Transcript Endocrinology & Cancer Endocrinology 317/319 Department of Biology University of Massachusetts Boston Kenneth L.

Endocrinology & Cancer
Endocrinology 317/319
Department of Biology
University of Massachusetts Boston
Kenneth L. Campbell
Assembled August 2007
Normal Cell Cycle & Controls
Rb
p53, p21
route to apoptosis
role of DNA repair
telomerase action
Oncogenesis - Chemical Signaling and Cancer
Basic Concepts
Tumor
Benign (self contained)
Malignant (migratory, prone to seeding tumors at other sites)
Hypertrophy - hypertrophic cells; hyperplastic tissue
Neoplasia - new, often irregular, growth or tissue
Proto-oncogenes = Normal gene precursors of oncogenes
I
V
Mutational Agents
I
V
Oncogenes = Gene associated with abnormal cell growth
Oncogene Product = Expressed protein coded by an oncogene
Mutagens
Radiation, Chemical - tend to be small changes, insertions, deletions, or base changes
Chromosome Rearrangements (in meiosis) - can be large changes, deletions, inversions
Viral Rearrangement - viruses can become lysogenic & excise & carry genes or foreign
promoter DNA to subsequent cellular hosts where these insert into non-homologous sites
& are expressed in a non-regulated or inappropriately regulated fashion, often leading to
oncogenesis via disruption of the normal events of the cell cycle or cell cycle regulatory
points.
Mitotic Cell Cycle & Its Controls
The normal stages of
mitosis are shown.
The cell must sense
the quality of its
environment to know if
it is safe to undergo
division.
It must know if other
tissues are directing it
to undergo division.
And, it must monitor
the completeness and
correctness of DNA
synthesis including
correction of the
necessary strand
breaks necessary due
to anti-parallel DNA
replication and due to
topoisomerase
activity.
Cell Size & Division Controls
G1/S
controls
G2/M
controls
Controlling cell division in yeast
and animals: does size matter?
Savraj S Grewal, Bruce A Edgar,
Journal of Biology 2:5, 2003.
Yeast & animals cells control cell growth & division differently. In yeast rates of cell growth are strictly &
simultaneously controlled by nutrient availability: growth rates & cell size are a direct function of
nutrient availability. Cell-size checkpoints function to ensure yeast cells divide only at a critical size
dictated by nutrients ensuring that proliferation rates in yeast are suited to environmental conditions. In
animals cells are influenced by many extracellular stimuli including nutrients, growth factors, mitogens
& patterning hormones, e.g., Dpp, Wnt, Hh & Notch. These signals mediate intercellular communication
& control both cell size & cell number ensuring proportionate organ & organismal growth. However, they
may control cell size & number non-coordinately; strict cell-size checkpoints may not be necessary.
Rather, normal overall proliferation is regulated by diverse stimuli that independently but coordinately
control cell growth & division.
The anti-parallel, helical, frequently coiled and supercoiled nature of
DNA within cells presents topological problems during replication that
can result in mistakes that must be monitored by the cell cycle
machinery.
During DNA replication the two strands are copied in opposite
directions using different methods. Topoisomerase is also involved
and makes cuts in one or both strands that must be ligated to
maintain sequence integrity. Thus, there are opportunities for
sequence mismatches or replication mistakes even during mitosis.
Rb protein: the first major checkpoint
pRb the Master Controller:
The First Checkpoint
Robert A. Weinberg, How Cancer Arises, Scientific American 275(3):62-70,
September 1996.
Phosphorylation of pRb
by cyclin/cyclin-kinase
complexes allows
release of pRb-bound
transcription factors
such as E2F. Now free,
the transcription factors
can alter expression of
genes necessary for cell
growth and DNA
synthesis.
Rachel A. Freiberg, Susannah L. Green, Amato J. Giaccia
Hypoxia and Cell Cycle
In: Cell Cycle Checkpoints and Cancer
Mikhail V. Blagosklonny, Ed.
ISBN: 1-58706-067-1
Human Papilloma Virus, HPV, perturbs the pRb checkpoint allowing cells to enter
S Phase under conditions that may not be optimal or safe for DNA synthesis or
cell replication.
