CELL CYCLE, APOPTOSIS AND CANCER

MICHAEL VAN HAUTE, M.D.

Edited to Word format by:

----------------------------------CELL CYCLE AND APOPTOSIS-----------------------------------

CELL DIVISION Metaphase
Spindle fibers align chromosomes
Occurs in every tissue during embryonic along midline (metaphase plate)
growth and later development Bipolar tension created by spindle
In adults, cell division in most tissues fibers attached to chromosomes
become quiescent initiates anaphase entry
Brought about by concerted interactions Anaphase
between various kinases, phosphatases, Paired chromosomes separate
proteases, and ubiquitin ligases. (chromatids) and move along
opposite sides of cell
THE CELL CYCLE Telophase
Chromatids arrive at opposite poles
Interphase of cell
G1 phase New membranes form around
S phase daughter nuclei
G2 phase Cytokinesis begins (actin-containing
Mitosis/mitotic phase (M) fiber ring around center of cell
Resting phase (G0) contracts 2 cells)
G0 (resting/quiescent) phase
May last hours, days, or the cells
lifetime
Terminally-differentiated cells may
remain in this phase
Stem cells retain their potential to
divide (and differentiate)
Cells returning from G0 re-enter at
early G1 phase

CYCLIN-DEPENDENT PROTEIN KINASE (CDKs)

Control timing of the cell cycle

Work by phosphorylating specific proteins
(at serine and threonine resides) at
G1 (growth) phase 6-12 hours precisely timed intervals
Synthesis of RNA and proteins, and Regulation:
enzymes needed for DNA replication Cyclin regulatory subunit (without it,
Growth and normal metabolic processes CDKs are virtually inactive)
Preparation for S phase CDK inhibitor proteins
S (synthesis) phase 6-8 hours Various other protein kinases and
DNA replicates to produce copies for phosphatases
both daughter cells
RNA and proteins continue to be CDK-CYCLIN INTERACTION
synthesized
G2 phase 3-4 hours
No DNA synthesis occurs
RNA and protein synthesis continues;
microtubules produced
Cells approximately double in size
M (mitotic) phase - actual cell division (~1
hour)
Prophase
DNA (chromatin) condenses to form
chromosomes
Centrioles move to opposite sides,
microtubules extend (mitotic
spindle)
Prometaphase
Nuclear membrane dissolves
Chromosomes attach to
microtubules

