Download cell cycle, stem-cell, cancer stem-cell

basic overview of
cancer
cell cycle, stem-cell, cancer stem-cell
Monday, January 30, 2012
• useful refs:
• harvey lodish Molecular Cell Biology
• robert weinberg Biology of Cancer
• useful weblinks:
• http://mydsn.org/docs-tools/BIO240/
Chapter-11.ppt
• http://www.hugo-international.org/resources/
Isik_Yulug_Molecular_Basis_of_cancer.ppt
Monday, January 30, 2012
hallmarks of cancer
Monday, January 30, 2012
Fig. 25-1:
Six characteristics of metastatic (malignant) tumor cells
Benign tumor cells
Necessary for continued
are not metastatic.
proliferation.
Blood supply
necessary for
the tumor to grow
and spread.
Intravasation and
extravasation.
Necessary for
continued
proliferation.
Requires protease activity
to penetrate basement
membranes and the
extracellular matrix.
Otherwise the
tumor cells will die,
Otherwise the
tumor will not grow.
Inhibition of one or more of these characteristics can inhibit cancer progression.
Monday, January 30, 2012
CANCER
cell cycle dysregulation, proliferative disorder
Monday, January 30, 2012
Cell Cycle
Monday, January 30, 2012
Progress in Cell Cycle is regulated
by Genes
✤
(Keep in mind what would happen in cell cycle in cancer cells)
Monday, January 30, 2012
Proliferative driver of cell cycle: Cyclins
Expression of cyclins fluctuates at certain phases of the cell cycle
Figure 8.9 The Biology Of Cancer (© Garland Science 2007)
Monday, January 30, 2012
Cyclin-Cdk
complex
✤
Cyclin binds to Cdk (Cyclin
dependent kinase) and
forms Cyclin-Cdk complex
(an active enzyme that
prepare cell to enter or next
phase of cell-cyle by
targeting certain substrate)
Monday, January 30, 2012
Restric(on Point (R): Decision making point the late G1 phase of the cell cycle at which a cell commits itself to comple(ng the remaining phases of the cell cycle, remaining in G1, or exi(ng the ac(ve cell cycle and entering into Go
Figure 8.10 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
UPREGULATION OF CYCLIN D BY RECEPTORS
Table 8.1 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
drug ther apy
$($
)$*
!
"
2
"
2
)
4
)/
*
4
4
535
5
(
4
4
14/
1/
-
-88
8
4
Monday, January 30, 2012
Figure 1. Signal Transduction Pathways Controlled by the Activation of EGFR.
Three steps can be schematically defined in the activation of EGFR-dependent intracellular signaling.2-17 First, the bin
specific ligand occurs in the extracellular portion of the EGFR or of one of the EGFR-related receptors (HER2, HER3, o
Dysregulation of cell
cycle causes cancer
Monday, January 30, 2012
Oncogenic mutation causes cancer
normal cells
All found in cancer cells
Monday, January 30, 2012
Table 8.3 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
CyclinD1 CDK2
Overexpression causes
cancer in mice
MMTV-D1K2 mammary and salivary tumors. A, H&Eand trichrome-stained histologic sections of MMTVD1K2 and MMTV-neu mammary tumors. B,
morphologic characterization of several
representative tumors arising in the 34 (L34-) and 44
(L44-) transgenic lines. C, left, immunoblot analysis
of extracts from four different MMTV-D1K2 and four
different MMTV-neu mammary tumors demonstrating
expression of the FLAG-tagged cyclin D1-Cdk2
transgene product (FLAG (D1K2)) and c-neu. Tumor
lysates were also analyzed for the levels of Ecadherin, α-SMA, and actin as a loading control. C,
center, immunoblot analysis demonstrating the
hyperphosphorylation of Rb on multiple residues in a
MMTV-D1K2 tumor extract relative to a MMTV-neu
tumor extract. P-Rb and P-p130 represent the
phospho-forms of Rb and p130, and Rb and p130
represent the corresponding unphosphorylated
forms. Multiple products of E2F-dependent genes
are up-regulated in the MMTV-D1K2 tumor relative to
the MMTV-neu tumor including BRCA1, p107, and
E2F1. Hira serves as a loading control. C, right,
lysates from MMTV-neu and MMTV-D1K2 tumors
were subjected to immunoprecipitation with antiFLAG–agarose to isolate complexes containing the
cyclin D1-Cdk2 fusion protein. Immunoblot analysis
indicated that these complexes contain the cyclin
D1-Cdk2 fusion protein (FLAG), p21, p27, and
PCNA.
Corsino P et al. Cancer Res 2007;67:3135-3144
©2007 by American Association for Cancer Research
Monday, January 30, 2012
Summary I
✤
Proliferative driver by Proto-oncogenes
✤
Alteration of proto-oncogene becoming oncogenes drives malignancy
(amplification, translocation) by pushing overexpression of cyclins
✤
Proto-oncogene: EGFR/HER1, HER2, MYC
✤
Oncogenes: EGFR Amplification, EGFR mutation, HER2
amplification, C-MYC amplification
Monday, January 30, 2012
Oncogenic mutations
alone are not sufficient
Monday, January 30, 2012
History 1970s
• Sir Henry Harris asked:
• Is malignancy
–Dominant, or
–Recessive?