Hoenil Jo, Jae Weon Kim, Implications of HPV infection in uterine cervical cancer,
Cancer Therapy 3: 419-434, 2005
Sequential phosporylation of Rb by cyclin/cdk complex inhibits the repressor activity of
pRb. The HPV E7 binds to the hypophosphorylated form of the pRb proteins. This binding
disrupts the complex between pRB & the cellular transcription factor E2F, resulting in the
liberation of E2F, which allows the cell to enter the S phase of the cell cycle.
p53: the second major checkpoint
p53, p21 & The Second Checkpoint
Robert A. Weinberg, How Cancer Arises, Scientific American 275(3):62-70,
September 1996.
Hypoxia, cellular exposure to reactive oxygen species, mitochondrial
damage, or direct damage of DNA by chemicals or radiation can stimulate
p53 actions that halt cell division, activate DNA repair mechanisms, &/or
stimulate the cell to undergo apoptosis (programmed cell death). This
protects the organism from clonal expansion of mutated cells.
Olivier Pluquet, Pierre Hainaut
Genotoxic and non-genotoxic pathways of p53 induction
Oncoserve Online, 2004
Oncoserve Online p53.mht
Hoenil Jo, Jae Weon Kim,
Implications of HPV infection in uterine cervical cancer
Cancer Therapy 3: 419-434, 2005
HPV infection also perturbs the
second, p53, checkpoint preventing
p53 from diverting cells with
damaged DNA toward cell cycle
arrest or cell death. Damaged cells
can then proliferate unchecked.
DNA damage induces p53 activation, leading to either cell
cycle arrest or apoptosis. The HPV E6 binds to E6-AP &
redirects it to p53, which results in the E6-AP-mediated
ubiquitination & rapid proteasomal degradation of p53.
RB/p53 Interactions To Regulate Cell Cycle & Apoptosis
Cell cycle transition from G1-S phase is mediated by Rb interactions with the E2F transcription factor
family, an important regulator of the cell cycle. Growth factors lead to phosphorylation of Rb in late G1
phase by cdk/cyclin. This is followed by release of E2F, allowing transcriptional activation of E2F target
genes; this promotes S-phase entry & cell proliferation. HPV E7 & Simian Virus 40 (SV40) promote
release of E2F from Rb. In contrast HPV E6 & the dominant negative, DN-p53 inhibit p53 activity leading
to cell proliferation.
Shehata, Cancer Cell International 2005 5:10 doi:10.1186/1475-2867-5-10
More Details on the Molecules & Molecular
Interactions Involved in the Cell Cycle Controls
&
The Actions of TGF & Other Growth Factors
p53
Rb
Cell Cycle
Checkpoints
www.physiomicsplc.com/cell%20cycle%20model.htm
http://www.wellesley.edu/Chemistry/chem2
27/nucleicfunction/cancer/cancer.html
http://www.eurogene.org/etext/c
ancgen/lectures/Bernards.htm
http://www.fhcrc.org/science/education/courses/cancer
www-medchem.ch.cam.ac.uk/picture.html _course/basic/approaches/fundamentals/cellcycle.html
p53 (& p21)
URL:
http://www.bccrc.ca/ci
/tm01_modelling.html
The BCCRC is the
research arm of the
BC Cancer Agency
(BCCA),
and is owned by the
BC Cancer
Foundation.
This page was last
modified at 5:20pm
on June 27, 2001
Rb
Only the stem or progenitor cells are able to divide. During the DNA synthesis, S, phase), the volume of the cell doubles
and the cell must check that it is not impinging on its neighboring cells. After mitosis, two daughter cells appear.
Carcinogenesis seems to be a multistage process where normal cells progress to cancer through a gradual accumulation
of genetic errors. This has led to the hypothesis that cancer may be caused by mutations that cause genetic instability. Cell
cycle controls, checkpoints, maintain the genetic stability of dividing cells. There are at least two important known
checkpoints, located in G1/S and G2/M involving tumor suppressors Rb and p53, respectively. The second is activated by
DNA damage. During carcinogenesis, these checkpoints fail to prevent abnormal cells from going through the cell cycle.
Rb & Cell Cycle Controls
Cyclin/Cyclin Kinases
INK4 & KIP
Cell cycle progression is governed by cyclin-dependent kinases (cdks). Cdk activities are regulated
by cyclin binding, by phosphorylation & by cdk inhibitors (especially the inhibitor of cdk4 (INK4)
family: p15, p16, p18 & p19; & the kinase inhibitor protein (KIP) family: p21, p27 and p57). Growth
factors like TGF- may modify expression & action of some of the INK4 & KIP proteins.