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CDKs PHOSPHORYLATE A VARIETY OF SUBSTRATE
PROTEINS
Lamin
Makes up highly organized meshworks
of filaments in the nuclear envelope
Phosphorylation depolymerizes lamin
Actin and myosin
Contraction pinches a dividing cell into
two equal parts (cytokinesis)
After cell division: myosin
phosphorylated again dissociates
from actin inactivation of
contraction
Retinoblastoma protein (pRb)
Tumor suppressor protein
Arrests cell division in G1 when DNA
damage is detected
DIFFERENT CDK-CYCLIN HETERODIMERS
Note: Interval of LOW CDK-CYCLIN ACTIVITY
when pre-replication complexes are assembled.
CYCLIN-DEPENDENT PROTEIN KINASES (CDKs)
Growth factors and cytokines initiate cells
to synthesize CDKs and cyclins via the
ERK/MAPK pathway
Growth factors
Soluble and diffusible polypeptides;
steroids
Regulate growth and differentiation of
numerous cell types
Participate in repair and regeneration,
chemotaxis, and metabolism
Families:
Platelet-derived growth factor
(PDGF) family bone formation,
soft-tissue repair/wound healing
Vascular endothelial growth factor
(VEGF) family angiogenesis
Epidermal growth factor (EGF)
family proliferation of mucosal
cells (healing of GI ulcers),
regeneration of epidermis
Insulin family IGFs
Hepatocyte growth factor organ
development and regeneration,
hematopoiesis
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Cytokines
Hormone-like molecules (peptides)
Immune system regulation,
inflammation, fever
Can also induce cell division
Produced in almost every nucleated
cell
Examples:
Interleukins activation and
chemotaxis of various immune cells
Tumor necrosis factor (TNF)
promotion of inflammation
GM-CSF growth of granulocytes
and monocytes
Interferon induction of resistance
of cells to viral infection
FUNDAMENTAL PROPERTIES OF CELL CYCLE
REGULATION
Alteration of CDK activity
Checkpoints
Irreversibility
Balanced growth and division
REGULATORS OF CDKs
Cyclin-dependent activating kinases (CAKs)
Add activating phosphates to CDKs
CDC25 phosphatase
Remove inhibitory phosphate from CDKs
CDK inhibitors (CKIs)
Ubiquitin ligases
Wee1
G2/M-phase kinase that adds an
inhibiting phosphate to the Tyr-15
residue of CDK1
Note: Each of the G1/S CDKs is regulated by
specific CAK and Wee1-like kinase isoforms
THE CDK-FREE INTERVAL
DNA pre-replication complexes (pre-RC)
assemble into chromosomes (at replication
origins) during early G1.
Note: A pre-replication complex (pre-RC) is a
protein complex that forms at the origin of
replication during the initiation step of DNA
replication. Formation of the pre-RC is required
for DNA replication to occur. Complete and
faithful replication of the genome ensures that
each daughter cell will carry the same genetic
information as the parent cell. Accordingly,
formation of the pre-RC is a very important part of
the cell cycle.
CDKs AND CYCLINS IN ACTION
G1 to S (Cyclin D; CDKs4, 6)
Catalytic role stimulation of
expression of genes required for G1
progression
Phosphorylation of pRB liberates
E2F (transcription factor)
Phosphorylation of other
transcription factors that target
and trigger genes encoding
components of S-phase CDK-cyclin
complex (complexed with CKI)
Non-catalytic role sink and reservoir
for CDK inhibitors (CKI) that inhibit S-
phase CDKs (CDK2)
Just before S phase, G1-phase CDK-
cyclin complexes degrade CKI S
phase begins
S to G2 (Cyclin E, A; CDK2)
Activated S-phase CDK-cyclin
complexes phosphorylate the pre-RC
assembled early in G1 DNA
replication x 1
M-phase CDKs and cyclins synthesized
(but inactive)
Recall: T loop on CDK covers its
ATP-binding site
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T loop has 2 critical residues:
Threonine 160
phosphorylation exposes ATP-
binding site of CDK even more
Tyrosine 15 phosphorylation
(added by Wee1) blocks the
ATP-binding site of CDK
inactivated
M phase (Cyclin B; CDK1)
M-phase CDK-cyclin complexes
(maturation-promoting factors, MPFs)
are activated
Phosphate on Tyr 15 of CDK1 is
removed by protein tyrosine
phosphatase (Cdc25 phosphatase)
Active complex phosphorylates multiple
proteins resulting in mitosis
Chromosome condensation,
breakdown of nuclear membrane,
mitotic spindle formation,
cytokinesis
Ubiquitin system (anaphase promoting
complex) is activated
CELL CYCLE CHECKPOINTS
G1/S checkpoint (Restriction point)
Trigger: ATM (ataxia telangiectasia
mutated) protein
Chromatin-bound serine/threonine
protein kinase, recruited and
activated by DNA double-strand
breaks
Phosphorylates and activates tumor
suppressors
(p53 guardian of the genome)
expression of CKIs p16 and p21
Phosphorylates a protein kinase
Chk2, which inhibits Cdc25
phosphatase
Note: All cells face a battery of insults to their
DNA from endogenous sources, for example
spontaneous cytosine deamination, replication
errors and base damage from oxygen radicals
generated as a product of normal metabolism.
Together with exogenous sources: UV, dietary
toxins, aromatic hydrocarbons, among others, this
adds up to a significant value that has been
estimated as 10 000 40 000 single strand breaks
(SSBs) and up to 50 double strand breaks (DSBs) per
cell per day.
G1 CHECKPOINT
- Typically arrests cell division if conditions
make cell division impossible or if the cell
passes into G0 for an extended period.
Ataxia telangiectasia mutated (ATM) is a
serine/threonine protein kinase that is recruited
and activated by DNA double-strand breaks. It
phosphorylates several key proteins that initiate
activation of the DNA damage checkpoint, leading
to cell cycle arrest, DNA repair or apoptosis.
Several of these targets, including p53, CHK2 and
H2AX are tumor suppressors.
G2 CHECKPOINT
- Cdc25, under favorable conditions,
removes the inhibitory phosphates present
within the maturation promoting factor
(MPF) (cyclin B/CDK1 complex)
 G2/M checkpoint
Trigger: ATR (ataxia telangiectasia
mutated-related) protein
Also a chromatin- bound
serine/threonine protein kinase
related to ATM
Phosphorylates another
serine/threonine protein kinase
Chk1, which phosphorylates Cdc25
phosphatase ubiquitinylated and
destroyed
There is crosstalk between the ATM/Chk2 and
ATR/Chk1 pathways and they share many
substrates.
APOPTOSIS IS PROGRAMMED CELL DEATH
Triggers:
DNA damage too extensive for effective
repair
Lack of necessary growth factors
Presence of death signal proteins
Pathologic conditions triggering it:
Viral infections
Severe stresses (heat, UV light, gamma
irradiation)
Can also be a physiologic event:
During embryonic development
Menstruation
With WBCs
APOPTOSIS
Morphologic changes that occur:
Cell shrinkage
Chromatin condensation
Formation of cytoplasmic blebs and
apoptotic bodies
Phagocytosis of apoptotic cells or cell
bodies
Biochemical processes that occur:
Activation of caspases and
endonucleases protein and DNA
breakdown
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Membrane alterations and recognition
by phagocytes
Must be differentiated from necrotic cell
death
Unobservable, does not induce an
inflammatory response
Products of degradation are released in
a controlled process
Pathways:
Intrinsic (mitochondrial) pathway
Extrinsic (death receptor) pathway
INTRINSIC (MITOCHONDRIAL) PATHWAY
Mitochondrial membrane permeabilization
by pro-apoptotic BH domain proteins (of
the BCL-2 family)
Increased mitochondrial permeability to
cytochrome c (major mitochondrial
signaling protein)
Leaked cytochrome c binds to apoptosomes
activation of pro-caspase 9 to caspase 9
caspase cascade activated apoptotic
death
Note: Caspases, or cysteine-aspartic proteases or
cysteine-dependent aspartate-directed proteases
are a family of cysteine proteases that play
essential roles in apoptosis (programmed cell
death), necrosis, and inflammation.
Note: Apaf-1 (adaptor proteins) apoptotic
protease-activating factor 1
Caspase recruitment domains, or Caspase
activation and recruitment domains (CARDs), are
interaction motifs found in a wide array of
proteins, typically those involved in processes
relating to inflammation and apoptosis. These
domains mediate the formation of larger protein
complexes via direct interactions between
individual CARDs. CARD domains are found on a
strikingly wide range of proteins, including
helicases, kinases, mitochondrial proteins,
caspases, and other cytoplasmic factors.
INTRINSIC APOPTOSIS PATHWAY: THE BCL-2
FAMILY OF PROTEINS

