Cancer Cell Biology Jacqueline Morgan MD Oct 7th, 2015
Cancer Cell Biology
Jacqueline Morgan MD
Oct 7th, 2015
Cell Cycle• M phase- Active cell
division• G1 phase- Protein & RNA
synthesis, normal cellular activites
• S phase- DNA replication• G2 phase- Short pre-
mitotic phase with double the DNA content
• Post mitosis cells can– Differentiate– Rest (G0 phase)- can
return to cell cycle– Die
Cancer Cell Biology
All the fun of regular cell biology, but with disrupted:
Proliferation
Apoptosis
Invasion
Metastases
Angiogenesis
Cell Kinetics
Healthy tissues
Cell division
Cell loss
Terminal differentiation
Tumor cell kinetics
Actual cell division occurs over same amount of time
Growth unregulated due to either:-
Increased growth factor signalling (Oncogenes)
or
Loss of normal checkpoint or apoptosis mechanisms (Tumor Suppressor)
Cell Kinetics• 3 levels of cell proliferation in normal tissues
– Static
– Expanding
– Renewing
Static
• Rarely divide after embryonic period• Well differentiated
– Neurons– Striated muscle cells– Oocytes
• Expanding
– Retain potential to divide when stimulated– Are normally quiescent
HepatocytesVascular endothelium
• Renewing
– Constantly proliferating cells
– Bone marrow– GI tract– Epidermis
Doubling Time• Time for tumor to double in size• Varies by tumor type 20-150 days
• 1mm tumor- 20 doublings• 5mm tumor- 27 doublings• 1 cm tumor- 30 doublings• 8cm tumor- 33 doublings
Gompertzian Growth• As tumors grow, the time to double tumor
volume increases• Concurrent exponential tumor growth and
exponential growth retardation
Cell Kinetics• Cell cycle- Approx. 24 hours
– (0.5 to 5 days) for most tumor cells– Not significantly different to non tumor cells
• But tumor mass doubling times approx. 20 – 150 days
• Only portion of tumor cells entering cell cycle at one time
• Tumor growth rate determined by:– Growth Fraction
• Fraction of cells undergoing division• Varies widely, 25-95%
– Cell death• Decreased in tumors relative to normal cells
Cell Cycle• M phase- Active cell
division• G1 phase- Protein & RNA
synthesis, normal cellular activites
• S phase- DNA replication• G2 phase- Short pre-
mitotic phase with double the DNA content
• Post mitosis cells can– Differentiate– Rest (G0 phase)- can
return to cell cycle– Die
Multi-hit hypothesis3-6 genetic alterations required to result in a malignant cell
May be
Inherited
or
Exogenous carcinogen
or
Endogenous cell process
Just another reason getting older sucks- more time to accrue more mutations
Inherited
eg. BRCA, Lynch
Typically Tumor suppressor genes
Born with propensity for tumor development
Earlier onset of cancer than non- gene mutation carriers
Incomplete penetrance
Exogenous Factors
UV Radiation
p53
Tobacco products
K-ras
Viral
HPV
Endogenous DNA damage
Spontaneous errors in DNA synthesis (1:1,000,000)
Free radical damage
Methylation
Oncogenes
Stimulate tumor growth by gene:-
Amplification
Mutation
Translocation (new promoter controlling gene)
Oncogenes
Growth Factors
VEGF
Receptor tyrosine kinases/Growth factor receptors
HER-2/neu, EGFR, c-kit
G protein signaling
ras
Nuclear transcription factors
Myc
Tumor Suppressor Genes
Loss of both copies typically required
Nuclear
Rb gene
p53
Extranuclear
PTEN
APC
TGF-B
Retinoblastoma Gene
Nuclear tumor suppressor
Holds cell in G1 arrest
Works along with cyclin dependant kinases inc. p16
Leiomyosarcoma
Retinoblastoma
p53
Tumor suppressor gene
Regulates both cell proliferation and apoptosis
Hold cells in G1 arrest (cell proliferation effect) until appropriate
Stimulates apoptosis in event of genetic damage that is not repaired.
Missense mutation results in ineffective protein that is resistant to degradation, so see an overexpression of p53 in tumors on IHC
PTEN
Extranuclear tumor suppressor
Opposes tyrosine kinases with dephosphorylation
Alters cytoskeleton
And then the cancer spreads...
Loss of Adhesion
Cadherins
Destabilising surrounding stroma
MMPs Matrix metalloproteinases
Migration
Cell surface integrins and IGF-2
Neovascularization
VEGf
Endometrial Cancer Type 1
Endometrioid
Low grade
Early stage
Arise from hyperplasia/EIN
Unopposed estrogen exposure
Endometrial Cancer Type I
Hereditary
5-10% Lynch (MSH2, MLH1, MSH6, PMS)
DNA Mismatch repair mutation
Sporadic Oncogenes
KRas G protein mutation
Tumor Suppressor Genes
PTEN phosphatase mutation - most common
MLH1 promoter methylation
Endometrial Cancer Type II
Non endometrioid
High grade
Advanced stage
Poor prognosis
Endometrial Cancer Type II
Sporadic Oncogenes
HER2-Neu
Over expression of tyrosine kinase
Tumor Suppressor Genes
p53
Mutated p53 protein is overexpressed, cell cycle arrest is impaired
Uterine Sarcomas
Rb gene
Nuclear tumor suppressor gene
Ovarian Cancer
Hereditary
BRCA 1&2 DS DNA repair
MLH1, MSH2, MSH6, PMS DNA mismatch repair
Ovarian Cancer
Sporadic Oncogenes
HER2-neu Tyrosine kinase
K-ras - G protien Serous borderline tumors
Ovarian Cancer
Tumor Suppressor Genes
p53 Transcription factor
p16 cyclin dependant kinase inhibitor
BRCA promoter methylation
Cervical Cancer
HPV
Early proteins
E6 and E7
HPV DNA integrated into host DNA or episomal
E6 binds to and inactivates p53 tumor suppressor gene
E7 binds to and inactivates Rb tumor suppressor gene
c-myc- Transcription factor, early mutation
Kras- G protein, late mutation
GTN
Mutation of p53 gene
Loss of Rb tumor suppressor
Overexpression of tyrosine kinases and EGFR
Hereditary
Maternal underexpression of p57 (Chromosome 19)
Recurrent molar gestation
More prone to GTN