Donovan et al. Breast Cancer Res 2000 2:116 doi:10.1186/bcr43
Mechanisms of cell cycle arrest by
transforming growth factor (TGF)-β
& deregulation in cancer
Cyclin
degradation
or p27
TGF-β receptor activation
phosphorylates Smad2. P~Smad2
then binds Smad4 & the complex
translocates to the nucleus to
modulate transcription. p15 & p21
genes are induced & c-myc & Cdc25A
are repressed by TGF-β, but these
may be indirect P~Smad2-Smad4
effects (dotted lines). TGF-β inhibits
G1 cyclin/cdks by increasing p15
binding to cdk4 & cdk6 & by
increasing p27 (+/-p21) binding to
cyclin E-cdk2, thereby inhibiting
retinoblastoma protein (pRb)
phosphorylation. *Components of the
TGF-β effector pathway that are
mutated &/or functionally inactivated
in human cancers; **molecules whose
activation or overexpression may
contribute to TGF-β arrest resistance.
Donovan et al. Breast Cancer Res 2000 2:116
doi:10.1186/bcr43
Another view of how extracellular factors may alter the status of
the pRb checkpoint & thereby change transcriptional activities.
http://www.benbest.com/health/cancer.html
Disruption of the cell cycle can result in replication of cells with:
damaged DNA
increased susceptibility to further DNA damage
ability to avoid apoptosis
ability to avoid immune surveillance
activated telomerase
Proto-oncogene
Gene mutation, gene movement, or change
in regulatory sequences or position
Oncogene
transcription
Oncogene-Product
Mechanisms of DNA damage/mutation
chemical – reactive agents, reactive oxygen species, environmental agents
radiation
replication damage – translocations, deletions, insertions
viral insertion/excision
Genes often involved in cancer formation,
hot-spots for primary or secondary mutations
Tumor Suppressors
Receptors
Transducers
Hormones
Transcription Factors
Sigma-Aldrich
Sigma-Aldrich
DNA DAMAGE RESPONSE
First Printed in R&D Systems 2003 Catalog
Retrovirus genome
Integration
of viral
transcripts
with cellular
DNA
Sigma-Aldrich
A. The retroviral genome: a gag region that encodes
viral internal structural proteins, the pol region that
encodes the virion RNA-dependent DNA polymerase
(reverse transcriptase; RT), and the env region that
encodes virion envelope proteins. The LTR region is the
long terminal repeat that appears at each end of the
integrated linear DNA. There are specific DNA
sequences in the LTR that define the initiator site for
RNA transcription and a poly(A) site on the 3’ end where
the viral polyadenylation occurs. There are also
transcription enhancer sequences that promote
production of high levels of transcripts. The LTR
elements provide all the necessary functions for
eukaryotic transcription to occur and for the provirus to
express genomic viral RNA. The virion RT converts the
retroviral genome into DNA that is subsequently inserted
into the host cell chromosomes and replicated by means
of the host cell transcription enzymes. Viral genetic
material that has integrated into host germ cell
chromosomes becomes inheritable; it is estimated that
3% of the human genome is from ancient retroviral
inserts. If the inserted viral genome stays intact, it is
replication competent and can replicate intact virus
particles. But, if, for example, pol is replaced with other
genetic material, such as a viral oncogene (v-onc), an
intact virus cannot be replicated and the genome is
replication deficient.
B. Insertion of a proviral LTR upstream of the first
coding exon of an oncogene (e.g., c-myc) results in a
transcript that no longer contains c-myc regulatory
sequences. The c-myc gene becomes constitutively
expressed, and cellular c-Myc levels increase.
DNA DAMAGE RESPONSE
First Printed in R&D
Systems 2003 Catalog
Apoptosis Pathways & Caspase Cascades
www.emdbiosciences.com/html/CBC/browsecancer.htm
www.dundee.ac.uk/biomedres/clarke.htm
DNA damage activation of G2 checkpoint regulators: p53 acts in an auto-regulatory
feedback loop with Mdm2 and p14ARF while pRb and p21WAF1/CIPI regulate cyclin BCdc2 kinase activity to re-enforce G2/M cell cycle arrest.
