Carcinogenesis Flashcards
DNA mutation
critical step in carcinogenesis
elevated levels of 8-OH-G found in tumours
DNA damage linked to cancer initiation
ROS activation of signalling pathways
ROS activiation of AP-1 and NFkB lead to transcription of celllar growth genes
enzymatic oxidants (superoxide dismutase, CU, Zn-SOD, Mn-SOD), catalase, glutathione peroxidase) and non-enzymatic enzymes (vitamin C, E, caratenoids, thiol antioxidants (glutathione, thioredoxin and lipoic acid), flavonoids, selenium) are anti-carcenogenic
antioxidants interact with various regulatory factors, including Ref-1, NFKb and AP-1
three stage model and mechanism of carcinogenesis
healthy, precancerous, early cancerous state
different theories
disease of cell differentiation, or stem cell disease
cell of singular origin
two key mechanisms for the induction of cancer
increased DNA synthesis and mitosis by nongenotoxic carcinogens may induce mutations in dividing cells through misrepair. Mutations may then clonally expand form and initiated preneoplastic cell state to a neoplastic cell state
there is an equillibrium between cell proliferation and cell death. If damage to DNA is extensive, the cel dies via apoptosis
protein p53
a uclear factor, protects cells form tumourigenesis
during cell proliferation, p53 checks the integrity of the DNA
it triggers mechanisms that eliminate oxidazed DNA bases
when damage is too great, p53 triggers apoptosis
uncontrolled apoptosis can be harmful to an organism, leading to destruction of healthy cells
balance of p32 and bcl2
more than half of cancers have defects in upstream or downstream genes of p53 functions
carcinogenic process = imbalance between cell proliferation and cell death shifted towards cell proliferation
therefore, cancer = disease of homeostasis
Bcl2
the bcl family of protien is also involved in oxidatice processes and apoptosis but can lead to tumour growth as part of its innate function
Bcl2 is a protien expressed on the outer membrane surface of mitochondria in healthy cells
it contributes to neoplastic (canser cell expandsion) by preventing normal clel turnover caused by physiological cell death
the bcl2 family includes both death agonists (Bax) and death antagonits (bcl2 and bcl xL)
oncogens and tumour suppressor genes
genes whihc when activated (oncogens) or inactivated (tumour suppressor genes) contribute to the clonal expansion of an inititated stem cell
tumour cells wiuth activated oncogenes have dysfunctional GJIC (gap junnctional intercellular communicaiton)
therefore, activated oncogens and GJIC are functionally linked by the singlaling pathways affected by oncogenes
initiation promotion progression
model of carcinogenesis
multi-stage and mechanism hypothesis
now based on the oncogene/ tumour suppressor theory of carcinogenesis
ROS and the three stages of carcinogenesis
initiation involves an non-lethal mutation in DNA< producing an altered cell followed by at least one round of DNA synthesis to fix the damage (9-OH-G)
produced during initiation
Ros and the promotion stage
characterised by the clonal expandion of initiated cells by the induction of cell proliferation and /or inhibition of apoptosis
requires the cts presene of the tumour promotion stimulus, and therefore, it is a reversivle process
many tumour promoters have a strong inhibiting effect on cellular antioxidant defense systems such as SOD, catalase, glutathione etc..
high level of ox stress is cytotoxic to the cell and halts proliferation by inducing apoptosis or necrosis
low level of ox stress can stimulate the cell division in the promotion stage and thus stimulate promotion of tumour growth
thus, produciton of ROS during this stage of carcinogenesis is the main line of ROS related tumour promotion
phorbol myristate acetate PMA
note, tumour promoters are not themselves mutagenic or carcinogenic
however, they cause tumour formation after initiation
PMA is a natural product from croton oil
PMA uses protein kinase C as its specific membrane bound receptor
can be used to stimualate ROS production in mouse macrophage
progression, ROS
cellualr and molecular changes from the preneoplastic to the neoplastic state
irreversible and is characterised by accumulation of additional genetic damage, leading to the transition of the cell from benign to malignant
this stage is characterized by genetic instability and disruption of chromosome integrity
Angiogenesis in cancer
an important step in the growth of any tumour
new blood vessles to feed the malignant cells
