Flashcards in MM 21-23 Cancer Deck (72):
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 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.
Promote cell survival by suppressing apoptosis.
Mitogens stimulate cell division by disrupting the intracellular controls that block cell cycle progress. CDK
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 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.
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.
A cell can enter G0 phase, during which it is mature and continues to perform its function but does not replicate.
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.
50% of cancers have a p53 mutation.
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.
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.
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.
Arise from epithelial cells. 90% of cancers.
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.
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.
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.
6 biological hallmarks of cancer
Sustaining proliferative signaling
Evading growth suppressors
Activating invasion and metastasis
Enabling Replicative immortality
Resisting cell death
4 Emerging biological hallmarks of cancer
Resisting immune destruction
Tumor promoting inflammation
Genome instability and further mutation
Deregulating cellular energetics
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
Some different functions of proto-oncogenes
Mitogens (Cellular signal transducers)
An oncogene (mutated proto-oncogene) whose snp mutation promotes excessive signaling of transcription factors of genes that promote division and inhibit growth.
In off state, Ras is bound to GDT. Active when bound to GTP.
EGF + EGFR -> Activated by EGFR tyrosine kinase residues + GRB2 + SOS + Ras + GTP-> RAF -> MET
20-30% of cancers have a ras oncogene.
EGFR, type of cancer gene and mutation
Epidermal Growth Factor Receptor (EGFR) normally requires cell surface bonding, after which it uses phosphorylation to spark the translation of proteins involved in mitosis.
The oncogenic is due to deletion mutation that causes the receptor to not require EGF binding, and so it is therefore active without being signaled.
MYCN, type of cancer gene and mutation
MYCN is a oncogenic transcription factor mutated by gene amplification in neuroblastoma.
Alters expression of hundreds of genes. Poor prognosis. But identifying it is important for therapeutic intervention.
CML, type of cancer gene and mutation
Chronic myeloid leukemia (CML) is an oncogene caused by translocation of 9-22, creating Philadelphia Chromosome. The translocation causes the fusion of genes which make an otherwise untranscribed section of DNA transcriptionally active. Permanently turns on (constitutive) a tyrosine kinase receptor.
Telomerase and cancer
Telomeres help prevent chromosomes from attack by nucleases. Repeated TTAGGG sequences. Shortens after each replication. Most cells, after telomeres get too short, cannot survive or undergo apoptosis. Highly replicative cancer cells, however, recruit telomerase to rebuild telomeres, allowing for infinite replication. Anti-telomerase therapies of being studied for cancer therapy.
Primary tumor cells spread via blood, lymph, or body cavities. It is difficult for metastasized cells to survive, but it only takes one. Large tumors have higher chance of metastasis but it can also occur before the tumor is detectable.
Seed and soil theory of metastasis
Tumor-host interaction is critical for successful metastasis. The primary tumor (seed) travels at random but only takes root in tissue that is environmentally suitable (soil).
Mechanistic theory of metastasis
The first site of metastasis is one in which there are small blood vessels.
Factors that assist metastasis (3)
Suitable tissue conditions
Accessible blood supply
Steps required for metastasis
Cancer must disrupt and degrade the cell to cell interactions of the extra cellular matrix. Then it invades and migrates through stroma (connective tissue). It then intravasates (invades) a blood or lymph vessel, travels, and extravasates, migrating again through tissue until it finds a suitable environment to proliferate. Once a certain secondary population is built, angiogenesis can occur.
How does a cancer cell invade and migrate through tissue?
Cells are attached together my adhesion molecules (integrins). Invading cancer cells must degrade the cell-cell attachments and then bust through any connective tissues (storma) by proteolysis. It then uses motility factors to migrate.
Angiogenesis in cancer cells
Vasculature is critical to supply nutrients and oxygen to growing cancer cells. Blood supply also allows for metastasis to spread further.
Tumor cell secrets angiogenic factors (VEGF) that make vessels permeable and break down of cell-cell adhesion (integrins). Vascular endothelial cells migrate through interstitial space towards tissue. Lumen is firmed and endothelial cells fuse, followed by the initiation of blood flow. Tumor growth can then thrive.
Note: Angiogenic vascular in tumor cells differs from healthy cells in that they are much more leaky, tortuous, and worse for drug delivery.
Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates angiogenesis. It also Increases endothelial permeability. Secreted in excess by tumor cells.
A growing field of tumor therapy. Expression is increased by cytokines, hypoxia, and growth factors. Regulated by p53 , VHL, and other tumor suppressors.
Autocrine and paracrine signaling
Audocrine: Signals that target sites on the same cell.
Paracrine: Signals that target neighbor cells.
Epidermal Growth Factor receptor (EGFR)
A group os tyrosine kinase receptors. In the same family as HER2. The EGFR is essential for ductal development of the mammary glands,
Ligand binding to extracellular domain on cause autophosphorylation of internal tyrosine kinase residues. Downstream signaling proteins initiate several signal cascades, principally the (MAPK and RTK), leading to DNA synthesis and cell proliferation. Such proteins modulate phenotypes such as cell migration, adhesion, and proliferation.