JAMES IV LECTURE
p53 pathways involving G2 checkpoint regulators and the role of their subcellular localisation
Z.E.WINTERS
J.R.Coll.Surg.Edinb., August 2002, 591- 598.
University Division of Surgery, University of Bristol, Bristol Royal Infirmary,
Malborough Street, Bristol BS2 8HW, UK.
King James IV lecture delivered at BASO, Glasgow, 27 November 2001
p53 re-enforces
G1 and G2 cell
cycle arrest after
DNA damage
through the
cyclindependent
kinase inhibitor
p21WAF1/CIPI.
Mdm2 and Bax
are other p53
transcriptional
targets, with
Mdm2 regulating
p53 levels and
Bax mediating
apoptosis.
JAMES IV LECTURE
p53 pathways involving G2 checkpoint regulators and the role of their subcellular localisation
Z.E.WINTERS
J.R.Coll.Surg.Edinb., August 2002, 591- 598.
University Division of Surgery, University of Bristol, Bristol Royal Infirmary,
Malborough Street, Bristol BS2 8HW, UK.
King James IV lecture delivered at BASO, Glasgow, 27 November 2001
The Process of Carcinogenesis
Cancer:
inappropriately controlled cell replication
leading to disruption of normal physiology,
metabolism or structure ultimately
disrupting homeostasis irreversibly
Neoplasm:
new cell growth; may be benign (not unlimited or
invasive) or malignant (cancerous leading toward
metastasis)
Hypertrophy – elevated size, for cell or tissue
Hyperplasia – elevated cell number
Path to Cancer:
Completion is rare due to endogenous controls & mechanisms!
Induction/Initiation/primary mutation
– fixation into the genome
-- avoidance of apoptosis
-- avoidance of immune rejection
Promotion
– stimulation of cell expansion of mutated clone
-- continued avoidance of apoptosis
-- continued avoidance of immune surveillance
Conversion/Transformation
-- epigenetic &/or secondary mutations
-- immortalization, activation of telomerase
-- loss of cell contact inhibition
-- angiogenesis of primary tumor
Progression
-- tertiary mutations
-- outgrowth of tumor
Metastases
-- breach of vascular endothelium
-- lodging & binding to capillary beds
-- invasion of secondary sites
Changes in Cancer
These range from the
molecular through cellular
& organ levels to the entire
organism. What begins in a
single cell, possibly even a
single alteration of one
chemical bond, ultimately
manifests as a terminal
physiological imbalance for
the host organism. This
might be termed the
“Butterfly Effect” in cancer.
Fabio Grizzi, Maurizio Chiriva-Internati,
Cancer: looking for simplicity and finding
complexity, Cancer Cell International
2006, 6:4, doi:10.1186/1475-2867-6-4.
Schematic of the route from a tissue stem cell through the
process of mutation & clonal expansion to malignancy
James E. Trosko, Randall J. Ruch, Cell-cell communication in carcinogenesis,
Frontiers in Bioscience, 3, d208-236, 2/15/1998.
Mathematical model of the route from a normal cell through
the various steps & processes leading to overt cancer
James E. Trosko, Randall J. Ruch, Cell-cell communication in carcinogenesis,
Frontiers in Bioscience, 3, d208-236, 2/15/1998.
Ball diagram of Nowell's hypothesis
Green balls represent cells that have developed a genetic abnormality & are expanding
or growing into a clone of cells. One of these cells develops a 2nd genetic abnormality,
blue ball. This then expands into its own clone of cells, subclones of the green
population. A third genetic mistake, dark red ball, leads to clonal expansion of a subsubclone. Eventually, a genetic mistake is made in one of the cells of the subclones or
sub-subclones that allows that cell to spin off a cancerous subclone.
http://www.barrettsinfo.com/content/5_how_does_cancer_develop_in_barretts.htm
The site was funded by AstraZeneca LP through an unrestricted educational grant to the
Ryan Hill Research Foundation, Seattle, WA
Another schematic of carcinogenesis emphasizes the early
steps in tumor formation including the role of cellular repair &
suppression of apoptosis but fails to note the importance of
secondary or tertiary mutations in allowing clonal expansion,
evasion of immune suppression, & establishment of unlimited
growth potential.
