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CANCER BIOLOGY
The cell cycle
Actively dividing eukaryote cells pass through a series of stages known collectively
as thecell cycle: two gap phases (G1 and G2); an S (for synthesis) phase, in which
the genetic material is duplicated; and an M phase, in which mitosis partitions the
genetic material and the cell divides
...
Metabolic changes prepare the cell for division
...

S phase
...
Each chromosome now
consists of two sister chromatids
...
Metabolic changes assemble the cytoplasmic materials necessary for
mitosis and cytokinesis
...
A nuclear division (mitosis) followed by a cell division (cytokinesis)
...

Mitosis
Mitosis is a form of eukaryotic cell division that produces two daughter cells with
the same genetic component as the parent cell
...
In actively dividing animal cells, the whole process
takes about one hour
...
This separation of the genetic material in a mitotic nuclear
division (or karyokinesis) is followed by a separation of the cell cytoplasm in a
cellular division (or cytokinesis) to produce two daughter cells
...
In
diploid multicellular organisms sexual reproduction involves the fusion of two
haploid gametes to produce a diploid zygote
...
In the adult organism, mitosis plays a role in cell replacement,
wound healing and tumour formation
...


The phases of mitosis
Prophase
Prophase occupies over half of mitosis
...
A structure known
as the centrosomeduplicates itself to form two daughter centrosomes that migrate
to opposite ends of the cell
...
The
chromosomes condense into compact structures
...


Prometaphase
The chromosomes, led by their centromeres, migrate to the equatorial plane in the
mid-line of the cell - at right-angles to the axis formed by the centrosomes
...
The spindle fibres
bind to a structure associated with the centromere of each chromosome called a
kinetochore
...
The chromosomes continue to condense
...

Anaphase
The shortest stage of mitosis
...
The separated
sister chromatids are now referred to as daughter chromosomes
...
)
Telophase
The final stage of mitosis, and a reversal of many of the processes observed during
prophase
...

Cytokinesis
The final cellular division to form two new cells
...

The cell then enters interphase - the interval between mitotic divisions
...
The process takes the form of one
DNA replication followed by two successive nuclear and cellular divisions (Meiosis
I and Meiosis II)
...

Meiosis I
Meiosis I separates the pairs of homologous chromosomes
...

Prophase I
The homologous chromosomes pair and exchange DNA to form recombinant
chromosomes
...

Zygotene: homologous chromosomes become closely associated (synapsis) to form
pairs of chromosomes (bivalents) consisting of four chromatids (tetrads)
...
chiasma)
...

Diakinesis: homologous chromosomes continue to separate, and chiasmata move
to the ends of the chromosomes
...

Metaphase I
Homologous pairs of chromosomes (bivalents) arranged as a double row along the
metaphase plate
...
(This is a
source of genetic variation through random assortment, as the paternal and
maternal chromosomes in a homologous pair are similar but not identical
...
Human beings have 23 different chromosomes, so the number of
possible combinations is 223, which is over 8 million
...

Cytokinesis
The final cellular division to form two new cells, followed by Meiosis II
...


Meiosis II
Meiosis II separates each chromosome into two chromatids
...


•

Meiosis generates genetic diversity through:
the exchange of genetic material between homologous chromosomes during
Meiosis I

•

the random alignment of maternal and paternal chromosomes in Meiosis I

•

the random alignment of the sister chromatids at Meiosis II

Meiosis in females

REGULATION OF CELL CYCLE
Cell-division control affects many aspects of development
...
The balance between CDK
activation and inactivation determines whether cells proceed through G 1 into S
phase, and from G2 to M, through regulatory mechanisms that are conserved in
more complex eukaryotes
...
Results from several studies indicate
a critical role for CKI-1, a CDK inhibitor of the Cip/Kip family, in the temporal
control of cell division, potentially acting downstream of heterochronic genes and
dauer regulatory pathways
...
Overview
Animal development from a single-cell zygote to fertile adult requires many rounds
of cell division
...
This cycle includes accurate duplication of the
genome during the DNA synthesis phase (S phase), and segregation of complete
sets of chromosomes to each of the daughter cells in M phase (Figure 1A)
...
Dependent on environmental and developmental
signals, cells in G1 may temporarily or permanently leave the cell cycle and enter a
quiescent or arrested phase known as G0
...
Simple representations of the cell cycle
...
M phase consist of nuclear division (mitosis) and cytoplasmic

division (cytokinesis) (B) variant cell cycles in which specific phases are omitted
...
C
...
Shapes outside the cycle indicate
increase and reduction of corresponding CDK/cyclin activity
...
These include rapid embryonic cell
cycles that lack G1 and G2 phases, meiotic cell cycles that allow formation of
haploid gametes, and endoreduplication (or: "endoreplication") cycles in which S
phases are not followed by mitosis
...
elegans development
...
In general, external signals affect this decision only until cells
commit to go through the entire cycle, at a time in G 1 known as "START" in yeast
and "Restriction point" in mammals
...
The basic components
of this machinery are conserved in all eukaryotes
...

The next level of questions include: how is cell division temporally and spatially
controlled during development, and how is progression through the cycle
coordinated with cell growth, differentiation, migration, and death? C
...
Insights into the basic regulators of cell-cycle progression
in C
...

2
...
CDKs are small serine/threonine protein kinases that require
association with a cyclin subunit for their activation
...

Metazoans, including C
...

Many levels of regulation impinge upon the CDKs to impose tight control over cellcycle progression
...


Figure 2
...
CDK activation requires cyclin (CYC)
expression and association
...
Activation
requires ubiquitin-dependent proteolysis of the CKI, phosphorylation of the CDK by a CDK-activating
kinase (CAK; red circle), and removal of the inhibitory phosphates by a Cdc25 phosphatase
...
Ubiquitin-dependent proteolysis of cell cycle regulators in late G1 and S
involves cullin-based E3 ligases such as SCF, while in M phase and early G1 the anaphase-promoting
complex (APC) is active
...


The paradigm for cell-cycle regulation through activation and inactivation of CDKs
applies to all eukaryotes
...
In addition, some regulators are absent in single cell eukaryotes,
including the pRb and E2F families, and nearly all regulatory genes have expanded
into subfamilies with multiple members in mammals
...
elegans uses well-recognizable homologs
of nearly all mammalian regulators, often represented by just a single member
(Table 1)
...
elegans
...

elegans cell-cycle genes into pathways that resemble those in mammals, and novel
regulatory elements have been discovered
...
C
...
RNAi: one-cell
entry/progression
arrest

cdk-4

Cdk4/Cdk6

Promotes Progression G1 arrest, starting late
through G1
embryogenesis

cdk-7

Cdk7

CDK
activating cdk-7(ax224 RNAi):
kinase/Pol II CTD kinase one-cell arrest

cyd-1

Cyclin
D1/D2/D3

G1 Cyclin,
promotes G1 arrest, starting late
progression through G1 in embryogenesis

cye-1 evl-10

Cyclin E1/E2

G1/S Cyclin

Kip1

Cip/Kip family CDK
Extra cell division
inhibitor
...