• Performed cell fusion
Figure 7.1 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
Harris Cell fusion
experiment
• the phenotype of fused cells showed loss of
tumorigenicity
• implied the presence of tumor supressor
genes
• in 1989 the first tumor supressor gene ie
Retinoblastoma (RB) is cloned
Monday, January 30, 2012
Retinoblastoma Gene Mutation in
both Alleles causes cancer
in mice and men
retinoblastoma in early childhood
Monday, January 30, 2012
medullary tumor of thyroid
cancer in Rb ko mice
Loss of
Heterozygosity
(LOH) is a
genetic
mechanism to
inactivate tumor
supressor gene
(TSG)
Monday, January 30, 2012
where does tumor supressor gene
belong in cell cycle?
Restriction
Point (R):
Decision making point the late G1 phase of the cell cycle at which a cell commits itself to comple(ng the remaining phases of the cell cycle, remaining in G1, or exi(ng the ac(ve cell cycle and entering into Go
Monday, January 30, 2012
RB Phosphorylation
Figure 8.19 The Biology of Cancer (© Garland Science 2007)
Figure 8.19 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
RB is a key gatekeeper of G1/S transition at R point
Loss of RB in precancerous cells relaxes G1/S and promotes
cellular proliferation
Figure 8.22 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
Figure 8.23a The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
Experimental evidence of C-MYC
override TSG function of RB:
Artificial C-MYC activation
causes S-phase entry in
quiescent cells
Figure 8.29 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
E2F is controlled by RB
Loss of RB function (by losing both alleles due to somatic mutation and Loss of
Heterozygosity) causes unregulated entry to cell cycle
Date
Monday, January 30, 2012
Summary
• RB gene is an important tumor suppressor
gene that regulates entry into cell cycle
• Passing or overriding Restriction Point to start
cell cycle is achieved by phosphorylating RB
Monday, January 30, 2012
Quality Control in
Cell Cycle?
live with (genomic) integrity or die (apoptosis)
Monday, January 30, 2012
Cell Cycle
Checkpoints
Purpose:
To maintain DNA integrity
Mechanisms:
Cell cycle arrest (buying time for DNA
Repair)
Activation of Apoptotic cell death
(catastrophic DNA damage)
Experimental evidence:
Using yeast model, cell cycle is prolonged
when yeasts are challenged with
damaging agents. DNA analyses showed
arrest at specific phase of cell cycle
Figure 8.4 The Biology of Cancer (©
Garland Science 2007)
Monday, January 30, 2012
Monday, January 30, 2012
Monday, January 30, 2012
Monday, January 30, 2012
Figure 9.8 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
Hair loss due to cyclophosphamide
Anything to do with genes? which gene is responsible?
Date
Monday, January 30, 2012
Note: p53 gene is knocked out in the germline using embryonic stem cell homologous
recombination technique
Monday, January 30, 2012
Summary II: Cell Cycle and
TSGs RB p53
• RB and p53 have unique genetic and
biochemical roles on controlling cell cycle
• Activation of proliferation (by removing
RB) also activates apoptotic machinery.
Therefore, cancer cells also inactivate wild
type p53 to survive
Monday, January 30, 2012
CANCER
genetic disorder
Monday, January 30, 2012
gen sana in
corpore sano
• majority of cancer patients
harbor somatic genetic
mutations
• minority of cancer patients have
inherited germline genetic
mutations
• enviromental risks will invariably
lead to somatic genetic changes
• eat healthy keep mutations away
(assuming your dna repair
genes are intact)
Monday, January 30, 2012
CANCER
stem cell
Monday, January 30, 2012
Monday, January 30, 2012
stem cell dna
repair juice
Monday, January 30, 2012
Monday, January 30, 2012
Monday, January 30, 2012
http://stemcells.nih.gov/info/2006report/2006chapter9.htm
How Do Cancer Stem Cells Arise? The molecular pathways that maintain "stem-ness" in stem cells are also active in numerous cancers. This similarity
has led scientists to propose that cancers may arise when some event produces a mutation in a stem cell, robbing it of the ability to regulate cell
division. This figure illustrates 3 hypotheses of how a cancer stem cell may arise: (1) A stem cell undergoes a mutation, (2) A progenitor cell undergoes
two or more mutations, or (3) A fully differentiated cell undergoes several mutations that drive it back to a stem-like state. In all 3 scenarios, the resultant
cancer stem cell has lost the ability to regulate its own cell division.
Monday, January 30, 2012
How Does Tumor Develop?
Monday, January 30, 2012
CSC HIERARCHY: Are all cancer
cells created equal?
Dirks, P
Monday, January 30, 2012
Monday, January 30, 2012
Figure 11.15 The Biology of Cancer (© Garland Science 2007)
Monday, January 30, 2012
properties of cancer
stem cells
Monday, January 30, 2012
cancer recurrence
Monday, January 30, 2012
WRONG TARGET. Traditional cancer therapies (top) kill rapidly dividing tumor cells
(blue) but may spare stem cells (yellow) that can give rise to a new tumor. In theory,
killing cancer stem cells (bottom) should halt a tumor's growth lead to its disappearance.
Monday, January 30, 2012
intervention opportunity:
targeting cancer stem
cell
Monday, January 30, 2012
Monday, January 30, 2012