Cancer Flashcards
Tumor
Lesions that occupy space and may or may not be an abnormal tissue mass (neoplasm)
Neoplasm
- abnormal tissue mass that results from dividing cells with abnormal gene regulation
- Benign or malignant
Cancer
Malignant neoplasm
Metastasis
Another cancer growth at a location different from the original neoplasm
What are the steps of cancer (in order)
1) Initiation
2) Promotion
3) Progression
Initiation (cancer)
- Genotoxic event (chemicals, radiation, viruses)
- Mutation of one or more genes controlling regulatory paths/sequence change
- undetectable
- Irreversible
- Can be the result of oncogene activation or suppression of tumor suppression genes
Promotion (cancer)
- Epigenetic event (gene activation/repression, leading to clonal expansion of certain gene)
- Enhancement of signal transduction pathways that indicate continuous growth
- Undeteceted
- Reversible in early stage (i.e. eating right/phys. activity)
Progression (cancer)
- Clastogenic event
- Continuous proliferation and change of the unstable karyotype
- Detected
Genotoxic event
Change in DNA sequence
Epigenetic event
Changes kin gene expression that are not the result of changes in the DNA sequence (i.e. DNA methylation and histone modification
Clastogenic event
- changes in karyotype brought on by mutation
- leads to rearrangement/deletion of genetic material, amplifications
Hallmarks of Cancer
1) Insensitive to growth suppression signals
2) Limitless reproductive potential
3) Promote inflammation
4) Can invade tissues, metastasize
Oncogenes
- Expression stimulates growth and cell division
- Regulation loss leads to extreme expression of these proteins
i.e Gas pedal on a car
Tumor Suppressors
- inhibit/check cell division
- Loss of reg leads to cell growth
i.e brakes on a car
Oncogene dominance
A single copy of the gene, rather than two, is necessary for growth training expression —- REAALLLLY BAD and why cancer sucks
Oncogene forms
1) Cellular proto-oncogenes (captured by retroviruses)
2) Virus-specific oncogenes (behave like cell proto-onco that are mutated)
3) Cellular porto-oncogenes that are mutated
What is a proto-oncogene
A normal gene that, when mutated, becomes and oncogene that can contribute to cancer
Viral Oncogenes Types
1) Transducing viruses
2) Non-transducing viruses
3) Non-transducing long-latency viruses
4) Retroviruses that contain a signaling envelope
Transducing viruses
Carries oncogene in retrovirus
Non-transducing viruses
oncogene activated by proviral insertion
Non-transducing long-latency viruses
Retrovirus protein that disrupts normal cell transcription regulation
Retroviruses that contain a signaling envelope
Viral envelop interacts with cell receptor, signaling proliferation
Main cellular proto-oncogenes
1) Ras (k-, N-, H-)
2) Myc (c-, L-)
Tumor suppressor genes (in carcinogenesis)
- Repress growth
- Recessive genes
- inactivating mutations, deletions, expression loss
Tumor suppressor genes (types)
- p53 (G1/G2 regulator)
- Rb
- p16^INK4A
Gene p16INK4A
- Tumor supressor gene
- Inactivated version on chromosome 9p21 very common in cancers
1) Gene mutation
2) Gene deletion
3) CpG Island Methylation
Rb
- Tumor suppression gene
- Inactivation, methylation and sequestration of Rb leads to Retinoblastoma, osteosarcoma
How many changes in the cell cycle lead to cancer?
MANY!!!
Tumor Microenvironment (and why it’s important/provides difficulties)
The tissue conditions where tumor live, which include normal/uncancerous cells (immune cells, fibroblasts, blood vessel cells), secretory factors and the extracellular matrix
- Proximity of other, noncancerous tissues MUST influence treatment decisions
- Fibrous growth around tumor (desmoplastic reaction)
- Can promote tumor progression and therapy resistance
Secretory Factors
Ezymes, signalling molecules (hormones), growth factors
Extracellular matrix
Fibrous proteins and proteoglycans that provide support in the multicellular environment
Three Goals of Cancer Treatment
1) Cure the Patient
2) Prolong life
3) Relieve symptoms (i.e. pain)
Types of Cancer Treatments
1) Surgery —————Cut it out
2) Radiation ————Zap it (DNA damage)
3) Chemotherapy —-Poison it (DNA damage)
4) Immunotherapy —Attack it (receptor-based)
KEY: DNA impact is usual target due to cancer being a proliferative thing
Radiation Treatment and cells most affected
- Uses energy to break DNA bonds
- Energy hydrolyzes water to create free radicals, which damage DNA
-Reproductive cells, cells with long dividing future, undifferentiated cells
Chemotherapy Agents (5)
1) Alkylating - denature macromolecules (DNA)
2) Intercalating - Cause structural change in DNA
3) Antimetabolites - Block synthesis of purine/pyrimidines (methotrexate)
4) Mitostatic - Inhibit tubular synthesis in mitosis
5) Platinum derivatives - Binds to DNA
Importance of cell death in cancer
1) Maximize cell killing (treatment)
2) In normal cell to prevent malignant transformation due to damage (preventative)
What is cancer cell death primarily a result of?
