MM 21-23 Cancer Flashcards
Steps in Cell replication
G1, S, G2, Mitosis
Generally, what are the external signals (cues) that determine a cell’s outcome (4)?
Death cues, survival cues, proliferation cues, growth inhibition cues.
Which external cues turned on/off result in a cancer cell?
Growth inhibition cues off
Growth proliferation cues on
Cell death cues off
Survival cues on
Growth factors
Growth factors are extracellular proteins or steroid hormones that bind to cell surface and transmit intracellular signaling to stimulate cell growth by encouraging the synthesis of proteins/macromolecules and by inhibiting their destruction.
Usually a steroid hormone (estrogen) that binds to a membrane receptor, activating a kinase, which turns on turns on transcription factors, thereby increasing mRNA production and stimulating cell growth.
Survival factors
Promote cell survival by suppressing apoptosis.
Mitogens
Mitogens stimulate cell division by disrupting the intracellular controls that block cell cycle progress. CDK
CDK complexes
Cyclin dependent Kinase (CDK) binds with cyclin, forming a CDK complex, which is partially activated. Full activation occurs upon phosphorylation by CDK activating kinase.
Being a Kinase complex, CDK complex stimulates cell cycle by phosphorylating. For example, it may phosphorylate Retinoblastoma protein (a tumor suppressor), thereby discouraging suppression and encouraging growth.
Extracellular signals that regulate cell proliferation and death
Growth factors, survival factors, mitogens.
Cell cycle checkpoints
The standard cell cycle is regulated by brakes at the middle and end of G1, beginning of S and end of G2. Regulatory subunits are cyclins.
Cyclins
Cyclins are regulatory subunits that allow cell the cell cycle to pass through checkpoint. (mid and late G1, beginning of S, end of G2). Cyclin levels fluctuate at different stages of the cell cycle, as determined by regulatory signals.
They are subunits that activate CDK complex by substrate binding.
Retinoblastoma protein
The retinoblastoma protein (pRb) is a tumor suppressor protein that inhibits E2f (a transcription factor). If a cell is ready to divide, pRb is phosphorylated by CDK complex and becomes inactive, which allows E2f to continue cell cycle progression. pRb prevents excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. Cancer can result should this mechanism get disturbed. Eg, overactivity or upregulation of of CDK4 or cyclin D1.
G0 phase
A cell can enter G0 phase, during which it is mature and continues to perform its function but does not replicate.
p53
p53 is a key tumor suppressor. DNA damage sensors launch a signal cascade that activate p53 by phosphorylation. p53 then goes on to induct p21, which then inhibits the phosphorylation of pRB by CDK complex. The phosphorylation of pRB inactivates it, thereby allowing pRB to stimulate cell proliferate. In other words, p53, in response to damaged DNA, acts to stop the cell cycle.
If cell damage is not repaired, p53 levels remain high, and cell undergoes apoptosis.
Driver mutation.
50% of cancers have a p53 mutation.
Extrinsic Apoptosis
Cells receive signals from neighboring cells to commit suicide. Signals bind to Death-inducing Cell Surface Receptor Signaling Complex (DISC), leading to activation of Initiator Caspase 8, which has downstream affects on cell function that result in DNA fragmentation and apoptosis.
Intrinsic apoptosis
The absence of survival and growth factors initiates apoptosis, as do mitochondrial malfunctions, infections, radiation, etc.
p53 level increase in response to damage or non-inhibition. They make the outer mitochondrial membrane permeable to Cytochrome C, which is released into the cytosol. Cytochrome C binds to Apoptotic protease activating factor (Apaf1), forming a complex that then binds to initiator cascade 9, forming an Apoptosome.
The Apoptosome (Cyt C, Apaf1, and cascade 9) activates other caspases and induces DNA fragmentation and apoptosis.
Caspase
Caspases are a family of protease enzymes that play an essential roles in programmed cell death. They are activated by internal/intrinsic (cytochrome C) and external/extrinsic (Death Receptors) cues.
When bound, Death Receptors activate Initiator caspase 8. Intrinsic Cytochrome C activates initiator caspase 9. They both then go on the activate the ‘executioner’ caspases that cause DNA fragmentation.
Benign vs Malignant
Benign tumors are localized growth that expands and displaces local tissue.
Malignant tumors are capable of metastasis by destroying tissues in which they infiltrate.
Carcinoma
Arise from epithelial cells. 90% of cancers.
Sarcoma
Develop from cells of the mesoderm, including bone, and muscle. Rare.
Clonal Evolution model of tumor growth
Mutant tumor cells with a growth advantage are selected and expanded. Each successive mutation provides an additional growth advantage.
Cancer Stem Cell model of tumor growth
A rare subset of tumor cells that that have the ability to self-renew and generate diverse tumor cells. The other daughter cells do not maintain the tumor.
Proto-oncogenes
Normal gene activity promotes cell proliferation. Normally they are intracellular signal transduction receptors that bind to growth factors. They stimulate transcription factors.
Oncogenes are the mutated type, and have a gain of function. A single mutated allele may cause cancer.
Eg. CDK
Tumor supressor genes
A class of mutation that may cause cancer. Normal gene activity is to inhibit cell proliferation or promote apoptosis. Both alleles must be inactivated (haploinsufficieny), causing failure of checkpoints and cell death mechanisms. Mutations can be gene amplification, SNP, del/ins, chromosomal rearrangement.
Eg. p53, pRB, BRCA1,
Care taker genes
A class of mutation that may cause cancer. Normal genes insure accurate replication and repair of DNA. Mutations result in genomic instability and further mutations.
Eg. Mlh
6 biological hallmarks of cancer
Sustaining proliferative signaling Evading growth suppressors Activating invasion and metastasis Enabling Replicative immortality Inducing angiogenesis Resisting cell death
4 Emerging biological hallmarks of cancer
Resisting immune destruction
Tumor promoting inflammation
Genome instability and further mutation
Deregulating cellular energetics
Retinoblastoma
A rare childhood cancer of the eye that involves the silencing of tumor suppressor gene for Rb, which normally adheres to E2F (a transcription factor) to control progression of cell cycle.
Examples of Tumor Suppressor genes
Rb
P53
BRCA1
APC