Cyclins

Late larval defects
...
1

Cdc25

Sterile lavae (RNAi;
CDK activating dual
early
embryonic
specificity phosphatase
defects)

Myt1/Wee1

CDK inhibitory kinase

pRb/p107

Suppresses cdk-4/cydCo-repressor
...
Similar to lin-35 loss of
Negative regulator G1 function (but weaker)

wee1
...

but suppresses cdkPos/Neg regulator G1
4/cyd-1

lin-36

unknown

Zn2+ finger protein
...

from failure in cellG1 cyclin degradation
cycle exit

F box factor

Hyperplasia, resulting
SCF substrate specificity
from failure in cellfactor
cycle exit

Gene
Alternate Homolog
name

Presumed function

mat-1 pod-5

APC3, Cdc27

Component APC
Ubiquitin ligase

E3

APC1

Component APC
Ubiquitin ligase

E3

APC8, Cdc23

Component APC
Ubiquitin ligase

E3

embpod-6
27

APC6, Cdc16

Component APC
Ubiquitin ligase

E3

emb30

APC4

Component APC
Ubiquitin ligase

E3 Arrest at metaphaseto-anaphase transition

podmat-2
3, evl-22
mat-3 pod-4

Cell-cycle phenotype
(loss of function)
Arrest at metaphaseto-anaphase transition
meiosis
Arrest at metaphaseto-anaphase transition
meiosis
Arrest at metaphaseto-anaphase transition
meiosis
Arrest at metaphaseto-anaphase transition
meiosis

DNA damage/DNA replication checkpoint
mrt-2

clk-2

hus-1

cep-1

rad-5

Rad1

DNA-damage
checkpoint protein

Deficient in apoptosis
in response to DNA
damage

ScTel2p

DNA-damage
checkpoint protein

Deficient in apoptosis
in response to DNA
damage

Hus1

DNA-damage
checkpoint protein

Deficient in apoptosis
in response to DNA
damage

p53

Transcription
DNA-damage
checkpoint

factor Deficient in apoptosis
in response to DNA
damage

Spindle assembly checkpoint
mdf-1

MAD1

Mitotic
Spindle
assembly defective
checkpoint protein
nocodazole
...
Regulators of the cell cycle
3
...
CDKs and cyclins
The C
...
At least two CDKs, CDK-1 and CDK-4, are essential for cell-cycle
progression (Boxem et al
...
These CDKs act at distinct times in the cell cycle and use specific
cyclin partners, similar to their mammalian orthologs (Table 1)
...
, 1994)
...
, 1999)
...
Several observations indicate that the postembryonic precursor cells in these mutants arrest in G2 phase: such cells show
normal expression of the rnr::GFP reporter and BrdU incorporation during S phase,
but fail to proceed into mitosis (as indicated by absence of chromosome
condensation and nuclear envelope breakdown)
...
Following RNAi of cdk-1 in adult
hermaphrodites, oocytes show delayed meiotic maturation, form an eggshell upon
fertilization, but neither align nor segregate homologous chromosomes
...

CDK-1 likely acts with mitotic cyclins of the A and B subfamilies (Kreutzer et al
...
A single full-length cyclin A gene (cya-1) is expressed in C
...
1 and cyb-2
...
While cyb-1 and cyb-3 each are individually

required during embryonic development, simultaneous inactivation of these
mitotic cyclins causes a more severe phenotype: cyb-1;cyb-3(RNAi) embryos arrest
at the one-cell stage and resemble cdk-1(RNAi) embryos (our unpublished results)
...

The cdk-4 Cdk4/6 kinase and cyd-1 D-type cyclin genes are required for progression
through G1 phase during larval development (Boxem and van den Heuvel,
2001; Park and Krause, 1999)
...
In contrast to larval divisions, only a few very late embryonic
divisions depend on cyd-1/cdk-4 activity (Boxem and van den Heuvel,
2001; Yanowitz and Fire, 2005)
...
Also, as one of its most important functions, cyd-1 and cdk-4 act
to antagonize the transcriptional repressor lin-35 Rb (see below; (Boxem and van
den Heuvel, 2001)
...
Also, cyd-1 and cdk-4 could primarily promote
growth, as in Drosophila (Datar et al
...
, 2000), which is not
incorporated in the embryonic divisions
...
Therefore, absence of G1 phases and maternal
contribution of DNA replication components likely explain the limited requirement
for cyd-1/cdk-4 during embryogenesis
Taken together, CDK-1 and CDK-4 act in G2/M and G1, respectively, like their
mammalian orthologs Cdk-1 and Cdk4/6
...

elegans also uses a Cdk2 ortholog, which acts subsequent to Cdk4/6 in mammals
to promote G1/S and S phase progression
...
3, which
shares 43% amino-acid identity with human Cdk2 (Boxem et al
...
Inhibition
of this gene by RNAi resulted in a variable phenotype, with animals arresting during
embryogenesis, during early or late larval development, and as sterile adults
...
C
...
This modest phenotype apparently depends on long lasting

maternal function, as RNAi results in embryonic lethality at approximately the
hundred-cell stage (Brodigan et al
...

Several other members of the Cdk superfamily are present in C
...
, 1999; Liu and Kipreos, 2000)
...
, 1995)
...
In
addition, partial inactivation of cdk-7 interfered with transcription and
phosphorylation of the RNA polymerase CTD
...

Several other CDKs are likely to act independent of the cell cycle
...
Two other CDKs, CDK8 and CDK-9, likely are involved specifically in regulating transcription (Liu and
Kipreos, 2000; Shim et al
...

3
...
CDK inhibitory proteins
Association with small inhibitory proteins is a universal mechanism of CDK
regulation (Sherr and Roberts, 1999), though the CKIs (Cyclin-dependent Kinase
Inhibitors) involved are highly divergent between yeasts and metazoans
...
The C
...
,
1999; Hong et al
...
Although both predicted proteins are similarly close in
amino-acid sequence to p21Cip1 and p27Kip1, only CKI-1 appears to act generally in
cell-cycle control (Boxem and van den Heuvel, 2001; Feng et al
...
, 2003; Hong et al
...

Several results have shown that CKI-1 acts to promote cell-cycle arrest throughout
development, analogous to p27Kip1 in mammals and Dacapo in flies
...
,

2003)
...
Moreover, similar defects were
observed in a fraction of cki-1(RNAi) embryos
...
, 1998)
...