Regulators of apoptosis (at least 24)

Contain BH (BCL-2 Homology) domains
binding sites for self-/heteroassociation
with other proteins with these domains
Three (3) subfamilies:
Anti-apoptotic proteins (BH 1-4)
Bcl-2, Bcl-xL, Bcl-w, MCL-1,
A1/BFL-1
Pro-apoptotic proteins (BH 1-3)
Bax, Bak, Bok

BH3-only proteins
Direct activators: BID, BIM
Sensitizers/de-repressors: HRK,
BAD, BIK, BMP, Noxa, PUMA
BH-3 ONLY PROTEINS APPEAR TO BE PIVOTAL IN
THIS PROCESS
Rheostat model direct binding and activation of
Bax/Bak
In the absence of DNA damage or stresses (e.g.
hypoxia), p53 is polyubiquitylated by ubiquitin
ligases, then degraded by proteasomes.
Note: If DNA damage is too great to repair, higher
concentrations of p53, due to COVALENT
MODIFICATIONS (phosphorylation and acetylation
to prevent polyubiquitylation), results in p53-
induced apoptosis

Neutralization model anti-apoptotic proteins are

neutralized, and Bak/Bax are displaced

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Whether cell death occurs depends on the relative concentrations of pro-apoptotic and anti-apoptotic proteins
in the outer mitochondrial membrane

AIF
apoptosis inducing factor chromatin condensation and DNA degradation Smac
Second mitochondria-derived activator of caspases (also AIP binding)
also known as DIABLO (direct IAB binding protein with low isoelectric point) Omi
a serine protease; mutations linked to development of Parkinsons disease (mice and humans) XIAP
X-linked inhibitor of apoptosis

