Neoplasia Flashcards
Epidemiology
Men vs. Women
Men
30% Prostate
Women
31% Breast
Lung and bronchus
Colon and rectum
The risk of cáncer from environmental causes is found to be
65%
The principal targets for genetic damage:
Prooncogens (RAS)
Tumor supressor genes (TP53, Rb)
Genes that regulate apoptosis
Six hallmarks of cancer
- Evading apoptosis
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Tissue invasión and metástasis
- Limitless replicative potential
- Sustained angiogénesis
Tell me about RAS
Activated RAS recruits RAF-1 and stimulates the MAP-kinase pathway to transmit growth-promoting signals to the nucleus. The mutant RAS protein is permanently activated because of inability to hydrolyze GTP, leading to continous stimulation
Cáncer asociado: Colon, vejiga
Tell me about the Retinablastoma Protein
Regulates G1 -> S
P = inactivated -> S
Activated RB prevents cell replication by binding to E2F family transcription factors
GF > higher D, 4, 6, E, 2 > P of Rb
Tell me about TGF
Growth factor inhibitor
Arrest cell cycle at G1
Tell me about theADENOMATOUS POLYPOSIS COLI-B-CATENIN PATHWAY
In resting cells (not exposed to WNT) B-catenin forms a macromolecular complex containing the APC protein. This complex leads to the destrucción of catenin B.
When cells are stimulated by secreted WNT molecules, the destrucción complex is deactivated, B-catenin degradation does not occur. B-catenin translocates to the nucleus where it binds to TcF, a transcription factor that activates several genes involved in the cell cycle. (Cyclin D1 and MYC)
Tell me about the TP53 gene
Antiproliferative efects
Regulates apoptosis
TP53 + MDM2 -> destrucción of TP53
Stressed cell -> TP53 is released from MDM2 and is activated as a transcription factor.
Activated TP53 induces the transcription of genes that cause cell cycle arrest, and those that cause apoptosis. (BAX)
Arrest by p21. -> prevents the P of RB -> no pass g1-> s
If DNA damage is repaired TP53 upregulates transcription of MDM2
If DNA damage cannot be repaired -> apoptosis
TP53 = guardian of the genome
Hypoxia activates TP53
How does FAs evade apoptosis?
FAS L (CD95L) + FAS (CD95)
->FADD + caspase 8 -> a Caspase 3 -> cell death
caspase 8 upregulates BID
How does tumor cells prevent apoptosis?
- Loss of TP53 -> reduced CD95
- High levels of FLIP (binds death-inducing signals, and prevent a C8)
- Overexpression of BCL2
- Loss of APAF-1 -> blocking the mitochondrial-cytochrome c pathway
The metastatic cascade
- Clonal expansion, growth, diversification, angiogenesis
- Metastatic subclone
- Adhesion to and invasion of basement membrane
- Passage through extracellular matrix
- Intravasation
- Interaction with host lymphoid cells
- Tumor cell embolus
- Adhesion to basement membrane
- Metastatic deposit
- Angiogenesis
- Growth
Invasion of extracellular matrix
- Detachment of tumor cells from each other
- Loosening of intercellular junctions (cadherins) - Attachment of tumor cells to matrix components
- laminin and fibronectin receptors - Degradation of ECM
Type IV collagenase and plasminogen activator - Migration of tumor cells
MAYOR CHEMICAL CARCINOGENS
Direct-acting carcinogens Alkylating agents: anticancer drugs Acylating agents: 1-acetyl-imidazole, Dimethylcarbamyl chloride Procarcinogens that require metabolic activation Aromatic hydrocarbons Aromatic amines, amides, azo dyes Natural plant and microbial products: aflatoxin B1, Griseofulvin, Betel nuts Others - nitrosamine and amides - Vinyl chloride, nickel, chromium - Insectides, fungicides - Polychlorinated bihenyls (PCBs) - Arsenic - Asbestos
VIRAL AND MICROBIAL ONCOGENESIS
RNA ONCOGENIC VIRUSES - Human T-cell leukemia virus type 1 DNA ONCOGENIC VIRUSES - HPV - Epstein-Barr virus (EBV) - Human herpesvirus 8 (HHV-8) - HBV