Thus, cki-1 Kip1 function is rate limiting for S phase entry, particularly in cells that
enter a prolonged quiescent state before re-entering the cell cycle
...
, 2003)
...
3
...
Proteins of the pRb
family exert this role through association with transcription factors, primarily with
E2F/DP heterodimers (together referred to as "E2F"; Stevaux and Dyson, 2002)
...
In
addition, to inhibit transcription, "repressive E2Fs" recruit pRb family members and
associated chromatin remodeling complexes such as the Nucleosome Remodeling
and Deacetylase (NuRD) complex
...
elegans have been identified as class
B synthetic Multivulva (synMuv) genes (see Vulval development)
...
The fact that these genes have similar, rather than opposite, loss-of-function
phenotypes provided strong in vivo evidence that E2F/DP can act as a
transcriptional repressor, in concert with pRb and NuRD
...

Homozygous lin-35 Rb mutants do not display a prominent increase in cell division,
although a fraction of such animals form extra intestinal nuclei (Saito et al
...


However, the contribution of lin-35 Rb to negative regulation of G1 progression
became apparent in double mutant combinations
...
In
addition, lin-35 inactivation synergistically increases the number of extra cell
divisions when combined with negative G1 regulators, such as cki-1 Cip/Kip, cdc14 Cdc14 and fzr-1 Cdh1/FZR (Boxem and van den Heuvel, 2001; Fay et al
...
, 2004)
...

Examination of additional double mutant combinations revealed that some of the
other synMuv class B genes also contribute to G1 control (Boxem and van den
Heuvel, 2002;Fay et al
...
Specifically, efl-1 E2F negatively regulates cell-cycle
entry, while dpl-1 DP appears to act both as a positive and negative regulator
...
Class A synMuv genes and
class B genes that encode NURD components have not been observed to affect the
cell cycle
...
elegans include cye-1 Cyclin E and rnr1, which encodes the ribonucleotide reductase large subunit
...
,
2003; Hong et al
...
Several genetic
observations are also consistent with lin-35 acting upstream of cye-1 to repress its
transcription (Boxem and van den Heuvel, 2001; our unpublished observations)
...
Genetic interactions between regulators of G1/S progression, indicating
conserved mechanisms and pathways
...

3
...
Positive and negative phosphorylation of CDKs
In all eukaryotes studied, CDKs are regulated by phosphorylation and
dephosphorylation of critical residues
...
Phosphorylation of these
residues by the related Wee1 and Myt1 kinases prevents activation of the
CDK/cyclin complex
...

Inhibitory phosphorylation allows for developmental regulation of CDK activity, as
demonstrated for the String and Twine phosphatases in Drosophila
...
elegans,
two different Wee1/Myt1 kinases are expressed (wee-1
...
3), as are four
phosphatases of the Cdc25 family (cdc-25
...
4)
...
3 null
mutants are embryonic lethal and cdc-25
...
In the latter mutants,
maternal product likely masks the embryonic function of cdc-25
...
1during female meiosis and embryonic divisions
(Ashcroft et al
...
, 2002)
...
1 and wee-1
...
Two independent dominant mutations in cdc25
...
, 2002; Kostic and Roy,
2002)
...
3 Myt1 cause spermatogenesis
defects, resulting from G2/M arrest during male meiosis (Lamitina and L'Hernault,
2002)
...

Which CDKs are regulated by inhibitory phosphorylation in C
...
3 each contain adjoining threonine and tyrosine
residues, while CDK-4 contains alanine and tyrosine at the corresponding positions,
similar to vertebrate Cdk4/Cdk6
...
3 mutations
affect CDK-1, whilecdc-25
...

In addition to inhibition, CDKs are also positively regulated by phosphorylation
...
Based on results in other species, CDK7 was examined as the candidate positive regulator (Wallenfang and Seydoux,
2002)
...

These results indicate strongly that CDK-7 kinase activity is required for CDK1 activation (see also: CDKs and cyclins)
...
5
...
In C
...
Blast cells undergo
excessive divisions in all post-embryonic lineages in lin-19/cul-1 and lin-23 loss-offunction mutants (Kipreos et al
...
, 1996)
...
Thus, cul-1 and lin-23 act to promote cell-cycle exit
...
, 1996)
...
, 2000)
...
elegans )
...
CYE-1 Cyclin E is a candidate critical target of CUL-1/LIN23 SCF, analogous to the role of vertebrate Cul1 SCF
...
elegans and cell-cycle
related functions have also been reported for three additional members
...
, 1999) and
are defective in progression through meiotic anaphase II (Liu et al
...
CUL-3 is specifically required for degradation of MEI-1, a
subunit of a katanin complex that severs microtubules and is essential for meiotic
chromosome segregation (Furukawa et al
...
, 2003; van den
Heuvel, 2004; Xu et al
...
Finally, cul-4is essential to prevent re-replication of
DNA, likely by promoting degradation of the replication licencing factor CDT1 (Zhong et al
...
These results demonstrate the importance of various cullinbased ubiquitin ligases in cell-cycle progression
...
As in other eukaryotes, C
...
emb-30 is required for the
metaphase-to-anaphase transition in meiosis and mitosis and encodes the APC
subunit APC4 (Furuta et al
...
Moreover, a screen for temperature-sensitive
embryonic lethal mutations revealed a large number of metaphase-toanaphase transition (mat) mutants (Golden et al
...
These mat mutants arrest
in metaphase of meiosis I and helped define five different genes that all encode
components of the APC (Table 1)
...

Degradation of securin releases separase, which cleaves cohesins and triggers sister
chromosome separation
...
elegans,
involving FZY-1 as the substrate specificity factor homologous to Cdc20/Fizzy,
the interactor of FZY-1, as candidate securin and SEP-1 as the C
...
, 2002)
...

Loss of function of fzr-1, the C
...
, 2002)
...
The latter mechanism
has been observed in human cells, in which Cdh1/FZR promotes accumulation of
p27Kip1 through degradation of the F box factor that targets p27 Kip1 for destruction
(Bashir et al
...
, 2004)
...
This assures that cellular
growth and the coordination of DNA synthesis with cell-size increase and
cytokinesis are monitored and do not fall out of regulated synchrony
...
Cyclins,
cyclin-dependent kinases (Cdks), and the Rbprotein are all elements of the control
system that regulate passage through the restriction point
...
Altered regulation of expression of at least
one cyclin as well as mutation of several proteins that negatively regulate passage
through the restriction point can be oncogenic
...
These cyclins (D1, D2, and D3)
assemble with their partners Cdk4 and Cdk6 to generate catalytically active kinases
...
Another key player in cell-cycle control is the
Rbprotein
...

Also, the Rb-E2F complex acts as a transcriptional repressor for many of these same
genes
...
Rb phosphorylation is initiated by
an active Cdk4 – cyclin D complex and is completed by other cyclin-dependent
kinases
...

Overexpression of Cyclin D1
Gene amplification or a chromosome translocation that places cyclin D1 under
control of an inappropriate promoter leads to overexpression of this cyclin in many
human cancers, indicating that it can function as an oncoprotein
...
(This phenomenon is analogous to the c-myc translocation in Burkitt’s
lymphoma cells discussed earlier
...
Initially
the ductal cells underwent hyper proliferation, and eventually breast tumors
developed in these transgenic mice
...