Where might those occur?
http://www.belleonline.com/n2v91.html
James E. Klaunig, Lisa M. Kamendulis, Yong Xu, Epigenetic Mechanisms of Chemical Carcinogenesis
Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine,
Indianapolis, IN
Another schematic emphasizing the cellular stages
in carcinogenesis, cellular mutation, & agents that
may be involved in the various steps.
http://www2.scitech.sussex.ac.uk/undergrad/coursenotes/ehh/lec4/4.html
This depiction of the steps in the in vivo process
compares these changes with what occurs during the
in vitro transformation of cells grown in tissue culture.
Cell Transformation Assays as Predictors of Human Carcinogenicity
The Report and Recommendations of ECVAM Workshop 391-3
ATLA 27: 745-767
The upper row represents disturbances in growth, differentiation,
& tissue integrity that lead to the phenotypes that characterize
the different stages of cancer, shown in the lower row. Multiple
genetic alterations underlie cancer development, including
oncogene activation & tumor suppressor loss of function.
Sigma-Aldrich
Note that even in well developed experimental models
we still lack clear markers or unique triggers for the
Promotion & Progression stages of carcinogenesis.
Zbigniew Walaszek, Margaret Hanausek, Thomas J. Slaga, Combined natural source
inhibitors in skin cancer prevention, Cellscience Reviews 1(3), ISSN 1742-8130.
This description
comes a bit closer
to what has been
observed; there still
is obvious
discussion of which
molecular or cellular
events contribute
specifically to the
Promotion,
Progression,
Conversion/
Transformation,
Invasion/ Metastasis
steps.
The interaction of
carcinogens with
cells that can lead
cells toward
formation of
malignant tumors.
Note the multiple
points at which a
carcinogen or
cells damaged by a
carcinogen may be
eliminated or
repaired.
Tobacco smoking and cancer: The promise of molecular epidemiology
Sophia S. Wang, B.S., Jonathan M. Samet, M.D., M.S.
Salud Publica Mex 1997;39:331-345.
Carcinogen exposure is not simply the amount of compound
applied to an organism but the amount to which the reactive
molecules in target cells are exposed, moreover, multiple
steps of response are involved in activation of cancer.
http://www.iem.cas.cz/Data/Img/big/genetic_exotox_fig1.jpg
Department Of Genetic Ecotoxicology, Institute of Experimental Medicine,
Academy of Sciences of the Czech Republic
A correlation of the events in carcinogen
metabolism with the stages of cells moving
toward clinical disease
Tobacco smoking and cancer: The promise of molecular epidemiology
Sophia S. Wang, B.S., Jonathan M. Samet, M.D., M.S.
Salud Publica Mex 1997;39:331-345.
Besides losing the ability to
correctly determine if their
environment is appropriate for
division & the characteristics
necessary for the immune
system to remove them as
damaged cells, cells on the path
to tumor & cancer formation also
gain several capacities: they
evade apoptosis, produce their
own growth factors, become
insensitive to growth
suppressors & cell contact
signals, gain telomerase activity
& overcome the Hayflick limit, &
express angiogenic factors &
molecules needed during
metastasis.
Douglas Hanahan & Robert A. Weinberg,
The hallmarks of cancer,
Cell 100:57–70, 2000.
The multi-step nature of carcinogenesis is again emphasized
when chronic inflammation seems involved in initiation
Figure 1 Inflammatory-epithelial interactions in multi-step carcinogenesis
Moss SF and Blaser MJ (2005) Mechanisms of Disease: inflammation and the origins of cancer. Nat Clin Pract
Oncol 2: 90–97 10.1038/ncponc0081
The process also remains similar when chronic
infection with a viral agent, e.g., HPV is involved.
Céline Delloye, Elodie Gautier, Michèle Ottmann, Epidémiologie et oncogénèse
liées aux infections par les Papillomavirus, Virologie Etudiants M1 ENS Lyon.mht
Eva Szabo &
Gail L. Shaw
A Specific
Disease:
Lung Cancer
http://www.moffitt.usf.edu/pubs/ccj/v4n2/article1.html
Initiation
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Tumor
Suppressor
Genes as
Initiation
Targets
Mutation or deletion of tumor suppressor (TS) genes may initiate many forms of cancer. For tumors to
develop, both alleles of the TS gene must be inactivated. In familial cancer syndromes, a mutant allele of a
TS gene is inherited and is present in every cell (e.g. p53 in Li Fraumeni). But, tumorigenesis is not
initiated until the second allele is inactivated in a somatic cell. In non-familial cases, inactivation of both
alleles occurs via somatic mutation or deletion. The end result is the same in both cases, the lack of a
functional TS gene leads to tumor development.
