2.3.

1 Cancer Biology Cheat Sheet

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Cancerous growth and classi​fic​ation Cancerous growth and classi​fic​ation (cont) Identi​fic​ation of Type of Cancer by
Pathol​ogist (cont)
Cancer cells are charac​terised by two distinct Cancers arising from epithelial tissues are
heritable proper​ties, which discri​minate them called “car​cin​omas” The surgeo​n/p​hys​ician will use the
from normal cells. histop​ath​ology of a benign or malignant tumour
Cancers arising from connective tissues or
to decide whether the lesion has been
First, they and their progeny reproduce despite muscle are called “sar​com​as”
completely excised and if it is likely to further
the normal constr​aints that inhibit cell division
Cancers arising from hemato​poietic tissue are metast​asise.
and prolif​era​tion. Cancer cells prolif​erate more
called “leu​kae​mia”
than the surrou​nding normal cells and so The majority of human cancers are
eventually crowd out and damage the local Cancers arising from lymphoid cells and carcinomas of various different sub-ty​pes.
tissue. tissues are called “lym​pho​mas”
Each carcinoma may arise from a distinct cell
A tumour or neoplasm is a relentless growing Each cancer cell often demons​trates features type and follow an extremely different disease
mass of abnormal cells. that reflect the cell of origin, however, as cells profile and outcome.
become more and more malignant this may
Second, cancer cells invade and colonize In low-grade lesions of epithelial tumours the
become increa​singly difficult for the pathol​ogist
territ​ories normally reserved for other cells. cancer cell may clearly resemble the cell or
to discri​minate by microscopy alone.
The invasion of cancer cells into other cellular origin, but may have started to prolif​erate and
territ​ories is called “metas​tas​is” and it may be the dividing cells may escape the basal layer of
Identi​fic​ation of Type of Cancer by
local or distant. the epithe​lium. In high-grade lesions, (that is
Pathol​ogist
moderate to severe cancer), the cells appear
Third, cancel cells are geneti​cally unstable.
Pathol​ogists are able to identify the relative much more undiff​ere​ntiated and demons​trate a
Fourth, cancer cells evade limita​tions to cell stages in cancer develo​pment from biopsy highly variable cell and nuclear size and shape.
prolif​eration escaping replic​ative senesc​ence.
specimens that are obtained. Abnormal mitotic figures are frequently seen,
Fifth, cancer cells have lost the ability to evidence of genetic instab​ility of the tumour.
Hist​opa​tho​logy and spec​ialized stains
differ​ent​iate. The transf​orm​ation of the cell from a low-grade
enable the identi​fic​ation of normal cells, low-
Cancer may be classified into two types benign grade cancer lesions through to high-grade lesion to a high-grade lesion arises by
or mali​gnant tumours, and in many cases the cell of origin successive cycles of DNA mutation and natural

can be identi​fied. selection.

As long as the cancer cells remain clustered
These various pathol​ogical classi​fic​ations for The acquis​ition of additional DNA mutations
together in a single mass enclosed in a fibrous
connective tissue or capsule the tumour is the most part reflect the cell of origin of the generates a selective advantage of the mutated

classified as benign and may be completely cancer, and are extremely important in cell over its normal neighb​ours, facili​tating
predicting disease outcome and prognosis, increased prolif​era​tion, overcoming natural
cured by surgical excision (assuming it is
likelihood and sites of metastasis and are barriers to growth in the surrou​nding tissue.
accessible surgic​ally).
essential for approp​riate treatments i.e. no Many successive rounds of genetic mutation
A tumour is classified as mali​gna​nt, if its cells
treatment versus local treatment, versus are required, as cells contain many distinct
have the ability to invade the surrou​nding
chemot​herapy plus or minus radiot​herapy. regulatory systems, which inhibit abnormal cell
tissue. Such cells may break loose and enter
There are various sub-sets of the benign prolif​era​tion. Tumour prolif​eration and
the blood stream or invade draining lymph
tumours including aden​omas, which is a expansion requires mainte​nance of its own
nodes. The more widely and rapidly a cancer
oxygen and nutrients and the ability to
spreads or metast​asises the more difficult it may benign epithelial tumour, which may undergo
overcome physical barriers at both the local
be to treat. mali​gnant transf​orm​ation to become an
site and at distant metastatic sites.
aden​oca​rci​noma.
Cancers are classified according to their tissue
and cell type of origin.

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 2.3.1 Cancer Biology Cheat Sheet
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Identi​fic​ation of Type of Cancer by Identi​fic​ation of Type of Cancer by Escaping Cell Senescence

