Carcinogenesis Flashcards
Hallmarks of cancer
- Cancer arise from mutations that are somatic in origin or through inheritance.
- Acquire six hallmarks to evolve to a neoplastic state
1. Self sufficient growth signals
2. Insensitivity to antigrowth
3. Evasion of apoptosis
4. Limitless replication potential
5. Tissue evasion and metastasis
6. Sustained angiogenesis - Two new hallmarks
1. Reprogramming energy metabolism
2. Evading immune destruction
Self Sufficiency in growth signals
Cancer cell can activate mitogenic signaling pathways independently of normal physiologic signals. This activates mutations, autocrine and paracrine signaling
Insensitivity to antigroth signals
- Cell produces agonist/inhibitos of growth and development signals
- TGF beta which sends anti proliferative signals is mutated and prevent cell restriction
- Cell lose function of TGFb or smads which promotes cell proliferation.
Evasion of Apoptosis
- Loss of function in pro apoptotic signals or over expression of anti apoptotic signals
1. disruption of BCL2 family balance
2. Increased expression of IAPs
3. Reduce expression of caspases
4. defects/ mutation in P53
Limitless Replicative Potential
- Cancer cells re-express telomerase in differentiated tissue
- this increase in recombination generates novel chromosomes
- Tumor cells shows aneuploidy abnormal number of chromosomes.
Sustained Angiogenesis
- Tumor cells can stimulate new blood vessel formation to deliver oxygen, nutrients, GF, and survival factors
- Tumor cells rely on glycolysis rather than the krebbs cycle for energy.
- Tumor cells, immune cells and ECM can produce angiogenic signals
VEGF
vascular endothelial growth-factor is produced in response to hypoxia induced transcription (HIF1) and aids in angiogenesis.
Tissue invasion and Metastasis
Alteration in cell surface markers and in ECM structure by using cadherins and intergrins
Cadherins
Calcium dependent adhesion is often mutated in cancer
Integrins
Cell surface protein that tranduce info about the extracellular environment and plays role inadhesion to the basement membrane
Benign tumor
Small localized and cell adhesion molecules hold tissues together
Malignant tumor
Grow and divide rapidly and invade nearby tissues.
The mutator Hypothesis
An early event in all cancer must be one that increase endogenous mutation rate allowing accumulaton of required genetic changes (genome instability).
Genome Instability
Shift between DNA damage and DNA repair. Facilitates the accumulation of mutations
Process effecting genome instability
- Defective mismatch repair
- DNA polymerase
- Recombination
- Double Strand Repair
- Nucleotide Metabolism Genes
- Amplification
- Chromosomal Segragation
Defects in mitotic checkpoints
-weakened mitotic checkpoints might allow one daughter cell to have both copies of one chromosome (aneuploid)
Cohesion defects
if sister chromatid cohesion is lost prematurely, the chromosomes will be mis-segregated.
Merotelic Attachment
Two spindle fibers bind to one kinetochore and leave one chromatid out. the lagging chromatid would be misegrageted or left out of both daugher cells during cytokinesis,
Multipolar mitotic division
Cells possess more than two centrosomes might form due to multiple spindle poles during mitosis resulting in aneuploid cells.
Deletion
Loss of all or parts of a CHR
Duplication
A segment of CHR is repeated
Inversion
Part of the CHR is oriented in the reverse of its normal orientation.
Translocation
Part of one CHR breaks off and attach to another non homologous CHR
Breakage fusion bridge cycle
SSDNA break is converted to an unstable CHR
Microsatellite Instability (MIN)
Microsatellites are repeptitive DNA sequences with repeating 1-7 base pairs.
- Prone to replication errors which is repaired by the MMR (mismatch repair) protein. if MMR is impairred the microsatellite become unstable
- MSI is a marker for faulty DNA repair and cancer arise when faulty DNA repairs leads to mutations in tumor suppressors or oncogenes.
Cancer Stem Cell Theory
Tumors contain a small amount of stem cells that are tumorigenic. Other tumor cells are differentiated and non tumorigenic. So therapy should target stem cell to be curative.
Origin of Cancer Stem Cells
Cancer stem cells arose from normal stem cells. Oncogenic mutations in differentiated tissues can casue cells to undergo de-differentiation and turning on self renewal genes.
Prevalence o stem cells
What % of stem cells retain prolifferative properties?
relative prevalence of stem cells would alter the therapeutic considerations.
Stage of Carcinogenesis: Initiation (I)
Initial change in chemical carcinogenesis are usually irreversible genetic damage.
- Epigenetic changes ( influencing function of cell without altering the DNA base pairs) act as an early event in carcinogenesis. This include
1. DNA methylation of promoter regions of genes will transcriptionally silence tumor suppressor genes
2. Carcinogen DNA adduct formation is central to theories of chemical carcinogenesis.
Stage of Carcinogenesis: Promotion (II)
Tumor promotion is the growth stimulation of an initiated tumor. Tumor promoters are not able to initiate tumor formation but they will sustain them once formed.
-Tumors overexpress COX 2 to stimulate carcinogenesis, growth and cell migration
Stage of Carcinogenesis: Transformation (III)
- Malignant conversion of preneoplastic cell to a neoplastic cell.
- stimulated by DNA damagin agents
- Mutations in cadherins allow epithelial cells to invade stromal cells.
- EMT (epithelial to mesenchymal transition) is a key component in transformation. tumor cells need it in order to enter the blood stream.
Stage of Carcinogenesis: Progression (IV)
- Comprises the expression of the malignant phenotype
- Prominent characteristics of malignant phenotype is genomic instability.
- May involve metastasis
Mutations in tumor suppressor genes
- Increase growth factors
- Decrease apoptosis
- Decrease cell cycle arrest
Mutations in protooncogenes
- Increase angiogenesis
- Increase invasion
- Increase metastasis