EXTRINSIC (DEATH RECEPTOR) PATHWAY

Three general steps

Binding of ligand to death receptor
Recruitment of cytosolic adaptor
proteins, which then recruit initiator
caspases (8 and 10)
Initiation of different signaling
cascades
Activation of effector caspases (3,
6, and 7)
Cleavage of BH3-only protein Bid

Note: Emerging information also implicates numerous

noncytotoxic signaling pathways, mainly mediated by
activation of NF-kB and MAPK, from the receptor/adaptor
protein complexes

Death receptors:
TNFR1 (TNF receptor 1)
Fas
TRAIL (TNF-related apoptosis-inducing ligand receptor)
Ligands: TNF (TNF) and FasL
Cytosolic adaptor proteins: TRADD and FADD
TNF receptor-/Fas-associated protein with death domain
Ligand binding prompts these adaptor proteins to bind to intracellular regions of death receptors
(also contain death domains)

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PATHWAY INTEGRATION

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-----------------------------------------------CANCER------------------------------------------------
REVIEW: G PROTEINS

Small GTPases
Activated state bound to GTP
Intrinsic GTPase activity GTP GDP
GAPs accelerate GTP hydrolysis
GEFs catalyzes GTP exchange
Molecular switch
P loop
Thr 35 and Gly 60

Note: SMALL GTPASES unlike the alpha subunit of

G proteins, a small GTPase can function
independently as a hydrolase enzyme to bind to
and hydrolyze a guanosine triphosphate (GTP) to
form guanosine diphosphate (GDP). The most well-
known members are the Ras GTPases and hence
they are sometimes called Ras superfamily
GTPases. A typical G-protein is active when bound
to GTP and inactive when bound to GDP (i.e. when
the GTP is hydrolyzed to GDP). The GDP can be
then replaced by free GTP. Therefore, a G-protein
can be switched on and off. GTP hydrolysis is
accelerated by GTPase activating proteins (GAPs),
while GTP exchange is catalyzed by Guanine
nucleotide exchange factors (GEFs). Activation of a
GEF typically activates its cognate G-protein, while
activation of a GAP results in inactivation of the
cognate G-protein. Guanosine nucleotide
dissociation inhibitors (GDI) maintain small
GTPases in the inactive state.

REVIEW: RECEPTOR TYROSINE KINASE (RTKs)

Note: MAPK pathways are activated by UV light,
radiation, cytokines, or the stress molecules of
inflammation, in the absence of Ras activation.

MAPKs mitogen activated protein kinases

(regulate proliferation, gene expression,
differentiation, mitosis, cell survival,
apoptosis)
ERK (extracellular signal-regulated kinases)
classic MAPK; enters nucleus and
phosphorylates transcription factors
MAPK cascade
ERK = MAPK
RECEPTOR TYROSINE KINASES: MAPK PATHWAY MEK = MAPKK
IRS-1 Raf-1 = MAPKKK
Recognizes phosphorylated tyrosine
residues (via SH2 domain) on receptor CANCER
First protein to be phosphorylated (at
tyrosine residues) point of When regulatory mechanisms that limit cell
nucleation for a complex of proteins division become defective cells undergo
Grb2 unregulated division and are able to resist
Adaptor protein; contains SH2 domain) apoptosis
No intrinsic enzymatic activity Almost always because of a genetic defect
Sos in one or more of the proteins that regulate
Contains a guanosine nucleotide- cell division
exchange factor (GEF) replaces GDP Inherited
with GTP on Ras Toxic compound from the environment
(mutagen/carcinogen)
High-energy radiation
At present, >300 genes are implicated in
cancer development
Tumor suppressor genes
Oncogenes

