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