Transcript 30 doublings

The Biology of Cancer
December 12, 2006
Cancer: A Cellular Disease
Principles of Cellular Growth
• Ability to produce exact replica
– essential component of life
• Normal cellular regulation
– Balance between division and death (apoptosis)
– Limits on proliferation
• Physical boundaries (e.g. basement membrane)
• Tissue pressure  contact inhibition
– Cell cycle regulation
• Error correction
– Lack of fidelity in cellular reproduction  genetic
instability
– Repair genes
– Immune mechanisms: removal of non-self cells
– Apoptosis
G0: Rest phase
G2:
Preparation
for Mitosis
Functional phases
Preparatory phases
M phase:
G1:
Preparation
for Synthesis
Cell Cycle Check Points
• Events of cell cycle highly ordered:
– different extra cellular/intracellular events
• Progression through cell cycle controlled by:
– regulation of gene products
– checkpoints genes
Normal cellular stop signals
• Cellular hypoxia (outgrowth of blood supply)
• Decreased availability of nutrients
• Alternation in cytokine/hormonal milieu
• Accumulation in toxic metabolites
• Inhibitition of cell-cell contact
Cancel: Cellular Derangements
• In-exact replica
– Genetic instability
– Loss of certain function, gain of others
• Abnormal cellular regulation: Loss of Balance
–
–
–
–
Enhanced proliferation
Disruption of Physical boundaries
Increased tissue pressure, loss of contact inhibition
Inhibition of apoptosis (programmed cell death)
• Loss of error correction
–
–
–
–
–
Lack of fidelity in cellular reproduction  genetic instability
Loss of Repair genes
Immune inhibition (anergy)
Inhibition of apoptosis
Selective advantage certain clones
Cell Cycle
Extra cellular Signals
• Complex regulation and division not in a vacuum
• Cell integrate signals into control mechanisms:
– Nutrient status
– Cell to cell contact
– Extra cellular peptides
• Growth factors cause cells in G0 phase through cell cycle
• Continued growth factor exposure
• Cytokines:
–
–
–
–
soluble mediators of cell to cell communication
interleukins, interferon, CSF
bind to receptors on surface of cells
cascade of biochemical signals activation/suppressing of genes
CARCINOGENESIS
Summary of the carcinogenic process.
Invasiveness
Initiation
Promotion
Progression
Metastasis
(eg Vogelstein model for colon cancer)
Normal
adenoma I
adenoma II
APC gene
Chr 5q
Ras
mutation
transformation
to hyperproliferation
proliferation
signal left on
adenoma III
DCC gene
8q21 allelic loss
carcinoma
P53
Chr 17p
tumour suppressor loss of tumour
involved in
suppressor and
differentiation
apoptosis
Causes of Cancer
Factor or Class of Factors
Percent of all
Cancer Deaths
Tobacco
30%
Diet
35%
Reproductive and sexual behaviour
7%
Occupation
4%
Alcohol
3%
Pollution
2%
Geophysical factors
3%
Industrial products
1%
Medicines and medical procedures
1%
Inherited
<5%
Life-cycle
• 1cm3 -> 1g tumor ( 109) cells
– 1 cm the limit of clinical detection
– 30 doublings occurred prior to clinical detection
• Only 10 more doublings (3 logs)
– 1kg of tumor
– terminal disease
• Pre-clinical phase 75% of “life of tumor”
Death: 1 kg
10 doublings
CT or U/S: 1 cm
30
doublings
Single cell
Cellular proliferation of tumors
• Heterogeneous as a result of:
– variability in blood supply/nutrients
– Clonal variation
Clonal Selection
• Increased volume as a result:
– Increased division
– Decreased death
Principles of Metastases
• Principle cause of death
• Mainly routes of dissemination:
– via blood steam
– lymphatic
• Are flow and organ specific
• Establishment of metastases is inefficient:
– subpopulation/clone have the abilities to metastases
– generally most malignant/aggressive
Steps in Metastatic Cascade
• Escape
• Travel through the blood/lymphatic system
• Arrest/attachment
• Establishment of clone
Metastases: Escape
• May be biologically facilitated by:
– ability to commit vascular invasion
– cell necrosis
– molecules of the cell surface
– protease ( enzyme) secretion by tumor
Metastases: Travel
• Blood supply ( angiogenesis) must be adequate
• Adequate lymphatic drainage
• Special circulatory circumstances
Angiogenesis
• Concept first put forward by Folkman
• Tumour produces factors to induce / generate its
own blood supply
• VEGF one of the most important mediators
• Interacts with endothelial cell receptors :
– VEGFR-1 and VEGFR-2
• Essential for normal embryonic vasculogenesis
• VEGF upregulated in many cancer types
Growth factors
eg TGFb, estrogen
Collagenases
ras Growth factors
receptors
CDK’seg EGFR, eRBb2
Angiogenic
factors
Eg VEGF
Cancer
Promotion
Autocrine promotion
Eg. contact
inhibition
Chemotherapy
Principles of Chemotherapy
• Exponential relationship between dose and
kill
– small decrease in drug dose results in large
increase in cell survival
• Cycling cells at greatest risk
• Multiple courses of therapy
– each treatment kills same proportion
(not number) of cells
– e.g.: 3 log killed 1010 to 107
1 log regrowth between cycles
Mechanisms of resistance
• Tumor sanctuaries
• Drug exposure/Selection pressure
– chemotherapeutic agents selects for resistant cells
• Resistance within a tumor a function of:
– inherent genetic instability of a tumor
– size of tumor ( # cells) Goldie-Coldman hypothesis
(chance resistance a size)
Stop
Block
Turn
Stop
growth
off
new
the
Stimulate
Chemotherapy
destruction
of
blood
renegade
factor
vessel
immune
barriers
“grow”
receptors
formation
signal
system
•Herceptin
•Endostatin
•Farnesyl
•Matrix
•Interferon
transferase
metalloproteinase
•Rituxan
•Angiostatin
•MoAb’s
inhibitors
inhibitors
•Tamoxifen
•COX2
inhibitors
Blood supply as the Target
VEGF
X
e.g. bevacizumab / Avastin®
X
Cell
membrane
Tyrosine
Kinase
VEGFR - 2
VEGF
trap
X
X
Signal Transduction
Blood supply as target:
Bevacizumab in colon cancer
Generalized Staging Principles: TNM
• Stage I
– Organ confinement
• Stage II
– Locally advanced / larger / penetration
• Stage III
– Nodal involvement
• Stage IV
– Metastatic
Look for: Molecular staging elements
Lymph Nodes
• Prognosticator
– E.g. colon N0  25% recurrence
(less than 4 negative nodes  50%)
N1 (1-3 nodes)  60% recurrence
N2 (4+ nodes)  70% recurrence
• Source of disease
– Axillary dissection as a therapeutic intervention
– TME
• Techniques for analysis
– Toluene fat dissolving techniques (yield)
– Immunohistochemistry for cytokeratins
• The sentinel node
– Extensive focused analysis
Pattern Recognition
• Colon
–
–
–
–
Mesenteric nodes
Drains through portal vein: first stop liver
Of those stage IV, 90 have liver mets, 70 only liver
Other sites peritoneal, nodes > lung >> [bone/brain]
• Lung
– Mediastinal nodes
– Pleural effusions
– Lung, Liver, adrenal, bone, brain
• Breast
– Axillary nodes
– Lung, liver, bone, brain
• Kidney or Melanoma  anywhere!
Unknown primary
• Peritoneal + ovarian masses
– Ovarian, PPC, Stomach, colon
• Axillary nodes
– Breast, lymphoma
• Brain metastases
– Lung, breast>> kidney..
• Bone metastases
– “Buy The Kid Long Pants”
The curable metastasis
• Surgery Colon cancer
– 35% 5yOS after complete resection of liver, lung or
splenic metastases
• Chemotherapy for testicular cancer or lymphoma
Thank-you for your attention!