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TYPES OF GENETIC MUTATION
CHARACTERISTICS OF CANCER CELLS
They compete with normal tissues for
nutrients
Angiogenesis, high metabolic rate
Various cancers produce TNF
cachexia
They do not respect usual cellular growth
limits
Immortalization
Telomerase activity maintained
They are able to evade apoptosis
p53 gene abnormalities
Encodes tumor suppressor p53
(guardian of the genome)
Inactive or deleted in ~50% of
human cancers
Pathways dysregulated in most of
the other 50%
Note: Mortal cells divide to produce 20-40
generations, then enter senescence. A terminal
nucleotide segment is lost each time chromatids
are duplicated, and if telomere extension by
telomerase is lacking, progeny cells enter
senescence to protect DNA damage.
They are able to proliferate even in the
absence of external growth factors
Can produce their own
mitogenic factors
Can overexpress their RTKs
Can structurally alter RTKs
(activate signal transduction
pathways in the absence of
mitogenic factors)
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They are far less adhesive to one another
(metastasis)
Some have the ability to produce blood
vessels (neoangiogenesis)
Imbalance between pro-angiogenic
(VEGF, PDGF, FGF) and anti-angiogenic
factors (angiostatin, endostatin,
thrombospondins)
Primary cancer site tumor outgrows
original blood supply hypoxia
pro-angiogenic factors
Metastatic site angiostatin and
endostatin limit neoangiogenesis
(usually not for long)
Note: ANGIOSTATIN
- N terminal
- At the primary tumor site has insufficient
activity to inhibit angiogenesis (where pro-
angiogenic processes predominate)
- Long lifetime travels through blood to
distant sites to inhibit angiogenesis at
secondary metastatic sites
- Anti-angiogenic activity is overcome when
and if the metastatic tumors develop, but
initially this anti-angiogenic activity slows
the development
TUMOR SUPPRESSOR GENES
Encode for tumor suppressor proteins
(proteins that normally restrain cell
division)
Activating mutations are autosomal
recessive tumors form only if both alleles
of a gene are defective
RB1 gene
Encodes Retinoblastoma protein (pRb)
Mutations associated with increased
risk of developing new cancers
N = 1604
Hereditary RB = 51%; sporadic RB =
5%
Note: In one study of 1604 patients with
retinoblastoma, the cumulative incidence rates for
second cancers 50 years after diagnosis of
hereditary and nonhereditary retinoblastoma were
51 and 5 percent, respectively
CONCLUSION: Genetic predisposition has a
substantial impact on risk of subsequent cancers in
retinoblastoma patients, which is further
increased by radiation treatment. A radiation
dose-response relationship is demonstrated for all
sarcomas and, for the first time in humans, for
soft tissue sarcomas. Retinoblastoma patients
should be examined for new cancers and followed
into later life to determine whether their
extraordinary cancer risk extends to common
cancers of adulthood.
Stability genes (caretaker genes)
Subtype of TSGs
Function in repair of major genetic
defects
p53
Guardian of the genome
If the defects are too many to
repair apoptosis
Mutations lead to high frequency of
unrepaired damage in a variety of
genes (includes proto-oncogenes
and other TSGs)
Somatic mutations high
frequency of mutations in
diverse cancers
Germline mutations Li-
Fraumeni syndrome (rare)
Note: GERM LINE MUTATIONS
- can be passed on to descendants through
their reproductive cells
- gives rise to a constitutional mutation in
the offspring, that is, a mutation that is
present in every cell
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- A constitutional mutation can also occur
very soon after fertilization, or continue
from a previous constitutional mutation in
a parent
SOMATIC MUTATIONS (acquired mutations)
- Involve cells outside the dedicated
reproductive group and which are not
usually transmitted to descendants.
LI-FRAUMENI SYNDROME
- Sarcoma, breast, leukemia and adrenal
gland (SBLA) syndrome
- Because the TP53 gene is responsible for
initiating DNA repair mechanisms and/or
apoptosis upon detection of DNA damage,
LiFraumeni syndrome, with one of the two
p53 copies already mutated, predisposes a
person to cancer development because only
one additional mutation (in the second p53
allele) is necessary to impair a significant
portion of the tumor suppressor system.
This "second hit", which can be affected by
environmental factors, can directly lead to
both p53 alleles being impaired and thus
potentiate cancer development. Indeed,
persons with LiFraumeni syndrome have
an approximately 25-fold increased risk of
developing a malignant tumor by age 50
than the population average, and are at
risk for a wide range of malignancies, with
particularly high occurrences of breast
cancer, brain tumors, acute leukemia, soft
tissue sarcomas, bone sarcomas, and
adrenal cortical carcinoma.
OTHER CARETAKER TUMOR SUPPRESSOR GENES Retinoblastoma

BRCA1, BRCA2 genes Hereditary breast- Most common intraocular tumor of

ovary cancer syndrome (HBOC) childhood
APC gene Familial adenomatous polyposis Mutational inactivation of both alleles of
ATM gene Ataxia telangiectasia the retinoblastoma (RB1) gene
In the presence of DNA damage, Inherited or sporadic
detaches from chromosomes and
phosphorylates/activates p53 and BRCA
XP gene Xeroderma pigmentosum