Loss of p16 Function
The group of proteins that function as cyclin-kinase inhibitors (CKIs) play an
important role in regulating the cell cycle
...
Loss of p16 would mimic cyclin D1
over expression, leading to Rb hyper phosphorylation and release of active E2F
transcription factor
...

Loss of Rb Function
As already noted, loss of Rb functions, whether by inherited or somatic mutation,
leads to induction of many types of cancers, childhood retinoblastoma most
notably
...
In contrast, tumor cells that
overexpress cyclin D1 or have lost p16 function generally retain wild-type Rb
...
We noted previously that the small DNA-containing human
papillomavirus (HPV) is able to induce stable transformation and transient
mitogenic stimulation of a variety of cultured cells
...
The E7 protein is essential for HPV-mediated
transformation of cells
...
Tumor derived growth factor β (TGFβ) is secreted by most
body cells and has a diverse range of biological activities
...
Loss of TGFβmediated growth inhibition contributes to the development and progression of a
variety of tumors
...
Binding of TGFβ induces formation of a complex of the type
I and type II receptors and phosphorylation and activation of the type I receptor by
the type II receptor kinase
...
The ligandactivated type I receptor phosphorylates conserved serines at the C-terminus of

either Smad2 or Smad3, which enables them to bind to one or more molecules of
Smad4, a common partner for all phosphorylated Smads involved in signaling by
both TGFβ and bone morphogenic proteins
...
One important gene
induced by TGFβ encodes p15
...
Thus by inducing expression
of p15, TGFβ causes the cell to arrest in G1
...

Tumor suppressor genes code for anti-proliferation signals and proteins that
suppress mitosis and cell growth
...
Often DNA damage will
cause the presence of free-floating genetic material as well as other signs, and will
trigger enzymes and pathways that lead to the activation of tumor suppressor
genes
...
The p53 protein, one of the most important studied tumor
suppressor genes, is a transcription factor activated by many cellular stressors
including hypoxia and ultraviolet radiation damage
...
p53 clearly has two functions: one a
nuclear role as a transcription factor, and the other a cytoplasmic role in regulating
the cell cycle, cell division, and apoptosis
...
p53 has been shown to regulate the shift from the respiratory to
the glycolytic pathway
...
The invariable consequence of this is
that DNA repair is hindered or inhibited: DNA damage accumulates without repair,
inevitably leading to cancer
...
Members of these families have increased incidence and decreased
latency of multiple tumors
...
The mode of inheritance of mutant tumor
suppressors is that an affected member inherits a defective copy from one parent,
and a normal copy from the other
...

Other inherited tumor suppressor gene syndromes include Rb mutations, linked
toretinoblastoma, and APC gene mutations, linked to adenopolyposis colon
cancer
...
Finally,
inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer
...
In what became known as the Knudson two-hit hypothesis, an inherited,
germ-line mutation in a tumor suppressor gene would cause cancer only if another
mutation event occurred later in the organism's life, inactivating the other allele of
that tumor suppressor gene
...
Each cell has two copies of the same gene, one from each parent, and
under most cases gain of function mutations in just one copy of a particular protooncogene is enough to make that gene a true oncogene
...
However, cases exist in which one
mutated copy of a tumor suppressor gene can render the other, wild-type copy
non-functional
...

Knudson's two hit model has recently been challenged by several investigators
...
This phenomenon is called haploinsufficiency and has been demonstrated
by
a
number
of
experimental
approaches
...
[113]

THEORY OF CARCINOGENESIS

Early theories about cancer causes
From the earliest times, physicians have puzzled over the causes of cancer
...


Humoral theory
Hippocrates believed that the body had 4 humors (body fluids): blood, phlegm,
yellow bile, and black bile
...

The belief was that too much or too little of any of the humors caused disease
...
This theory
of cancer was passed on by the Romans and was embraced by the influential doctor
Galen’s medical teaching, which remained the unchallenged standard through the
Middle Ages for over 1,300 years
...


Lymph theory
Among theories that replaced the humoral theory of cancer was the formation of
cancer by another body fluid, lymph
...
Of all
the fluids, the most important were blood and lymph
...
The lymph theory gained rapid support
...


Blastema theory
In 1838, German pathologist Johannes Muller demonstrated that cancer is made
up of cells and not lymph, but he believed that cancer cells did not come from
normal cells
...
His student, Rudolph Virchow (1821-1902), the

famous German pathologist, determined that all cells, including cancer cells, are
derived from other cells
...
” In the 1860s, German surgeon, Karl
Thiersch, showed that cancers metastasize through the spread of malignant cells
and not through some unidentified fluid
...
This belief was maintained
despite the failure of injury to cause cancer in experimental animals
...
They made this
conclusion based on their experiences with breast cancer in members of the same
household
...
They proposed that cancer patients should be isolated, preferably
outside of cities and towns, in order to prevent the spread of cancer
...
In fact, the first cancer hospital in France was forced to move from the
city in 1779 because people feared cancer would spread throughout the city
...

http://www
...
org/cancer/cancerbasics/thehistoryofcancer/the-history-of-cancer-cancer-causestheories-throughout-history

Carcinogenesis or oncogenesis or tumorigenesis is the actual formation of
a cancer, whereby normal cells are transformed into cancer cells
...


Cell division is a physiological process that occurs in almost all tissues and under
many circumstances
...
Mutations and epimutations in DNA that lead to cancer (only certain
mutations and epimutations can lead to cancer and the majority of potential
mutations and epimutations will have no such effect) disrupt these orderly
processes by disrupting the programming regulating the processes
...
This results in uncontrolled cell division and the evolution of those
cells by natural selection in the body
...
Benign tumors do not spread to other parts of the body
or invade other tissues, and they are rarely a threat to life unless they compress
vital structures or are physiologically active, for instance, producing a
hormone
...

More than one mutation is necessary for carcinogenesis
...
[1] On average, for example, 15 "driver mutations" and
60 "passenger" mutations are found in colon cancers
...

Oncovirinae, viruses that contain an oncogene, are categorized as oncogenic
because they trigger the growth of tumorous tissues in the host
...

Cancer is fundamentally a disease of regulation of tissue growth
...
[3] Genetic and epigenetic changes can occur at
many levels, from gain or loss of entire chromosomes, to a mutation affecting
a single DNA nucleotide, or to silencing or activating a microRNA that controls
expression of 100 to 500 genes
...
Oncogenes may be normal genes that are expressed
at inappropriately high levels, or altered genes that have novel properties
...
Tumor suppressor genes are genes that inhibit cell division, survival, or other
properties of cancer cells
...
Typically, changes in many genes are required to
transform a normal cell into a cancer cell
...
Many of these changes are mutations,
or changes in the nucleotide sequence of genomic DNA
...
Aneuploidy, the presence of an abnormal number of chromosomes, is
one genomic change that is not a mutation, and may involve either gain or loss of
one or more chromosomes through errors in mitosis
...
Genomic amplification occurs when a cell gains many copies (often
20 or more) of a small chromosomal region, usually containing one or more
oncogenes and adjacent genetic material
...

