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)
what triggers the intrinsic pathway for Apoptosis? (3)
-stress
-cell injury
-radiation DNA damage
what are 2 anti-apoptotic genes?
BCL-2 and BCL-XL
what are 2 pro-apoptotic genes?
BAX and BAK
what happens when BAX and BAK are activated?
Intrinisic pathway: form holes in mitochondrial membrane, releasing cytochrome c → Activation of caspase 3 → Cell death
how is BCL-2 correlated to cancers and what type of cancers?
Follicular lymphomas (B-cell cancer of lymphocytes) (~85%):
-translocation t(14:18) of the Ig heavy chain (14) and the BCL-2 gene (18)
how do Follicular lymphomas (B-cell cancer of lymphocytes) grow and why?
Indolent (slow-growing) lymphoma due to reduced cell death (less apoptosis since BCL-2 is anti-apoptotic) and accumulation of B cells
why do normal cells die?
after 60-70 doublings, telomeres shorten leading to senescence
what happens normally if TP53 or RB function is lost?
formation of dicentric chromosomes (2 centromeres) = additional DNA breaks during next mitosis = genomic instability = cell death
(safeguard against survival of mutated cells)
what happens if TP53 or RB function is lost BUT telomerase is reactivated in these damaged cells?
immortality with extensive mutations and development of cancer
Tumors require _____ to enlarge beyond ~1-2mm
blood supply
how do tumors form a blood supply? (2)
New vessels sprout from existing vessels or are recruited from bone marrow
how does the formation of new vessels (Neovascularization) allow tumors to grow?
New endothelial cells promote tumor growth (i.e. secrete PDGF)
how does the formation of new vessels (Neovascularization) allow tumors to spread/metastasize?
New vessels are leaky which can promote metastasis of tumor cells
how is hypoxia related to Neovascularization?
↓O2 = hypoxia-induced factor 1 (HIF1α) activates transcription of vascular endothelial growth factor (VEGF)
what 4 things influence VEGF transcription?
-hypoxia –> HIF1α: activates transcription
-p53: inhibits growth/blocks transcription
-RAS –> MAP kinase pathway AND MYC: allow self-sufficient growth = cells can grow without blood supply?
clinically, _____ block VEGF activity and are used to treat multiple cancers
Angiogenesis inhibitors (i.e. bevacizumab)
what are the 2 phases of Invasion and Metastasis?
-Invasion of ECM and vascular dissemination (BVs and lymphatics)
-Homing of tumor cells (decide where they are headed to)
what are the steps of invasion of the ECM? (4 steps)
- Detachment of tumor cells from each other
- Degradation of basement membrane (BM)
- Attachment to novel ECM components
- Migration of tumor cells
what is the part of desmosome that attaches epithelial cells together?
E-cadherin
(“intercellular glue”, antigrowth properties)
E-cadherin function is lost in almost all of these types of cancer?
epithelial cancers
what does E-cadherin normally bind to, holding it in the cytoplasm?
β-catenin
what happens when E-cadherin is lost, that will stimulate growth?
β-catenin can translocate to the nucleus –> growth stimulated
The process whereby epithelial cancer cells obtain characteristics of connective tissue cells and invade
Epithelial to Mesenchymal Transition (EMT)
what normal molecules are affected in the Epithelial to Mesenchymal Transition (EMT)?
transcription factors (i.e. SNAIL, TWIST)
-downregulate E-cadherin
-upregulate intermediate filaments (i.e. vimentin, smooth muscle actin)
what happens during Basement Membrane (BM) Degradation?
Tumor cells secrete proteolytic enzymes or
induce stromal cells to elaborate proteases (e.g. Matrix metalloproteinases (MMPs))
how do MMPs regulate invasion? (2)
-remodel the BM
-cause release of growth factors from the extracellular matrix
In normal cells, if ______ which attach cells to BM are lost, apoptosis occurs.
integrins
T/F Cancer cells avoid apoptosis when integrins are lost due to other mutations
true
Cleavage of ____ and ____ opens binding sites for tumor cells when there is Altered Attachment to the ECM
collagen IV and laminin
T/F migration of tumor cells is a complex, multi-step process
true
what directs tumor cell locomotion?
tumor cell-derived cytokines (e.g. autocrine motility factors)
how do tumor cell-derived cytokines (e.g. autocrine motility factors) direct tumor cell locomotion?
Tumor cells signal stromal cells to release paracrine factors to promote movement.
how are most tumor cells found in the circulation?
alone
(detected in “liquid biopsies”)
what protects tumor cells in the blood from immune recognition?
Aggregation with platelets
Homing of tumor cells requires what? (2)
adhesion to vascular
endothelium and movement through BM
Many tumors metastasize to first capillary bed whereas others exhibit _____
organ tropism
Tumor cells are often inefficient at colonizing new sites such that “dormant” micrometastases may survive for long periods without progression. why is this a bad thing?
treatments target fast growing cells so these cells aren’t killed
Tumor cells secrete cytokines and growth factors which stimulate _____ cells to alter the environment allowing the tumor to _____
stromal cells
colonize
The immune system helps prevent tumor ____ or ____
formation or progression
T/F there is an ↑ frequency of cancer in immunocompromised hosts (congenital, transplant, AIDS)
true
what is the main immune defense against tumor formation?
Cell-mediated immunity
what cells are involved in the Cell-mediated immunity to fight against tumor formation?
-CTLs (CD8+ Cytotoxic T-lymphocytes)
-NK Cells
-Macrophages
these cells are the major immune defense mechanism against tumors
(including those caused by oncogenic viruses HPV, EBV)
CTLs (CD8+ Cytotoxic T-lymphocytes)
although there is no evidence for Humoral immunity/ protective anti-tumor antibodies to spontaneous tumors, how are antibodies used?
as some cancer treatments (therapeutic)
Tumor cells often express _____ that stimulate the host immune system to kill cancer cells
antigens
what are 2 examples of how tumor cells express antigens?