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 ONCOGENES
Onco- = onkos () = bulk, mass, or
tumor
Derived from protooncogenes
Genes that encode proteins that
promote cell division or promote
resistance to apoptosis and cell survival
Activating mutations oncogenes
(autosomal dominant)
First oncogene discovered was a viral one
(src)
Most prominent oncogene in human cancers
is mutated Ras
In 25-30% of human cancers
GTPase activity is lost

ONCOGENES MAY FUNCTION AS:

Growth factors
VEGF, PDGF, FGF, EGF
Receptor tyrosine kinases
HER (Human EGF receptor)
Cell proliferation and
differentiation
Amplification, overexpression
uncontrolled cell proliferation
cancer
HER1 bladder, breast, kidney,
prostate, lung cancers
HER2 invasive breast cancer

Knudsons two-hit hypothesis

Note: Using this approach, it was shown that many
families with familial retinoblastoma did indeed
harbor mutations or deletions of RB1 in the
germline (the first hit), and tumors from RB
patients nearly always contained mutation or loss
of the other RB1 allele Cytoplasmic tyrosine kinases
Philadelphia chromosome t(9;22)
Chronic myeloid leukemia
Translocation ABL1 (chrom. 9) to
BCR (chrom. 22)
BCR-ABL1 oncogene Bcr-abl
fusion protein uncontrolled
proliferation of myelocytes; escape
from apoptosis
Imatinib mesylate (Gleevec)
tyrosine kinase inhibitor (first-line
treatment for Ph+ CML)
JAK2
Polycythemia vera
Point mutation V617F
constitutive tyrosine kinase activity
cell proliferation
Regulatory GTPases
Ras oncogene (rat sarcoma)
Point mutations Ras with normal
Note: This two-hit hypothesis is not only applicable
GTP binding but no GTPase activity
in RB but also to other TSGs
always in activated (GTP-bound)
form
Found in 20-25% of all human
cancers, 30-50% of lung and colon
CA, 90% of pancreatic CA
Reovirus can potentially kill Ras-
activated tumor cells

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 Transcription factors
c-Myc gene
Regulatory gene (chrom. 8) encoding
transcription factor myc
Normally, myc regulates cell
proliferation, differentiation, and
apoptosis by regulating p53
Translocation (8; 14)
overexpression uncontrolled
proliferation of B cells (Burkitts
lymphoma
Epstein-Barr virus (EBV) infection

Note: Regulatory gene is a gene involved in Note: The development of a malignant tumor
controlling the expression of one or more other requires a permanent change in genetic
gene information in a cell line and it takes years to
Starry sky lipid droplets (no one knows why) complete.
Chemo regimens: R-CHOP, EPOCH-R (R =
Rituximab monoclonal antibody against CD20 on B
cells)

EXAMPLES OF PROTOONCOGENE PRODUCTS

Note: The initial genetic alteration occurs in a

single cell. If this is not repaired, it is passed to
daughter cells during cell division. If one of these
daughter cells acquires a further genetic
alteration(s), it passes this and the original
alteration on to its daughter cells.

OVERVIEW OF CANCER TREATMENT

Surgery
For diagnosis and therapy
Curative
Palliative (debulking/control of
symptoms)
CARCINOGENESIS Radiation
Target DNA
Development involves both genetic and Free radical generation
epigenetic events altered expression of Not all cells are created equal
numerous genes Curative, palliative
A multistep process accumulation of Chemotherapy
multiple gene mutations (genetic hits) Antimetabolites mimic purines,
are required for cancer to develop pyrimidines
Alkylators cause direct DNA damage
Minimum of 4 changes will generate Vinca alkaloids spindle poisons
transformation: Topoisomerase inhibitors
pRb suppression Monoclonal antibodies adjuvant therapy;
p53 suppression target oncogene products
Ras activation Complementary and alternative therapies
Telomerase overexpression
Tumor initiation
Normal cells are changed so they are
able to form tumors -END-
Tumor promotion
Various factors permit descendants of
initiated cells to survive and expand in Please refer to the PowerPoint Presentation for
number much clearer images. Good luck and God bless
Tumor progression Batch 2016!
Increased growth speed and
invasiveness occur

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