Carcinogenesis Flashcards
Four classes of normal regulatory genes?
- Growth-promoting proto-oncogenes, 2. Growth-inhibiting tumor suppressor genes, 3. Genes that regulate programmed cell death (i.e.,
apoptosis) , 4. Genes involved in DNA repair
Considered dominant because mutation of a single allele
can lead to cellular transformation
Growth-promoting proto-oncogenes
Usually both normal alleles of tumor suppressor genes must be
damaged for transformation to occur.
Tumor suppressor genes
May act like proto-oncogenes (loss of one copy is
sufficient) or tumor suppressor genes (loss of both copies).
Genes that regulate apoptosis and DNA repair
needs growth factors to proliferate ?
Normal cell
How normal cell reacts to growth factors?
Growth factor (GF) binds to its receptor (GFR) – GFR activation results in several cytoplasmic signal
transduction molecules which transfers signals to nucleus – Activation of several nuclear regulatory factors that
initiates DNA transcription resulting in cell proliferation
have the capacity to proliferate without external stimuli, which usually occurs as a consequence of oncogene activation.
Tumors
Normal cellular genes whose products promote cell proliferation
Proto-oncogenes:
Mutant proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals.
Oncogenes
Oncogenes they can work at the level of?
1/Growth Factors, 2/Growth Factor receptors, 3/Cytoplasmic proteins involved in signaling, 4/ Nuclear regulatory proteins 5/ Cell
cycle regulators.
Examples of oncogenes?
AMPLIFICATION & OVEREXPRESSION / MUTATION
Examples of oncogenes,
AMPLIFICATION & OVEREXPRESSION / MUTATION
Examples of oncogenes/ AMPLIFICATION & OVEREXPRESSION ?
HER2
(growth factor receptor) in breast carcinoma
Examples of oncogene/ MUTATION?
EGFR (epidermal growth factor receptor)
mutation in lung adenocarcinoma resulting in constitutional
activation of receptor
encode proteins that inhibit cellular proliferation by
regulating the cell cycle. ?
Tumor suppressor
which code for proteins involved in regulating the
cell cycle, repairing damaged DNA or, if the DNA is damaged beyond repair,
inducing programmed cell death ( apoptosis ) ?
Tumor suppressor genes
Failure of tumor suppressor gene function leads to?
failure of growth inhibition which is characteristic of tumors
Governor of the Cell Cycle
?
RB Gene:
exerts anti proliferative effects by controlling the G1- to-S
transition of the cell cycle ?
Rb
Almost all cancers have a disabled G1checkpoint due to
?
mutation of RB genes
Guardian of the Genome?
TP53 Gene
central monitor of stress in the cell • Can be activated by DNA damage.
p53 protein
controls the expression and activity of genes involved
in cell cycle arrest, DNA repair, cellular senescence, and apoptosis. ?
Activated p53
Eg of Tumor suppressor genes?
RB Gene/ TP53 Gene
functions to prevent
propagation of malignant cells by stimulation of apoptosis and
cell cycle arrest in affected cells
?
P53
Exposure to carcinogens and mutagens in normal cells (normal
53) results in?
DNA damage by stimulation of apoptosis or cell
cycle arrest to allow DNA repair.
Exposure to carcinogens and mutagens in cells with mutant
non functioning 53 results?
expansion of affected cells
Evasion of Cell Death
The balance between pro-apoptotic (e.g., BAX,
BAK) and anti-apoptotic molecules (BCL2, BCL-XL).
• In 85% of follicular B cell lymphomas, the anti-apoptotic gene
BCL2 is activated by the t(14;18) translocation.
Normal cells after certain numbers of divisions reach?
terminally
non-dividing (replicative senescence)
How cells count number of divisions?
Unknown but possibly by shortening of “telomeres” at the end
of each chromosome, which when shortened beyond certain
point leads to stimulation of P53-dependent cell cycle arrest
Germ cells?
Dividing
They have enzyme (telomerase) leads to cell’s sustained
ability to replicate
Cancer cells replication by?
By acquiring telomerase activity (detected in over
90% of tumors), this gives the malignant cell a stem-cell like features
caused by defects in DNA mismatch repair genes
?
Familial colon carcinoma as well as endometrial and ovarian
carcinoma
process through which new blood vessels form from
pre-existing vessels
Angiogenesis
produced by
tumor cells is the main growth factor responsible for Angiogenesis?
Vascular Endothelial Growth Factor [VEGF]
Ability to invade tissues, occurs in four steps: ?
- Loosening of cell–cell contacts :
- Degradation of ECM,
- Attachment to novel ECM components,
- Migration of tumor cells.
Cell–cell contacts are lost by the inactivation of
E-cadherin
Basement membrane and interstitial matrix degradation is
mediated by?
proteolytic enzymes secreted by tumor cells and
stromal cells.
Migration/motility of tumor cells by ?
tumor-derived cytokines”
motility factor”.
Patients with HNPCC syndrome (Hereditary Non-Polyposis
Colorectal Cancer) have defects in?
mismatch repair system, leading to development of carcinomas of the colon.
Patients with xeroderma pigmentosum :increased risk for the
development of cancers of the?
skin exposed to UV light.
process which results in the transformation of normal cell
to neoplastic cell by causing genetic alterations and cumulative
genetic defects
Carcinogenesis
is an agent that participates in causing the tumor, its
ultimate site of action is mainly DNA
?
Carcinogen
causing hepatocellular carcinma ?
HBV
causing lung cancer
?
Tobacco
Over a period of time, many tumors become more
aggressive and acquire greater malignant potential & less
responsive to therapy ?
tumor progression
Carcinogens types?
1) Chemical Carcinogens (2) Radiation Carcinogens (3) Microbial Carcinogens
Chemicals?
ALKYLATING AGENTS / ACYLATING/AROMATIC AMINES, AMIDES, AZO DYES /Chemotherapy drugs (e.g., alkylating agents) : leukemia.
Chemotherapy drugs (e.g., alkylating agents) : leukemia. ?
Chemicals carcinogen
Therapeutic irradiation of the head and neck can give rise to ?
thyroid cancers years later.
Skin cancers (melanomas, squamous cell carcinomas, and
basal cell carcinomas). • Fair skinned people. • Melanomas are associated with intense intermittent
exposure, as occurs with sunbathing
From?
UV radiation
human papilloma virus (HPV),
/ HBV ?
2.Oncogenic DNA Viruses e
3.Helicobacter pylori, is implicated in the?
genesis of both gastric
adenocarcinomas and gastric lymphomas.
