tumor biology
DESCRIPTION
Optional! Chapter 20 1205-1265. Cell biology 2014 (updated 18/2, 4/7 - 13 & 1/1 -14). Lecture 12:. Tumor biology. Cancer: latin word for crayfish. Will develop cancer. Will die of cancer. Cell Biology interactive media ”video” or ” interactive ”. Basic tumor nomenclature. - PowerPoint PPT PresentationTRANSCRIPT
Lecture 12:
Cancer: latin word for crayfish
Will develop cancer Will die of cancer
Optional!Chapter 201205-1265
1
Cell Biology interactive media ”video” or ”interactive”
Cell biology 2014 (updated 18/2, 4/7 -13 & 1/1 -14)
Basic tumor nomenclatureBenign tumor Malignant tumor = cancer
Metastasis forming cell(primary killer)
Carcinoma: derived from epithelial cells (90% of all cancers)
Sarcoma: derived from connective or muscle tissue
Leukemia: derived from hematopoietic cells (BM and blood)
Lymphoma: derived from lymphocytes (lymph nods) 2
Autonomouscancer cells
Old fasion view
Endothelial cells
A heterotypic cell biology viewImmune cells
Other cells
Non-autonomousheterogeneouscancer cells
Different views on cancer biology
In vitro propagated cell lines can only rarely be established from tumor biopsies tumor cells depends on their specific surrounding
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Tumor progression
A malignant tumor does not arise from a single genetic change;many changes are required to produce a life threatening cancer
Tumor progression is defined as the acquisition of permanent changes in characteristics of selected subpopulations of the tumor
Progenitors of the same clone, but still a heterogeneous tumor
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Definitions: oncogenes and tumor suppressors
Ras
p53Rb
An oncogene is a gene that when mutated, or overexpressed, contributes to converting a normal cell intoa tumor cell (constitutive activity dominant phenotype)
A tumor suppressor-gene is a gene whose loss, or inactivation, contributes to converting a normal cell into a tumor cell (recessive phenotype)
Bcl-2
CKI
point mutation overexpression
Inactivating point mutations or loss of the entire gene(germ line mutation in one allele and/or acquired somatic mutations) 5
The normal stability of the genome makescancer development statistically improbable
1. Microsatellite INstability (MIN): Point mutationsCommon causes: defective DNA mismatch repair genes
2. Chromosomal INstability (CIN): AneuploidyCommon causes: aberrant centrosome numbers
defective spindle regulatory proteinsdefective checkpoint control
3. Chromosome breaks and translocations Common causes: eroded telomeres
DNA breaks
Tumors acquire the capability to rapidly accumulate genetic changes by e.g., the following mechanisms:
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Common cause of gene loss and amplification
DNA strand break
DNA duplication
End fusion
Chromosome separation, novel breaks
Gene loss
Gene amplificationTelomereDNA break
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1. Self-sufficiency in proliferative signals
3. Evading cell death (apoptosis)
2. Insensitivity to anti-growth signals
4. Limitless replicative potential
5. Sustained angiogenesis
6. Metastasis capability
Make new blood vessel!
Adopted from Hanahan & Weinberg, Cell 2000
The six hallmarks of cancer – A cell biology perspective
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Tumor progression - molecular mechanisms• To be able to turn into a malignant tumor, each of the six hallmarks has to be fulfilled • This is done by changing the level/activity of various proteins
G1 G1
Only one protein per pathway needs to be changed!