Philadelphia Chromosome Formation:
Classic Case of Chromosomal Rearrangement in Carcinogenesis
Rearranged chromosomes: the c-abl
oncogene from the distal tip of
chromosome 9q34 when translocated to
the bcr (break-point cluster region)
locus on chromosome 22q11.2 forms the
t(9;22) translocation found in >95% of
CML, chronic myelogenous leukemia. It
generates a chimeric gene that
expresses a chimeric bcr-abl mRNA &
fusion protein that localizes to the
cytoplasm & remains constitutively
active in phosphorylating STAT-5 &
suppressing apoptosis.
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Promotion
Conversion, Transformation
Angiogenesis
Expression of angiogenic factors, e.g., VEGF forms, promote
vascularization of tumors & establish the routes by which
metastasis-capable tumor cells may reach the blood supply &
secondary tumor sites.
http://cancer.duke.edu/pated/PFRCNews/Pictures/angiogenesis.jpg
Receptor-binding specificity of VEGF family members & VEGFR-2
signalling pathways
The multitude of VEGF
forms along with the
number of available
receptors & linked
transduction pathways
demonstrate the wide
range of effects tumor
expression of these
factors may have on
both tumor cells & their
surrounding tissue cells.
Hiroyuki Takahashi, Masabumi Shibuya, The vascular endothelial growth factor (VEGF)/VEGF receptor
system and its role under physiological and pathological conditions, Clin. Sci. (2005) 109, 227-241
Clinical Science
www.clinsci.org
Events leading to angiogenesis and metastasis
Sigma-Aldrich
MMPs
Initial tumor,
distal to vasulature,
becomes hypoxic
Early tumors are small, <1 mm3 in diameter. Without angiogenesis tumors cannot grow further even
though active cell division counter-balanced by apoptosis continues to occur. Tumor cells most distal to
blood supply become hypoxic & produce hypoxia inducible factor-1α (HIF-1α) which accumulates in the
cytoplasm & translocates to cell nuclei. This promotes transcription of many target genes, including that
for vascular endothelial growth factor (VEGF). Thus, an angiogenic switch is activated that stimulates
formation of the new vascular necessary for tumor growth. Tumor cell/stromal cell/endothelial cell
interactions cause secretion & activation of matrix metallo-proteinases (MMPs) that degrade the
extracellular matrix and permit budding of new blood vessels from existing vessels. Proliferation &
migration of vascular endothelial cells are triggered by angiogenic factors secreted by tumor cells, such
as VEGF & basic fibroblast growth factor (bFGF). Blood vessels established within tumors permit invasion
of tumor cells into the bloodstream where they are carried to additional sites in the body. If they become
attached or lodged, & invade the local blood vessels, they may then establish new tumors or metastases.
Telomerase
Here the role of telomerase is emphasized &
the process is depicted as a series of road
signs linked to molecular & cellular markers.
http://www1.elsevier.com/homepage/sab/oncoserve/cl_si/cl1/stampfer.htm
Clinical relevance: There is mounting evidence
that cellular senescence acts as a "cancer brake"
because it takes many divisions to accumulate all
the changes needed to become a cancer cell. In
addition to the accumulation of several mutations
in oncogenes & tumor suppressor genes, almost
all cancer cells are immortal &, thus, have
overcome the normal cellular signals that prevent
continued division. Young normal cells can divide
many times, but these cells are not cancer cells
since they have not accumulated all the other
changes needed to make a cell malignant. In most
instances a cell becomes senescent before it can
become a cancer cell. Therefore, aging & cancer
are two ends of the same spectrum. The key issue
is to find out how to make our cancer cells mortal &
our healthy cells immortal, or at least longerlasting. Inhibition of telomerase in cancer cells may
be a viable target for anti-cancer therapeutics while
expression of telomerase in normal cells may have
important biopharmaceutical & medical
applications. In summary, telomerase is both an
important target for cancer & for the treatment of
age-related disease.
