ to produce growth factors
normal stromal cells
how can Growth Factor Receptors be affected in cancer and which is more common?
-Mutant receptors
-Receptor overexpression (more common)
what are 2 examples of specific Growth Factor Receptor overexpression and what specific cancers do they typically lead to?
-EGF receptor (ERBB1): epithelial H&N tumors (80-100%)
-HER2/NEU (ERBB2): breast cancers (30%)
how are HER2/NEU breast cancers treated?
with receptor antibodies –> Herceptin (which will attack and bind the receptor so no more growth factor is produced = tumor stops growing)
how can Signal Transducing Proteins be affected in cancers? what are 2 examples?
Mutation in the genes that couple receptors to their nuclear targets:
-RAS
-ABL
what is the most commonly mutated proto-oncogene growth factor receptor?
RAS
what type of enzyme does the ABL proto-oncogene code for?
Non-receptor associated tyrosine kinase
what type of cancer are mutations in the ABL proto-oncogene associated with?
Chronic myeloid leukemia (CML)
explain the pathophysiology of Chronic myeloid leukemia (CML) and the ABL proto-oncogene?
- t(9:22) creates BCR-ABL fusion protein with unregulated kinase activity
- RAS/RAF pathway activation
- MAPK
- transcription of MYC protein
- cell cycle progresses
(unregulated kinase activity = protein is constantly turned on even without more GF = constantly dividing)
how is Chronic myeloid leukemia (CML) treated?
inhibitor of BCR-ABL fusion kinase binds and disables the protein → Gleevec/imatinib
how can Nuclear Transcription Factors be affected in cancer?
Growth autonomy can occur from mutant genes that affect transcription
(promotion of growth by affecting cyclins (regulatory) OR CDK activation with repression of their inhibitors)
what are some genes that when mutated can act as Nuclear Transcription Factors to cause autonomous growth in cancer? (5)
MYC, MYB, JUN, FOS, REL
how does the MYC gene affect transcription and cause autonomous growth when mutated?
-activates cyclin-dependent kinases (CDKs)
-represses CDK inhibitors (CDKIs or CDKNs)
=TOTAL: promote growth by bypassing first checkpoint in growth cycle
what are the common Burkitt lymphoma translocations that affect the MYC Nuclear Transcription Factor and what Ig chain is involved?
t(8;14) = (MYC, Ig heavy chain)
[ALSO: t(2;8) = (kappa light chain, MYC) and
t(8;22) = (MYC, lambda light chain)]
what is a major histological identifier for Burkitt lymphoma?
“Starry Sky” Pattern –> a lot of fast growing lymphocytes = die fast = MACs come to eat dead cells
what do Tumor Suppressor Genes normally do?
Inhibit cell proliferation
what does a disruption in Tumor Suppressor Gene function lead to?
growth promotion
for Tumor Suppressor Genes disruption to lead to tumor development, what must occur?
Two mutations “hits” required –> to lose function, you have to lose both copies of the gene
what is a Tumor Suppressor Gene mutation that can cause a specific cancer and what is the cancer?
RB gene –> retinoblastoma (ocular malignancy)
(40% familial and 60% sporadic forms)
what does the RB gene (a Tumor Suppressor Gene) normally do? (3)
-Encodes a DNA-binding protein
-Enforces G1 to S phase transition where cells exit the cell cycle temporarily (quiescence) or permanently (senescence) to differentiate or die (via apoptosis)
-Binds transcription factors associated with cell differentiation (myocyte, macrophage, melanocyte etc.)
(i.e. stops cell from growing and tells it to differentiate)
what phosphorylation state is the RB gene (a Tumor Suppressor Gene) in when inhibiting growth? is anything bound to it?
-hypophosphorylated
-E2F is bound
=blocks growth
what phosphorylation state is the RB gene (a Tumor Suppressor Gene) in when promoting growth? is anything bound to it?
-hyperphosphorylated
-E2F unbinds
=cell growth
Why is RB not mutated in all cancers?
Other genes that control RB phosphorylation can mimic RB loss
what are ways other genes can control RB phosphorylation and mimic RB loss? (3)
-Cyclin D or CDK4 overexpression
-Inactivation of CDKIs (e.g. p16)
-Oncogenic DNA viruses (e.g. HPV) deactivate RB (deactivate NOT mutate)
a Central Theme of malignancy is that the loss of cell cycle control through one or more of what 4 key regulators is present in most human cancers?
p16, cyclin D, CDK4, RB
what does the TP53 gene normally do?
A central monitor of stress, the “guardian of the genome”, protects by:
-activates cell cycle arrest (quiescence)
-induces permanent cell cycle arrest (senescence)
-Triggers apoptosis (if repair fails)
how does the p53 protein normally appear?
-short half-life
-bound to the protein MDM2 which targets p53 for destruction
how does the p53 protein do under stress?
activates genes that arrest the cell cycle in G1 or G2 and induces DNA repair genes:
-If DNA damage is repaired→ Normal state
-If repair fails → induces apoptosis or senescence
How does p53 arrest the cell cycle?
causes transcription of CDKIs (p21) and other molecules which:
-inhibit cyclin/CDK complexes
-prevent phosphorylation of RB
how can altered p53 lead to cancer?
DNA damage –> p53-dependent genes not activated –> mutant cells go through cell cycle without repair –> malignancy
what is the Significance of p53 effects in cancers?
> 70% of human cancers have defects in
TP53 (gene):
-The rest have defects up or downstream of TP53 gene
how are RB and p53 similar in how viruses affect them? (These are proteins)
can be rendered non-
functional by DNA viruses (e.g. HPV, HBV)
describe what happens during the normal Adenomatous Polyposis Colicatenin (APC) Pathway.
Normally, APC helps degrade β-catenin (acts as a tumor suppressor gene) –> preventing its translocation to the nucleus and transcriptional activation of growth promoting genes (MYC gene and gene for cyclin D1)
what happens if APC is absent of not functioning?
β-catenin is not degraded –> goes to the nucleus and cell proliferation occurs
APC mutations are seen in what type of cancers?
colon cancers (70-80%)
when autophagy normally occur and what is it?
When nutrients are scarce, normal cells arrest growth and convert own organelles, proteins and membranes into energy
how do neoplastic cells use autophagy?
to remain dormant, making them resistant to
cancer treatment which attacks dividing cells.
____ genes can control autophagy and when function is lost, it can cause tumor formation.
tumor suppressor genes
What is the Warburg effect?
Cancer cells shift glucose metabolism away from mitochrondria to aerobic glycolysis and so glucose is partially broken down and used to produce lipids and nucleic acids so the cancer can divide faster
what 2 type of genes cause downstream effects that favor the Warburg effect of metabolism?
-Oncogenes
-loss of tumor suppressor genes
what is Oncometabolism?
Mutations in metabolic enzymes involved in the Krebs cycle lead to a new DNA methylation pattern which alters cancer gene expression –> Potential drug targets
what are the 2 pathways for Apoptosis?
-intrinsic (activates p53 response)
-extrinsic (T cell destruction of infected cell)