For example, a single protein in a mitogenic signaling pathway:
Even if two tumors would belong to the same diagnostic group, they still have a unique combination of genetic alterations 9
myc myc
Cdk G1
Cdk S
Rb
DNAreplisome
ORCCdc6P
P DNAreplisome
Mcm
Mitogenic signaling (growth promoting signals)
E2F
Production of DNA replisome components
Production ofS cyclin
Initiation of replication
1. Self-sufficiency in proliferative signals Th
e re
tinob
last
oma
path
way
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1. Cell type specific mitogenic pathways
Cell type A Cell type B Cell type C
RTK Wnt Hedgehog
Cells from different tissues express distinct sets of growth factor receptors and signaling proteins
Alterationsin tumors: RTK signaling Wnt signaling Hedgehog signaling
Major mitogensignaling pathway:
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G1
myc
Ras
Raf
Erk
XGF Wnt
Dishevelled
b-catenin
G1 myc
Frizzled
G1 myc
RTK
Gli
Fused
Patched
Smoothened
Gli
SuFu
Hedgehog
GSK-3b AxinAPC
1. Aberrant proliferative signals in tumors 12
The
retin
obla
stom
a pa
thw
ay
Cdk G1
Cdk S
Rb
DNAreplisome ORC
Cdc6PP
p15Mitogen signaling
E2F
HPV E7
p21p16
2. Insensitivity to anti-growth signals
TGF-b
viral
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Survival factor signaling
Caspase 9 Caspase 3
Apoptosis
BH3only
Caspase 8
Adaptor
Deathreceptor
Ligand
BaxBcl-2
3. Evading cell death (apoptosis)
p53
Cyt. C
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PI-3 K
3. Survival factor signaling
P3 3
PTENP
PP
P
PKB/Akt
Bad
Apoptosis
elF4E
Cell growth
GPCR or RTK
or
+
G1
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Telomerase, usuallynot expressed insomatic cells
-GGGTTAGGGTTAGGGTTA
-CCCAATCC
5´
AUCCCAAU
G GG T T A
3´
3´5´
Complementarity due to therepetitive sequence
3´5´
Chromosome lackingtelomeres will trigger a p53 dependent cellcycle block
Telomeres: stretches of repetitive DNA at the chromosome ends that can form a protective loop structure
4. Limitless replicative potential
To maintain telomere length tumor cells can re-start expression of telomerase. An alternative mechanism employs enzymesthat are involved in DNA recombination 16
5. Sustained angiogenesis
Blood vessel
Endothelial cell< 100 mm
Too longDiffusion of O2 and nutrients
I am suffocating!Let’s express VEGF
Make new blood vessel!
VEGF: Vascular endothelialgrowth factor
17Anim. 23.7-angiogenesis
5. Vascular Endothelial Growth Factor - VEGF
VEGF gene
VEGFHIF-1
HIF-1Ub
UbUb
pVHL
Constitutively produced
in all tissues
…hypoxia (low O2)
Constitutively degraded via
pVHL, unless…
Proteosome
Ras
1.
2.
3.
4. Ras dependent signaling can increase expressionlevels of HIF-1
HIF-1: Hypoxia induced factorpVHL: von Hippel–Lindau syndrome (hereditary cancer) is caused by a germline mutation in the VHL gene
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5. Angiogenic factors affecting endothelial cellsActivators Inhibitors
VEGF Thrombospondin-1
Loss of p53 loss of angiogenisis inhibition
p53p53
Tumor with active p53
No angiogenesis
Tumor without active p53
Angiogenesis 19
5. Summary: regulation of angiogenesis
Thrombo-spondin-1VEGF
HIF-1 p53pVHL
Angiogenesis
Ras
Avastinä
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1.
2.3.
1.
2.3.
Loss of cell-cell adhesion
Loss of hemidesmosomes
Proteolytic degradation of the ECM
Metastasis, the ability of cancer cells to migrate, results frommultiple mutation events
4.
4. Migration through the ECM
40-120 nmBasal lamina
6. Metastasis capability
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Loss of E-cadherin is an important step in generating daughter tumors (metastasis) in carcinomas
6. Example of loss of cell-cell adhesion
Benign tumor Malignant tumor
Loss of E-cadherin decreased cell adhesion
Metastasis
Migration, resettlement and further proliferation
Tumor progression
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6. Penetration of basal lamina
Collagen IV fibril
Laminin
1.
2.
3.
1. 2. 3.