A well-known example of this is the Philadelphia chromosome, or translocation of
chromosomes 9 and 22, which occurs inchronic myelogenous leukemia, and results
in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase
...

Disruption of a single gene may also result from integration of genomic
material from a DNA virus or retrovirus, and such an event may also result in the
expression of viral oncogenes in the affected cell and its descendants
...
[7][8][9] Epimutations, can also occur by acetylation,
methylation, phosphorylation or other alterations to histones, creating a histone
code that represses or activates gene expression, and such histone epimutations
can be important epigenetic factors in cancer
...
[12] A further source of epimutation is due to increased or
decreased expression of microRNAs (miRNAs)
...
[13][14] First, there exists a highly positive correlation (Spearman’s
rho = 0
...
5 × 10−8) between the risk of developing cancer in a tissue and
the number of normal stem cell divisions taking place in that same tissue
...
[15] This correlation means that if the normal stem cells from a tissue
divide once, the cancer risk in that tissue is approximately 1X
...
And if the normal stem cells from a tissue divide
100,000 times, the cancer risk in that tissue is approximately 100,000X
...
[14] Second,
statistics show that most human cancers are diagnosed in aged people
...
DNA is
the only cellular component that can accumulate damage during our whole life,
and stem cells are the only cells that can transmit our DNA from the zygote to the
cells we have when we die
...
This implies that most cancers arise
from normal stem cells
...
The type of
cancer is generally based on the part of your body and the type of cell where the
cancer first developed
...

There are three main types of cell where cancer develops:
•

Epithelial cells
...

About 80-90% of cancers are this type
...
Cancers that develop in this type of cell
are called leukaemias and lymphomas
...


•

Connective tissue cells
...
About 1% of cancers are this type
...

Types of cancer
It’s important for doctors to know what type of cancer you have because different
types of cancer can behave very differently and respond to different treatments
...


Cancer types by site
Most people are aware of cancer types when they are described according to
where the cancer first started in the body (the primary site)
...
The most common sites for cancer to develop include the:
•

skin

•

lungs

•

breasts

•

prostate

•

colon and rectum (large bowel)
...
This can be
just as important in how a cancer behaves and responds to treatment as the site
where it started
...
The cells, organised together, make up all
of our tissues and organs
...
Some types are very common and are found in almost all the
organs in our body
...

The main types of cells in our body are:
•

Epithelial cells These cover the outside of our body (as skin) and make up tissues
that line the inside of our bodies and cover our organs
...


•

Connective tissue cells These cells are found in supportive and connective tissues
in our body such as the muscles, bones and fatty tissue
...

Carcinomas
Cancers that start in epithelial cells are called carcinomas
...
Most lung, breast, prostate and bowel cancers are carcinomas
...


•

Adeno cells form the lining of all the glands in the body including those in the
breast, bowel, stomach, ovaries and prostate
...


•

Basal cells are found in the skin
...


•

Squamous cell carcinomas start in squamous cells

•

Adeno carcinomas start in the adeno cells

•

Transitional cell carcinomas start in the urothelial cells

•

Basal cell carcinomas start in the basal cells
...

Cancers that start in the lymphatic system (which helps the body fight infection)
are called lymphomas
...

Sarcomas
Cancers that start in connective tissue cells are called sarcomas
...
They make up fewer than 1 in 100 (1%) of cancers
...

Cancers that start in other types of cells
Cancer can develop in other types of cells but these cancers are rare
...


Role of Growth Factors in progression of cancer
Under physiological conditions, cells receive fate-determining signals from their
tissue surroundings, primarily in the form of polypeptide growth factors
...
Although
disturbance in homeostasis and tumor initiation are instigated by oncogenic
mutations rather than by growth factors, the latter are the major regulators of all
subsequent steps of tumor progression, namely (1) clonal expansion, (2) invasion
across tissue barriers, (3) angiogenesis, and (4) colonization of distant niches
...
When studying mechanisms
enabling limb innervation in chick embryos, they grafted a lump of a mouse
sarcoma onto an embryo and observed more extensive attraction of nerve fibers
to the lump
...

Two “transforming growth factors,” TGF-alpha and TGF-beta were isolated from
murine sarcoma
...
Some gene families, in particular protein
kinase cascades placed downstream of GF receptors, are often mutated in tumors
such as melanomas (B-RAF), pancreatic (RAS), breast (ErbB-2/HER2), and brain
cancer (EGFR), but co-existence of such mutations is very rare and some tumors are
characterized by enhanced secretion of GFs and chemotactic cytokines
...
GFs are
compact polypeptides, which bind to transmembrane
receptors harboring kinase activity, to stimulate specific combinations of
intracellular signaling pathways, such as the mitogen-activated protein kinase
(MAPK), the phosphatidylinositol 3-kinase (PI3K), phospholipase C and
transcription factors like the signal transducers and activators of transcription
(STATs) or SMAD proteins
...


1
...
Unlike the paracrine mode of action of
GFs that dominates physiological processes like embryogenesis and wound
healing; many cancer cells acquire the ability to synthesize GFs to which they
are responsive
...
Accelerated intraepithelial proliferation
An important feature of intraepithelial lesions is the integrity of the
surrounding basement membrane
...

3
...
GFs play critical roles in
basement membrane disruption, penetration by cancer cells into
neighboring tissues, the vascular or lymphatic systems (intravasation), as
well as their departure from the bloodstream (extravasation) and
subsequent colonization of distant organs
...
Intravasation, extravasation, and dissemination
Paracrine interactions among cancer cells, macrophages, and
endothelial cells critically facilitate intravasation of post-EMT cells
...
Because macrophages are often found in close
proximity to microvessels, this self stimulatory loop enhances intravasation
...
Once in the
circulation, tumor cells adhere to platelets, especially on stimulation by
thrombin, thereby gaining mitogenic stimuli (e
...
, PDGF and
lysophosphatidic acid) and protection from natural killer cells
...
GF-induced angiogenesis
The generation of new vessels is critical for tumor growth beyond few
millimeters of size
...
Growth
factors like the vascular endothelial growth factors (VEGFs), FGFs, and TGF-_

play important roles in both vasculogenesis and angiogenesis, and VEGF
antagonists limit angiogenesis in animals and in patients
...
Neuregulins and the EGF family
The family comprises eleven polypeptides sharing a conserved EGF
domain
...
All EGF family members
bind to a group of four receptor tyrosine kinases, namely ErbB-1/ EGFR
through -4
...
Insulin-like growth factors
The insulin-like growth factor (IGF) axis consists of two cell surface
receptors (IGF1R and IGF2R), two ligands (IGF1 and IGF2), a family of six highaffinity IGF binding proteins (IGFBP1–6), as well as associated IGFBP
degrading enzymes
...
Transforming growth factor-β
TGF-β exists in three isoforms (TGF-β1, TGF-β2, and TGF-β3), but the
extended superfamily includes more than 30 additional cytokines, classified
into several subfamilies [e
...
, bone morphogenetic proteins (BMPs) and
activins]
...