-Cancer cells transformed by oncogenic viruses (HPV, EBV) express viral proteins
-Unmutated proteins can elicit an immune response
Unmutated proteins can elicit an immune response. what is an example?
-Cancer-testis antigens: normally expressed only in germ cells in the testis. If expressed in other cell types (i.e. tumor) then the immune system reacts
what does an Effective Immune Response against cancer cells look like?
- Dead cancer cells release “danger signals”
that stimulate innate immune cells (phagocytes and antigen presenting cells)
- CTLs are activated to then kill surrounding
tumor cells
High levels of ____ and ____ in tumors correlates with better clinical outcomes
CTLs and Th1 cells
what are 3 ways that cancers can avoid the immune system?
-acquired mutations that prevent CTLS from recognizing the tumor cell as foreign
-Tumor cells express factors that actively suppress host immunity
-immune checkpoints bypassed
what are normal immune checkpoints?
inhibitory pathways that normally help maintain self-tolerance and control the immune response
how are immune checkpoints altered by tumor cells?
activated by the tumor cell to prevent immune response to tumor growth
what are 2 immune checkpoints that we know of that tumor cells can use to evade the immune system? how does each work
-PD-L1 (programmed cell death ligand 1): expressed on tumor cell surface = binds to PD-1 receptor on CTL = CTL loses ability to kill tumor cell
-CTLA4 receptor: expressed on CTL –> When bound, this inhibits T cell function
how can Checkpoint Inhibitors be used in cancer treatment?
Antibodies used to block checkpoints and thereby allow the immune system to kill tumor cells
there is a 10-30% response rate when using Checkpoint Inhibitors in what types of cancers>
a variety of solid tumors
(melanoma, lung cancer etc.)
T/F Checkpoint Inhibitors have Autoimmune adverse effects
true
this cancer treatment uses endogenous or synthetic substances to improve or restore immune system function to fight cancer
Immunotherapy
what are the different types of Immunotherapy? (5)
-Monoclonal antibodies (inhibitors of PD1, PDL-1,
CTLA-4)
-Non-specific immunotherapies (IFNα, IL-2)
-Oncolytic virus therapy
-T-cell therapy [chimeric antigen receptor (CAR) T
cells engineered to express antibodies on surface creating potent tumor cell killers)
-Cancer vaccines
what are the Monoclonal antibodies for cancer therapy that are approved by the FDA that we have to know? (5)
-Rituximab
-Herceptin
-Cetuximab
-Pembrolizumab
-Nivolumab
what does Rituximab target and what cancer is it indicated for?
-targets: CD20 (B-cell marker)
-cancer indication: B-NHL (lymphomas)
what does Herceptin target and what cancer is it indicated for?
-targets: HER2/neu
-cancer indication: Breast cancer
what does Cetuximab target and what cancer is it indicated for?
-targets: EGFR
-cancer indication: Head and neck squamous cell carcinomas
what 2 monoclonal antibodies are PD-1 antagonists?
-Pembrolizumab
-Nivolumab
what do Pembrolizumab and Nivolumab target and what cancer are they indicated for?
-targets: PD-1
-cancer indication: Melanoma
While typically protective, inflammatory cells can modify the tumor microenvironment so it promotes tumor progression. How? (2)
-Advanced tumors contain mainly M2 Macrophages = promote angiogenesis, fibroblast proliferation and collagen deposition (healing, repair, cell growth)
-WBCs secrete: GFs, proteases, VEGF, and TGF-β (from M2 Macs.)
WBCs secrete growth factors (i.e. EGF). how does this inflammation promote tumor progression?
causes cell proliferation
WBCs secrete proteases, how does this inflammation promote tumor progression?
-liberate growth factors from ECM
-degrade adhesion molecules
-foster invasion
WBCs secrete TGF-β (from M2 Macs.), how does this inflammation promote tumor progression?
suppresses CTLs
T/F Defects in DNA repair have ↓↓ risk for cancer and cause genomic stability.
false
Defects in DNA repair have ↑↑ risk for cancer and cause genomic instability.
what are 3 types of normal DNA repair and what do they do/fix?
-DNA mismatch repair (MMR): fixes single nucleotide mismatches
-Nucleotide excision repair: fixes DNA crosslinks (thymine dimers)
-Homologous Recombination Repair: repairs DNA strand breaks (normally in gametes only)
what syndrome is affected by defects in DNA mismatch repair (MMR) and what type of cancers can this lead to?
hereditary non-polyposis colon cancer (HNPCC) syndrome → colon cancer
repetitive DNA sequences (1-7bp) that are prone to replication errors which are repaired by normal MMR enzymes.
Microsatellites
how are Microsatellites affected when MMR enzyme function is lost?
begin to vary in number = microsatellite instability (MSI)
how is microsatellite instability (MSI) used clinically?
When detected, MSI is a marker of faulty DNA repair but by itself it does not seem to have any clinical effect
what disease is affected by defects in nucleotide excision repair and what type of cancers can this lead to?
xeroderma pigmentosum –> skin cancer
what diseases are affected by defects in homologous recombination repair and what type of cancers can this lead to? (2)
-Fanconi anemia –> bone marrow failure and more susceptible to cancer development (leukemia is common)
-BRCA1, BRCA2 –> mutations in these 2 tumor suppressor genes accounts for 80% of familial breast cancer
describe what is meant by Multi-step Carcinogenesis. give an example
-Cancer results from accumulation of multiple mutations, including genes that regulate apoptosis and senescence
-Example: Colon Carcinoma