Loss of hemidesmosomes/laminin receptor (integrin)
Expression of collagenase
Cytoskeletal changes Epithelial–mesenchymal transition (EMT) 23
Reprogramming / de-differentiation of cells:
6. Making it through the connective tissue
Cell secretes proteases to clear a path through the ECM
Blo
od v
esse
l
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6. Sites of metastasis – blood flow
Tumor cell entering the blood system
Capillary of the lung
Lung metastasis
Capillary of the liver
Liver metastasis
Stomach or intestinal tumor cell entering the blood system
• Blood flow pattern determine the metastasis pattern in most case (~70%)
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6. Sites of metastasis – microenvironment
Capillary of the lung
No lung metastasisdue to non-
favorable ”climate”
• ”Seed-soil” pattern determine the metastasis pattern in other cases (~30%)
X X
Prostate tumor cell entering the blood system
Capillary of a bone
Adjacent bone cells produce specific factors needed fortumor cell growth
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Tumor progression: Familial adenomatous polyposis
X XX X
X X
X X
1.
2. 3.
4. 6.
5.X X
X X
1.
2.
3.
4.
6.5.
Self-sufficiency in proliferative signals Insensitivity to Anti-growth signalsEvading cell death Sustained angiogenesis
Metastasis capability
Limitless replicative potential
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Alberts et al. Fig. 20-46
Note dual action of APC: Hallmarks 1 & 6
By chance loss of the intact APC allele!
G1
Wnt
b-catenin
Self-sufficiency inproliferative signals
Chromosomal instability Metastasis capability
MMP7
AP
C
Step I. Starting point of familial adenomatous polyposis
APC
GSK-3b AxinAPC
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VEGF
Ras
Oncogenic mutation in RAS
G1
XGF
Self-sufficiency inproliferative signals
Sustained angiogenesis
p15
Smad 4
Insensitivity toanti-growth signals
Loss of SMAD4
TGF b-
Step II. Progression of colon carcinoma
Hallmarks 1, 2 & 5 29
p53
p21
Insensitivity toanti-growth signals
Loss of p53
Sustained angiogenesis
PUMA BaxThrombo-spondin-1
Aberrant/incomplete proliferation signals
DNA damage
Evading cell death
Bcl-2
Step III. Progression of colon carcinoma
Hallmarks 2, 3 & 5 30
AUCCCAAU
Limitless replicativepotential
Expression of telomerase Loss of E-CADHERIN
Metastasis capability
The End
Step IV. Progression of colon carcinoma
Hallmarks 4 & 6 31
Fulfilling the hallmarks of cancer in colon cancer
1. Self-sufficiency in proliferative signals
3. Evading cell death (apoptosis)
2. Insensitivity to anti-growth signals
4. Limitless replicative potential
5. Sustained angiogenesis
6. Metastasis capability
AUCCCAAU Telomerase
p53
p53
p53Smad 4
Ras
Ras
E cadherin
APC
APC
Fulfilling hallmarks 1 – 6 within a life time depends on genomic instability 32
Breast cancer in Sweden
• 6,623 new cases in 2002 (early onset)• Incidence/year ~115 per 100,000
Mortality/year ~ 35 per 100,000
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The TNM system for clinical staging
Tumor/ Node/ Metastasis:• T, clinical/mammographic
evaluation of tumor (0-4).• N, clinical evaluation of regional
lymph nodes (0-3).• M, distant metastases (0, 1).
• Stage 0: Tis N0 M0
Stage I: T1 N0 M0
Stage 2: T1-3 N1 M0
Stage 3: T1-4 N1-3 M0
Stage 4: T1-4 N1-3 M1 (is: in situ well encapsulated)
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Stage and prognosis
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Routine prognostic and predictive factors
• TNM (Tumor/Node/Metastasis)• Histologic type and grade (as judge by the
appearance under the microscope)• Molecular markers: Ki-67, estrogen and
progesteron receptors, and ERBB2 (EGF receptor).
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Decision tree: breast cancer treatment at NUST: clinical/mammographic evaluationN: regional lymph nodesM: distant metastases
Non-specificMix of cytostatic drugs, e.g., FEC (5-FU, epirubicin, cyklofosfamid)or SBG 2000-1 mixIrradiation therapy
SpecificTAM: Tamoxifen (anti-estrogen)A temporary cure!(3-60 (?) years)
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Future goals of (molecular) diagnostics
• Early detection• Accurate prognosis• Good prediction (of therapy response)• Reveal molecular therapy targets
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