Telomerase & Senescence
in Cancer
http://claim.springer.de/EncRef/CancerResearch/samples/0001.htm
Progression
Generation of the Mutator Phenotype in Oncogenesis
Possible Route to the Multiple Mutations Seen in Later Cancer Stages
Evolutionary Dynamics of Mutator Phenotypes in Cancer: Implications for Chemotherapy, Natalia L.
Komarova and Dominik Wodarz, 2003, Cancer Research, 63, 6635-6642. (Full text (HTML) and PDF
versions of the article are available on the Cancer Research website.) PubMed ID: 14583456
Hypothetical Model
of Chemoresistance
in Human Ovarian
Cancer Cells
Fraser et al. Reproductive
Biology and Endocrinology
2003 1:66
doi:10.1186/1477-7827-1-66
In chemosensitive ovarian cancer cells (A), cisplatin increases p53, leading to upregulation of proteins
promoting cell cycle arrest, e.g., p21, & pro-apoptotic proteins such as Bax & Fas. This activates both the
intrinsic (mitochondrial) & extrinsic (death-receptor) apoptotic paths with the overall result being activation of
the execution caspase-3 (& -7, not shown). In these cells, cell survival mediators such as Xiap, Akt, and Flip (in
red) are downregulated or are in their inactive state. Prohibitin may also play a role in inhibiting cell cycle
progression via the Rb-E2F pathway by binding Rb. In a chemoresistant cell (B), increased p53 ubiquitination by
MDM2 results in maintenance of low levels of p53, despite the presence of cisplatin. Also, cisplatin fails to
downregulate Xiap, thereby maintaining an active state of the PI3K/Akt pathway, & binding of TNFR2 by TNFα
leads to upregulation of FLIP through the NFκB pathway, thus inhibiting the pro-apoptotic actions of NFκB
through TNFR1. Overall, because the caspase cascade now fails to be activated by the chemotherapeutic agent,
these cells lose their capacity to undergo apoptosis. They have become chemoresistant.
Stages of tumour development
Malignant cell
Proliferation
Cytotoxics
Endocrine
EGFR inhibitors
HER2 antibodies
Angiogenesis
Antiangiogenics
Novel
agents
Vascular
targeting
agents Novel
agents
Invasion
Metastatic
Cancer
Invasion
Dissemination
of other organs
of other
organs
Neovascular
endothelial
maintenance
Table 1. Examples of Dietary Factors or Chemopreventive Agents That Target Specific Stages of Carcinogenesis
Prevention Strategy Examples
Tumor Initiation
Inhibit carcinogen activation
Epigallocatechin gallate (EGCG), selenium, phenyl isothiocyanate
(PEITC), indole-3-carbinol, coumarins, ellagic acid, genistein
Scavenge electrophiles
Ellagic acid, EGCG, avicins, chlorophyllin
Enhance carcinogen detoxification Oltipraz, D-glucarate, diallyl sulfide (DAS), PEITC, EGCG, Nacetylcysteine, resevratrol
Tumor Promotion/Progression
Scavenge reactive oxygen species
Antioxidants (carotenoids, α-tocopherol, ascorbic acid, EGCG,
proanthocyanidins, avicins), calorie restriction, selenium
Alter gene expression
Retinoids (all-trans retinoic acid, fenretinide), calorie restriction,
monoterpenes (D-limonene), fluasterone, dehydroepiquadrodsterone
(DHEA)
Decrease inflammation
Nonsteroidal anti-inflammatory drugs (NSAIDs), calorie restriction, DHEA,
fluasterone, avicins, antihistamines, D-glucarate, glucocorticoids, di- and
triterpenoids
Suppress proliferation
Avicins, calorie restriction, selenium, DHEA, fluasterone,
difluoromethylornithine, tamoxifen, retinoids, genistein, D-glucarate,
glucocorticoids
Induce differentiation
Retinoids,calcium, sodium butyrate
Encourage apoptosis
DHEA, fluasterone, fenretinide, sodium butyrate, avicins
Zbigniew Walaszek, Margaret Hanausek, Thomas J. Slaga, Combined natural source
inhibitors in skin cancer prevention, Cellscience Reviews 1(3), ISSN 1742-8130.