This cytokine induces a cytostatic effect on many epithelial cell types, and it
is also able to control proliferation, differentiation, and programmed cell
death in most other cell types because the receptors, heterotetrameric
serine/threonine kinases, are widely expressed in derivatives of all three
embryonic cell layers
...
VEGFs
VEGFs regulate both vasculogenesis and angiogenesis
...
In addition, alternative exon splicing
generates four VEGF isoforms
...

ONCOGENE AND THEIR ROLE IN CANCER

An oncogene is a gene that has the potential to cause cancer
...
[2]
Most normal cells will undergo a programmed form of rapid cell death (apoptosis)
when critical functions are altered
...
[3] Most oncogenes
require an additional step, such as mutations in another gene, or environmental
factors, such as viral infection, to cause cancer
...
Many cancer drugs target
the proteinsencoded by oncogenes
...
1947-53 head of Copenhagen
University geophysics research) at around 1950, but was rejected by
contemporaries as nonsense
...
[7]
The first confirmed oncogene was discovered in 1970 and was
termed src (pronounced sarc as in sarcoma)
...
Experiments performed by Dr
...
Steve Martin of
the University of California, Berkeley demonstrated that the Src was indeed the
oncogene of the virus
...
P
...
[9]
In 1976 Drs
...
Michael Bishop and Harold E
...
For this
discovery, proving Todaro and Heubner's "oncogene theory", Bishop and Varmus
were awarded the Nobel Prize in Physiology or Medicine in 1989
...

Some oncoproteins are accepted and used as tumor markers

Proto-oncogene
A proto-oncogene is a normal gene that could become an oncogene due to
mutations or increased expression
...
[11] Proto-oncogenes code for proteins that help to
regulate cell growth and differentiation
...
Upon activation, a proto-oncogene (or its product)
becomes a tumor-inducing agent, an oncogene
...
The MYC gene is implicated in
Burkitt'sLymphoma, which starts when a chromosomal translocation moves an
enhancer sequence within the vicinity of the MYC gene
...
When the enhancer sequence is wrongly placed,
these transcription factors are produced at much higher rates
...
Bcr-Abl codes for a tyrosine
kinase, which is constitutively active, leading to uncontrolled cell proliferation
...
There are three basic methods of activation:
1
...
An increase in the amount of a certain protein (protein concentration),
caused by
• an increase of protein expression (through misregulation)
• an increase of protein (mRNA) stability, prolonging its existence and thus
its activity in the cell
• gene duplication (one type of chromosome abnormality), resulting in an
increased amount of protein in the cell
3
...
This type of
mutation in a dividing stem cell in the bone marrow leads to
adult leukemia
Philadelphia Chromosome is an example of this type of translocation
event
...
The broken end of chromosome 22 contains the
"BCR" gene, which fuses with a fragment of chromosome 9 that contains
the "ABL1" gene
...
This fused gene encodes
for a protein that displays high protein tyrosine kinase activity (this
activity is due to the "ABL1" half of the protein)
...
As a result, the Philadelphia
Chromosome is associated with Chronic Myelogenous Leukemia (as
mentioned before) as well as other forms of Leukemia
...
[14]Mutations in such microRNAs (known as oncomirs) can
lead to activation of oncogenes
...

Classification
There are several systems for classifying oncogenes,[16][17] but there is not yet a
widely accepted standard
...
There are several categories that are commonly
used:
Category

Examples

Cancers

Gene functions

Growth factors,
c-Sis
or mitogens

epidermal growth
factor
receptor (EGFR), pl
atelet-derived
growth
factor
receptor (PDGFR),
andvascular
endothelial growth
factor receptor
(VEGFR),HER2/neu

glioblastomas, fibrosarc
omas, osteosarcomas, induces
cell
breast
carcinomas, proliferation
...


colorectal and breast
Src-family, Sykcancers, melanomas,
ZAP-70 family,
ovarian cancers, gastric
and BTK family of
Cytoplasmic tyro
cancers, head and neck
tyrosine kinases,
sine kinases
cancers,
pancreatic
the Abl gene in CML
cancer, lung cancer,
- Philadelphia
brain cancers, and
chromosome
blood cancers[20]

mediate
the
responses
to,
and
the
activation
receptors of cell
proliferation,
migration,
differentiation,
and survival[21]

CytoplasmicSerin
e/threonine
kinases and their
regulatory
subunits

Involved
in
organism
development,
cell
cycle
regulation, cell
proliferation,
differentiation,

Receptor
tyrosine kinases

Raf
kinase,
and cyclindependent
kinases (throughov
erexpression)
...
[25]

Transcription
factors

malignant
T-cell
lymphomas and acute
myleoidleukemias,
breast
cancer,
pancreatic
cancer,
retinoblastoma,
and
small cell lung cancer[26]

myc gene

-They regulate
transcription of
genes
that
induce
cell
proliferation
...
An oncogene may cause a cell to secrete growth factors even
though it does not normally do so
...
It may also cause production of growth hormones in
other parts of the body
...
Receptor kinases add phosphate groups to receptor
proteins at the surface of the cell (which receive protein signals from
outside the cell and transmit them to the inside of the cell)
...
They can cause cancer by turning the receptor permanently on
(constitutively), even without signals from outside the cell
...
Ras is
activated by growth factor signaling (i
...
, EGF, TGFbeta) and acting like a
binary switch (on/off) in growth signaling pathways
...

Oncogenes and tumor suppressor genes
Two of the main types of genes that play a role in cancer are oncogenes and tumor
suppressor genes
...
When a proto-oncogene
mutates (changes) or there are too many copies of it, it becomes a "bad" gene that
can become permanently turned on or activated when it is not supposed to
be
...
This
bad gene is called an oncogene
...
For it to work properly, there need to be
ways to control how fast it goes
...
It helps the cell grow and divide
...

A few cancer syndromes are caused by inherited mutations of proto-oncogenes
that cause the oncogene to be turned on (activated)
...
They generally activate
oncogenes by:
•
•

Chromosome rearrangements: Changes in chromosomes that put one gene
next to another, which allows one gene to activate the other
Gene duplication: Having extra copies of a gene, which can lead to it making
too much of a certain protein

Tumor suppressor genes
Tumor suppressor genes are normal genes that slow down cell division, repair DNA
mistakes, or tell cells when to die (a process known as apoptosis or programmed
cell death)
...


A tumor suppressor gene is like the brake pedal on a car
...
When
something goes wrong with the gene, such as a mutation, cell division can get out
of control
...