Upregulation of Cyclin D4 in mantle cell lymphoma
Expression of cyclin D4 is under control of IgH promoter. As a result of translocation, cyclin D4 is unregulated. Cyclin D4 binds to CDK4, which phosphorylated pRB, thereby inactivating it and allowing E2F proceed with cell proliferation.
Necrosis ve apoptosis
Necrosis occurs when a cell is damaged by external force, such as poison, toxin, starvation, lack of blood, etc. Usually effects surrounding cells too.
Apoptosis occurs to to internal cues. Effects single cells.
At which check point do pRB, CDK4, Cyclin D4, p53, p21, R2F act at?
Late G1, allowing/preventing DNA replication.
Cell is damaged, stressed, or triggered by signals to self destruct.
The cell shrinks and proteins are activated to degrade cellular components.
Enzymes break down the nuclease. And signals are sent to retrieve macrophages.
The cell breaks into many small pieces. Macrophages recognize and ingest the cell parts.
Death receptors (DRs) receive endogenous ligand, causing internal activation of cascade 8.
Internal signals trigger release of Cytochrome C from mitochondria, leading to the activation of caspase 9.
Both cascade 8 and 9 lead to activation of cascade 3,6,7 (execution proteins).
Note: The internal domain of death receptors and the release of cytochromes can both be activated by p53.
Signals from neighbor cells saying to stay alive. The absence of trophic signals may stimulate apoptosis.
A family of transmembrane receptors that activate caspase 8 and trigger apoptosis.
They include TNF (tissue necrosis factor), ApoL, and FasL.
Neoplasm is an abnormal growth of tissue, and, when it also forms a mass, is commonly referred to as a tumor. Malignant neoplasms are also simply known as cancers.
Ras point mutation
A Ras point mutation may lead to the prevention of Ras dephosphorylation, turning it on permanently.
Ras deletion mutation
A deletion mutation coding for the epidermal growth factor receptor (EGFR) may turn on the receptor permanently, leading to constant autophosphorylation of the tyrosine kinase domain. This leads to constant activation of Ras.
The Philadelphia chromosome is a translocation between chromosomes 22 and 9. The fusion section creates a gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is "always on", causing the cell to divide uncontrollably.
Common cause of leukemia cancer cells.
Vascular endothelial growth factor (VEGF)
Epidermal Growth Factor
Platelet Derived Growth Factor (PGDF)
Loss of tumor suppressors (p53, VHL)
Metastasized cells may lack oxygen. Stimulates angiogenesis.
Impairs drug delivery.
Selects for more resistant cells.
Platelet Factor 4
Tissue Inhibitor of Metalloproteinases (TIMP)
Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. Initiates transcription of VEGF, PGDF.
VHL (Von Hippel-Lindau)
VHL is a protein complex that degrades HIF1 (a transcriptional factor for VEGF and PGDF), thereby acting as an inhibitor of angiogenesis.
Colon cancer risk factors
Smoking, family history, poor diet, obesity, alcohol.
Signs of colorectal cancer
Weight loss, pencil stools, blood in stool, change of bowel patterns, anemia/fatigue, abdominal pain.
How does a cell become cancerous?
Normally requires severe (6-7) subsequent mutations, that occur over decades. Involves at least one oncogene and loss in several tumor suppressors.
TNM staging system
T - size of Tumor
N - if it has spread to lymph Nodes
M - if it has Metastasized
Colon cancer staging
Stage 1: Tumor is in inner wall only
Stage 2: Tumor is in muscle wall
Stage 3: Tumor has spread to nearby lymph
Stage 4: Tumor has metastasized (Advanced cancer)
Colonoscopy vs sigmoidoscopy
Colonoscopy examine entire length of colon, sigmoidoscopy examines only lower third.
Sessile vs pundulated
Sessile: tumor is bound to a stalk.
Pundulated: Tumor is bound to lumen surface.
What Gene is mutated in most all sporadic and inherited colon cancers
Adenomatous polyposis coli (APC) is a tumor suppressor gene that occurs in most colon cancers.
The protein made by the APC gene helps control how often a cell divides, how it attaches to other cells within a tissue, or whether a cell moves within or away from a tissue.
What gene is mutated in most familial inherited colon cancer?
FAP - familial adenomatosis polyposis.
One mutated allele is inherited, the other occurs spontaneously.
Disregulates Cyclin D1 and others.
Genes associated with predisposition to cancers
-Breast/ovarian: BRCA1, role in DNA repair
-Retinoblastoma: Rb, prevent excessive cell growth.
-Renal Cell Carcinoma: VHL (von Hippel-Lindau), a ubiquiton ligase that target proteins for degradation.
-Familial Melanoma: CDKN2A, involved in Rb pathway-cell cycle regulation.
All involve one inherited allele and another sporadic mutation.
Treatment for Colon Cancer
Stage 1-2: Laparoscopic surgery
Stage 3: Colectomy with adjuvant therapy (5-FU)
Stage 4: Colectomy or colostomy. Chemo and targeted therapies.