A cell cycle event due to activation of cell cycle checkpoints (i.e activation to induce death)
Mechanisms of Cell Death
1) Apoptosis
2) Necrosis
3) Autophagy
4) Mitotic Catastrophe
5) Senescence
Necrosis (and symptoms)
- Mechanism of cell death
- Membrane reptures, organelle segregate and cytoplasm swells, chromatin degrades, failure of physiological pathways, inflammation (guts spill out)
Necrosis mechanism (BIG PLAYERS
- Two Players
1) RIP-1
2) PARP-1
Apoptosis and symptoms
- Programmed cell death
- Characterized by:
- membrane blobbing (bulging, protruding), cytoplasm fragmentation, chromatin condensation and degradation via DNA cleavage
NO INFLAMMATION
Cell involved in Apoptosis
Hemapoetic cells and liquid tumors
Signals of Apoptosis
1) Membrane asymmetry lost
2) Phosphatidylserine exposed on cell surface
Apoptosis Mechanisms/Triggers
1) DNA Damage (ATM/P53)
2) Death Receptor Signalling (CD95, Fas Receptor – Caspase 8 mediated)
3) Cell Membranes — Sphyingomyelinase activation and it’s hydrolysis to ceramide (ceramics triggers apoptosis genes)
4) Mitochondrial Damage — ceramide mediated process (see step 3)
Apoptosis (Bax and Bak)
- Bax an Bak causes increased mito membrane permeability after being activated by BH3 (Bid, Bim, Bad, Noxa) via:
1) binding to anti-apoptotic Bcl-2 proteins (disabling it)
2) Binding directly to BH3 proteins causing it to open pores
Open pores release cytochrome c
Autophagy Symptoms
1) Membrane blebbing
2) Accumulation of two autophagic vacuoles in cytoplasm
3) Nucleus - partial chromatin condensation but no nuclear/DNA fragmentation
4) Increased lysosomal activity
NO inflammation
Autophagy mechanism
1) Beclin released from Bcl-2, forms Class III PI3K, which forms nucleation complex
2) Conjugation cascades elongates nucleation complex and creates limiting membrane
3) Limiting membrane forms around the cytosol targets and brings to lysosome
4) Lysosome destroys, nutrients released into the cell
Autophagy
- Self-eating
- Used to recycle cell products from the degradation of old proteins and organelles
- Survival mechanism in response to stress (Dan damage, pathogens, nutrient starvation)
Mitotic catastrophe
- Cell death caused by bad mitosis (deficiencies in cell cycle checkpoints)
i. e. abnormal CDK1/cyclin B activation — poor cycle transition
Mitotic catastrophe symptoms
1) no change in cell membrane
2) large cytoplasm
3) Micro- and multi nucleation, nuclear fragmentation
Mitotic catastrophe mechanisms
1) Cell cycle defects
- P53 (G2 checkpoint)
- BUB-kinase (spindle checkpoint)
- No spindle assembly
2) Hyperamplification of centrosomes
3) Caspase-2 Activation during metaphase (delayed apoptosis)
Fates of cells with aberrant mitosis
1) Mitotic death (die without exiting mitosis)
2) Delayed death (got to G1, keep dividing until death)
3) G1 arrest - senescence
Senescence
Permanent cell cycle arrest (usually due to cell damage)
Senescence symptoms
1) No change in membrane
2) Flattened cytoplasm w/ greater granularity
3) Nucleus has heterochromatic structure (tightly-packed)
Senescence mechanisms (Two pathways)
- All cells involved
- Inflammation cause by cell itself (secretory factors)
Paths (activated when telomeres are too short):
1) p53-p21 2) p16 -Rb
Predominant cause of cancer
Environmental factors, not mutations during cell division
p53
Guardian of the genome!!!
-Commonly inactivated protein that results in cancer
Functions:
1) Regulates gene expression
2) Facilitates DNA repair
3) Activates apoptosis of damaged cells