Inherited abnormalities of tumor suppressor genes have been found in some family
cancer syndromes
...
But most
tumor suppressor gene mutations are acquired, not inherited
...
Acquired mutations of this
gene appear in a wide range of cancers
...
Most
tumor markers are made by normal cells as well as by cancer cells; however, they
are produced at much higher levels in cancerous conditions
...
Most tumor markers are proteins
...

Many different tumor markers have been characterized and are in clinical use
...
No “universal” tumor marker that can detect any
type of cancer has been found
...
Sometimes, noncancerous
conditions can cause the levels of certain tumor markers to increase
...
Moreover, tumor markers have not been
identified for every type of cancer
...
Although an elevated level of a tumor marker may suggest the presence of
cancer, this alone is not enough to diagnose cancer
...

Tumor marker levels may be measured before treatment to help doctors plan the
appropriate therapy
...
More information about staging is available in the NCI fact
sheet Cancer Staging
...
A
decrease in the level of a tumor marker or a return to the marker’s normal level
may indicate that the cancer is responding to treatment, whereas no change or an
increase may indicate that the cancer is not responding
...

How are tumor markers measured?
A doctor takes a sample of tumor tissue or bodily fluid and sends it to a laboratory,
where various methods are used to measure the level of the tumor marker
...
Usually these “serial measurements,” which show
whether the level of a marker is increasing, staying the same, or decreasing, are
more meaningful than a single measurement
...
However, some national and international
organizations do have guidelines for the use of tumor markers for some types of
cancer:

•

•

The American Society of Clinical Oncology (ASCO) has published clinical practice
guidelinesExit Disclaimer on a variety of topics, including tumor markers for
breast cancer, colorectal cancer, lung cancer, and others
...


What tumor markers are currently being used, and for which cancer types?
A number of tumor markers are currently being used for a wide range of cancer
types
...
Tumor markers that are currently in
common use are listed below
...
29
•

Cancer type: Breast cancer

•

Tissue analyzed: Blood

•

How used: To assess whether treatment is working or disease has recurred

CA19-9
•

Cancer types: Pancreatic cancer, gallbladder cancer, bile duct cancer, and
gastric cancer

•

Tissue analyzed: Blood

•

How used: To assess whether treatment is working

CA-125
•

Cancer type: Ovarian cancer

•

Tissue analyzed: Blood

How used: To help in diagnosis, assessment of response to treatment, and
evaluation of recurrence
Calcitonin
• Cancer type: Medullary thyroid cancer
•

•

Tissue analyzed: Blood

•

How used: To aid in diagnosis, check whether treatment is working, and assess
recurrence

Carcinoembryonic antigen (CEA)
•

Cancer types: Colorectal cancer and some other cancers

•

Tissue analyzed: Blood

•

How used: To keep track of how well cancer treatments are working or check if
cancer has come back

CD20
• Cancer type: Non-Hodgkin lymphoma
•

Tissue analyzed: Blood

•

How used: To determine whether treatment with a targeted therapy is
appropriate

Chromogranin A (CgA)
• Cancer type: Neuroendocrine tumors
•

Tissue analyzed: Blood

•

How used: To help in diagnosis, assessment of treatment response, and
evaluation of recurrence

Chromosomes 3, 7, 17, and 9p21
•

Cancer type: Bladder cancer

•

Tissue analyzed: Urine

•

How used: To help in monitoring for tumor recurrence

Circulating tumor cells of epithelial origin (CELLSEARCH®)
• Cancer types: Metastatic breast, prostate, and colorectal cancers
•

Tissue analyzed: Blood

•

How used: To inform clinical decision making, and to assess prognosis

Cytokeratin fragment 21-1
•

Cancer type: Lung cancer

•

Tissue analyzed: Blood

•

How used: To help in monitoring for recurrence

EGFR gene mutation analysis
•

Cancer type: Non-small cell lung cancer

•

Tissue analyzed: Tumor

•

How used: To help determine treatment and prognosis

Estrogen receptor (ER)/progesterone receptor (PR)
•

Cancer type: Breast cancer

•

Tissue analyzed: Tumor

•

How used: To determine whether treatment with hormone therapy and some
targeted therapies is appropriate

Fibrin/fibrinogen
•

Cancer type: Bladder cancer

•

Tissue analyzed: Urine

•

How used: To monitor progression and response to treatment

HE4
•

Cancer type: Ovarian cancer

•

Tissue analyzed: Blood

•

How used: To plan cancer treatment, assess disease progression, and monitor
for recurrence

HER2/neu gene amplification or protein overexpression

•

Cancer types: Breast
junctionadenocarcinoma

cancer,

gastric

cancer,

and gastroesophageal

•

Tissue analyzed: Tumor

•

How used: To determine whether treatment with certain targeted therapies is
appropriate

Immunoglobulins
•

Cancer types: Multiple myeloma and Waldenströmmacroglobulinemia

•

Tissue analyzed: Blood and urine

•

How used: To help diagnose disease, assess response to treatment, and look
for recurrence

KRAS gene mutation analysis
•

Cancer types: Colorectal cancer and non-small cell lung cancer

•

Tissue analyzed: Tumor

•

How used: To determine whether treatment with a particular type of targeted
therapy is appropriate

Lactate dehydrogenase
• Cancer types: Germ cell tumors, lymphoma, leukemia, melanoma,
and neuroblastoma
•

Tissue analyzed: Blood

•

How used: To assess stage, prognosis, and response to treatment

Neuron-specific enolase (NSE)
•

Cancer types: Small cell lung cancer and neuroblastoma

•

Tissue analyzed: Blood

•

How used: To help in diagnosis and to assess response to treatment

Nuclear matrix protein 22
•

Cancer type: Bladder cancer

•

Tissue analyzed: Urine

•

How used: To monitor response to treatment

Programmed death ligand 1 (PD-L1)
•

Cancer type: Non-small cell lung cancer

•

Tissue analyzed: Tumor

•

How used: To determine whether treatment with a particular type of targeted
therapy is appropriate

Prostate-specific antigen (PSA)
•

Cancer type: Prostate cancer

•

Tissue analyzed: Blood

•

How used: To help in diagnosis, assess response to treatment, and look for
recurrence

Thyroglobulin
•

Cancer type: Thyroid cancer

•

Tissue analyzed: Blood

•

How used: To evaluate response to treatment and look for recurrence

Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1)
•

Cancer type: Breast cancer

•

Tissue analyzed: Tumor

•

How used: To determine aggressiveness of cancer and guide treatment

5-Protein signature (OVA1®)
•

Cancer type: Ovarian cancer

•

Tissue analyzed: Blood

•

How used: To pre-operatively assess pelvic mass for suspected ovarian cancer

21-Gene signature (Oncotype DX®)
•

Cancer type: Breast cancer

•

Tissue analyzed: Tumor

•

How used: To evaluate risk of recurrence

70-Gene signature (Mammaprint®)
•

Cancer type: Breast cancer

•

Tissue analyzed: Tumor

•

How used: To evaluate risk of recurrence

Can tumor markers be used in cancer screening?
Because tumor markers can be used to assess the response of a tumor to treatment
and for prognosis, researchers have hoped that they might also be useful in
screening tests that aim to detect cancer early, before there are any symptoms
...
If a test is highly sensitive, it will identify most
people with the disease—that is, it will result in very few false-negative results
...