Table 2. Effective Cancer Prevention in Both Experimental Animals and Humans
Mechanisms
Dietary Restriction
Combinations of Phase I and II Detoxification
Combination of Antioxidants
Combination of Anti-Tumor Initiation and Anti-Tumor Promotion
Inhibitors of Signal Transduction Pathways
Inhibitors of Androgens and Estrogens
Compounds*
• Glucocorticoids
• Tamoxifen
• Chlorophyllin
• D-Glucarate
• α-Lipoic Acid
• Silymarin
• EGCG
• Oltipraz
*One should always have in mind that individual compounds are effective but combinations of different agents are much more effective
Zbigniew Walaszek, Margaret Hanausek, Thomas J. Slaga, Combined natural source
inhibitors in skin cancer prevention, Cellscience Reviews 1(3), ISSN 1742-8130.
Common Anti-oxidants
Zbigniew Walaszek, Margaret Hanausek, Thomas J. Slaga, Combined natural source
inhibitors in skin cancer prevention, Cellscience Reviews 1(3), ISSN 1742-8130.
Carcinogenesis
Stages & Mechanisms:
Breast & Colon Cancer
Breast Cancer Continuum:
intervention possibilities
Prevention of Recurrence
Women at
Increased
Risk
PreMalignant
Conditions
1.7 % to
14%
LCIS 6.5%
ADH 5.1%
NonInvasive
Cancer
DCIS 7.2%
Prevention of Clinically
Detectable Breast Cancer
Tumors
< 1cm
11.8%
Early Stage
node neg
25.1%
Prevention of
Progression
Early Stage
node pos
47.1%
Prevention of Contralateral
Breast Cancer 3.2%
Late Stage
Cancer
Recurrence
of Breast
Cancer
Breast Cancer staging
With thanks to Professor W.Jonat
Breast Cancer staging 2
With thanks to Professor W.Jonat
Breast Cancer staging 3
With thanks to Professor W.Jonat
Staging Classification of Breast Tumour
OVEREXPRESSION OF p68 RNA HELICASE IN COLORECTAL TUMORS
We and others have shown that p68
RNA helicase is overexpressed in colon
cancer. In particular, hyperplastic polyps
which eventually develop via adenomas
into malignant adenocarcinomas, are
devoid of significant p68 RNA helicase
immunostaining (see Figure).
However, adenomas as well as
adenocarcinomas show p68 RNA
helicase overexpression, suggesting
that p68 RNA helicase may contribute to
the malignant transformation of colon
cells.
Janknecht Laboratory , Mayo Clinic
http://mayoresearch.mayo.edu/mayo/research/janknecht_lab/overexpression.cfm
Normal Arrangement of Elements of an Epithelium
The multiple layers between the epithelial cells & the vasculature
must be breached for a cancer to become metastatic.
Progression of Colon Cancer
National Cancer Institute
Video Links for Other Lectures or Film Loops on
Carcinogenesis, the Cell Cycle & Endocrinology
General Site (multiple films):
http://www.powershow.com/view/3ba793ODE2M/Normal_Cell_Cycle_Controls_powerpoint_ppt_presentation
Putting the Breaks on Cancer (Vogelstein, Johns Hopkins University):
http://media.hhmi.org/hl/03Lect1.html
Carcinogenesis: Are the toxicity models correct?
Comments and Bibliography by Kenneth L. Campbell
Department of Biology, University of Massachusetts Boston
JAMES IV LECTURE
p53 pathways involving G2 checkpoint regulators and the role of
their subcellular localisation
Z.E.WINTERS
J.R.Coll.Surg.Edinb., August 2002, 591- 598.
University Division of Surgery, University of Bristol, Bristol Royal Infirmary,
Malborough Street, Bristol BS2 8HW, UK.
King James IV lecture delivered at BASO, Glasgow, 27 November 2001
DNA damage
activates cell cycle
checkpoints: Cell
cycle progression is
regulated by phasespecific cyclindependent kinase
(CDK) enzymes the
activity of which
depend on
association with
specific cyclin
proteins. Cyclin
B/Cdc2 kinase activity
drives the G2/M phase
transition. G1/S phase
arrest depends on the
retinoblastoma
protein (pRb) binding
the E2F transcription
factor. p16 is a G1
cyclin-dependent
kinase inhibitor.
Olivier Pluquet, Pierre Hainaut
Genotoxic and non-genotoxic pathways of p53 induction
Oncoserve Online, 2004
Oncoserve Online p53.mht