Although tumor markers are extremely useful in determining whether a tumor is
responding to treatment or assessing whether it has recurred, no tumor marker
identified to date is sufficiently sensitive or specific to be used on its own to screen
for cancer
...
However, an
increased PSA level can be caused by benign prostate conditions as well as by
prostate cancer, and most men with an elevated PSA level do not have prostate
cancer
...
Moreover, it is not clear whether the benefits of PSA screening outweigh
the harms of follow-up diagnostic tests and treatments for cancers that in many
cases would never have threatened a man’s life
...
An analysis of 28 potential markers for
ovarian cancer in blood from women who later went on to develop ovarian cancer
found that none of these markers performed even as well as CA-125 at detecting
the disease in women at average risk
...

Scientists are also evaluating patterns of gene expression for their ability to help
determine a patient’s prognosis or response to therapy
...
The trial is ongoing to see whether women at
intermediate risk of recurrence, based on the 21-gene test, do better with
chemotherapy in addition to hormone therapy than with hormone therapy alone
...

Diet and Physical Activity: What’s the Cancer Connection?
How much do daily habits like diet and exercise affect your risk for cancer? Much
more than you might think
...
The good news is that you
do something about this
...

• Be physically active on a regular basis
...

The evidence for this is strong
...

•

Control your weight
...
Being overweight
or obese increases the risk of several cancers, including those of the breast (in
women past menopause), colon and rectum, endometrium (the lining of the
uterus), esophagus, pancreas, and kidney, among others
...
One of the main ways is
that excess weight causes the body to produce and circulate more estrogen and
insulin, hormones that can stimulate cancer growth
...
Use our easy online BMI calculator to find out your score
...
Ask your
doctor what your BMI number means and what action (if any) you should take
...
Also try to limit your
intake of high-calorie foods and drinks
...


Be more active
...
The other key is to
be more physically active
...
It can also help improve your hormone levels and the way your
immune system works
...
This is over and above usual
daily activities like using the stairs instead of the elevator at your office or doing
housework
...

Moderate activities are those that make you breathe as hard as you would during
a brisk walk
...
Vigorous activities make you use large muscle groups and make your
heart beat faster, make you breathe faster and deeper, and also make you sweat
...

Being more physically active than usual, no matter what your level of activity, can
have many health benefits
...

Eating well is an important part of improving your health and reducing your cancer
risk
...

• Read food labels to become more aware of portion sizes and calories
...
”
• Eat smaller portions when eating high-calorie foods
...

• Limit your intake of sugar-sweetened beverages such as soft drinks, sports
drinks, and fruit-flavored drinks
...

Limit how much processed meat and red meat you eat
...

• Choose fish, poultry, or beans instead of red meat (beef, pork, and lamb)
...

• Prepare meat, poultry, and fish by baking, broiling, or poaching rather than by
frying or charbroiling
...

• Include vegetables and fruits at every meal and snack
...

• Emphasize whole fruits and vegetables; choose 100% juice if you drink
vegetable or fruit juices
...

Choose whole grains instead of refined grain products
...

• Limit your intake of refined carbohydrate foods, including pastries, candy,
sugar-sweetened breakfast cereals, and other high-sugar foods
...
The recommended limit is lower for
women because of their smaller body size and slower breakdown of alcohol
...
In terms of cancer risk, it is the amount of
alcohol, not the type of alcoholic drink that is important
...


Reducing cancer risk in our communities
Adopting a healthier lifestyle is easier for people who live, work, play, or go to
school in an environment that supports healthy behaviors
...

We all can be part of these changes: Let’s ask for healthier food choices at our
workplaces and schools
...
Support restaurants that help you to eat well by offering
options like smaller portions, lower-calorie items, and whole-grain products
...

The bottom line
It has been estimated that as much as one-third of all cancer deaths in the US are
related to diet and activity factors
...

How can cancer be detected early?
In many cases, the sooner cancer is diagnosed and treated, the better a person's
chance for a full recovery
...
Often a doctor can find early cancer during a physical exam or with routine
tests, even if a person has no symptoms
...
The doctor may suggest other exams
for people who are at increased risk for cancer
...
The doctor's advice will be based on your age, medical history,
family history, and other risk factors
...
(More information and free booklets about self-exams are available from
the National Cancer Institute's Cancer Information Service)
...
The Cancer Information Service also can tell you about such
programs
...
You should also check regularly for new growths, sores that do not heal,
changes in the size, shape, or color of any moles, or any other changes on the skin
...

Colon and Rectum - Beginning at age 50, you should have a yearly fecal occult
blood test
...
A small amount
of stool is placed on a plastic slide or on special paper
...
This test is done becausecancer of the colon and
rectum can cause bleeding
...
If blood is found, the doctor orders more tests to help make a diagnosis
...
A digital rectal exam should be done
during regular checkups
...
In this exam, the doctor uses a thin, flexible tube
with a light to look inside the rectum and colon for abnormal areas
...
Also,
by looking in a mirror, you can check inside your mouth for changes in the color of
the lips, gums, tongue, or inner cheeks, and for scabs, cracks, sores, white patches,
swelling, or bleeding
...
Any symptoms in your
mouth should be checked by a doctor or dentist
...

Exams For Men
Prostate - Men over age 40 should have a yearly digital rectal exam to check
the prostate gland for hard or lumpy areas
...


Testicles - Testicular cancer occurs most often between ages 15 and 34
...

If you find a lump or notice another change, such as heaviness, swelling, unusual
tenderness, or pain, you should see your doctor
...

Exams For Women
Breast - When breast cancer is found early, a woman has more treatment choices
and a good chance of complete recovery
...
The National Cancer Institute encourages
women to take an active part in early detection
...
Women should ask their doctor about:
•

Mammograms (x-rays of the breast);

•

Breast exams by a doctor or nurse; and

•

Breast self-examination (BSE)

A mammogram can often show tumors or changes in the breast before they can be
felt or cause symptoms
...
This is especially true in the breasts of young women
...

Between visits to the doctor, women should examine their breasts every month
...
Any changes should be reported to the doctor
...

Cervix - Regular pelvic exams and Pap tests are important to detect earlycancer of
the cervix
...

For the Pap test, a sample of cells is collected from the upper vagina and cervix with
a small brush or a flat wooden stick
...


Women should start having a Pap test every year after they turn 18 or become
sexually active
...




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