Pathol​ogist (cont) Pathol​ogist (cont)
Senesc​ence: loss of a cell's power of division
Pathol​ogists and scientists have developed This genetic instab​ility increases the likelihood and growth.
special stains, antibodies to surface proteins that a cancer cell will experience a mutation in
Normal highly differ​ent​iated cells do not divide.
and key components of the cytosk​eleton and a gene such as a proto-​onc​ogene or a tumour
This ability to stop prolif​erating is called “Cell
signalling pathways, together with suppressor gene, which plays an important role
Senesc​enc​e”.
chromo​somal and DNA analysis to help to in either promoting or inhibiting cell
identify specific cancers and various subtypes. prolif​era​tion. This may be a mechanism to prevent cancer
develo​pment. Cell senescence in human cells
This is important as the cancer type and the cell These genes are critical genes that regulate
is mediated by the shortening of telomeres,
of origin dictates specific therapies. cell growth and the cell cycle. As the tumour
which are the repetitive DNA sequences and
becomes increa​singly malignant, through the
The change from a normal cell to a cancer cell associated proteins that cap the end of each
successive acquis​ition of mutations in the DNA,
is called “cell transf​orm​ation”. chromo​some.
evidence of genetic instab​ility becomes more
Cancer cells lack the structural features and apparent. Chromo​somes can be seen to have The enzyme “Telom​erase” maintains these
cellular functions of normal cells. Cancer cells abnorm​alities in structure and number, in repetitive telomeric sequences. In adult human
typically show an enlarged nuclei, dense DNA prepar​ations of metaphase chromo​somes of cells the gene encoding for the catalytic subunit
and changes to the cytosk​eleton, so that the tumour cells. telomerase is switched off, or not fully activated,
cell is unable to maintain its normal shape. therefore the telomeres in these cells tend to
It is probable that cells, which maintain an
Pathol​ogists have long recognized that there is become a little shorter with each successive
optimum level of genetic instab​ility, may be the
spectrum of histol​ogical features that cell division, and eventually the telomeric cap
most likely tumour cells to survive
on the chromosome can become danger​ously
correlate with the progre​ssion of cancer. These
In normal cells, genetic instab​ility is rare. The shortened, arresting the cell cycle preventing
include abnormal cellular morphology and
presence of genetic instab​ility in tumour cells cell division, as long as the cell contains broken
presence of mitoses, or “mitotic index” and
makes it increa​singly likely that at least one cell or inadequate DNA.
assessment the degree of invasi​veness of the
within the tumour cell acquires a mutation. This
tumour. In normal cells that still produce functional p53
may allow the cancer cell to overcome certain
and have intact cell cycle checkp​oints, this
There is now strong evidence that these selection barriers, which include the ability of
shortening of the telomerase results in an
histol​ogical and clinical charac​ter​istics have a the cell to prolif​erate under less than optimum
arrest of cell division, i.e., “rep​lic​ative
molecular basis. There is much data to suggest condit​ions, such as under low oxygen
that cancer develops and becomes more senesc​ence”
condit​ions, or in the absence of specific growth
malignant, as multiple genetic abnorm​alities factor stimul​ation. In cancer cells or pre-cancer cells, which have
accumulate in the cell. acquired mutations in p53 or specific cell cycle
However, if the level of genetic instab​ility
By the time of clinical presen​tation most cancer checkpoint proteins, the shortening of the
becomes too high and serious mutations occur,
cells will demons​trate evidence of genetic telomerase and the signal generated maybe
this may lead to extinction of the abnormal cell.
instab​ility. This will include the inability of the ignored, and the cell cycle progresses resulting
Thus for a cancer cell to survive it requires
cancer cell to repair DNA damage, or correct in massive chromo​somal damage. The
some level of genetic instab​ility, so that it has
replic​ation errors in specific nucleo​tides. Many accumu​lated mutations may promote cancer
survival advantage, but does not acquire so
cancer cells are unable to maintain the integrity develo​pment.
many mutations that it becomes extinct.
of their genome.
Cells that are more rapidly cycling through the
cell cycle are more likely to acquire DNA
mutations and there is less time during S phase
for repair.

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 2.3.1 Cancer Biology Cheat Sheet
by Molly via cheatography.com/30516/cs/9590/

Normal cell growth and differ​ent​iation Normal cell growth and differ​ent​iation (cont) Normal cell growth and differ​ent​iation (cont)

The number of cells in a multic​ellular organism Terminal differ​ent​iation of these progenitor cells Progre​ssion from the G2 checkpoint into
is usually tightly controlled with a balance is stimulated by growth factors and cytokines mitosis may be prevented if the DNA has not
existing between the rate of cell division and resulting in cellular specia​liz​ation in terms of cell been adequately and completely replic​ated, or
differ​ent​iation, and the rate of cell death. structure and function, specific for the tissue chromosome separation in mitosis is delayed
type. These highly differ​ent​iated cells that make due to incomplete attachment chromo​somes to
In the fully developed human body, the total
up a functional tissue will, in general, retain the mitotic spindle.
number of differ​ent​iated functional cells making
their specific proper​ties, even when placed in a
up a particular tissue does not change
signif​ica​ntly, with most tissue cell popula​tions novel enviro​nment and will not interc​onvert to Regulation by specific Protein Kinases
being subject to slow turnover through cell another cell type.
The family of cyclin dependent kinases, CDKs,
division or differ​ent​iation, and cell death. Failure in the regulation of cell division and
regulate progre​ssion of the cell cycle by
differ​ent​iation or cell death results in serious
As cancer is caused by disruption of the control phosph​ory​lating selected proteins on serine
effects on the tissue or organ function.
of cell growth and differ​ent​iation, it is important and threonine residues.
to understand the molecular mechanisms that Cancer is a product of uncont​rolled
he cyclin dependent kinases themselves are
regulate the normal cell cycle and control cell prolif​eration of a single cell and often results
regulated by complex formation with specific
death. from loss of control of cell division coupled with
proteins known as cyclins, which bind the
Some cells persist throughout the lifetime of a lack of apop​tosis – (progr​ammed cell death)
kinases and regulate their activity
the organism without cell divisi​on. These Each phase of the cell cycle is tightly controlled The are two subsets of cyclins:
include nerve cells, heart muscle cells, sensory and has a specific set of checkp​oints at which
The G1 cyclins, which bind to the CDKs during
receptor cells for light and sound, and lens time the cell cycle can stop.
G1 and regulate entry into S-phase
fibres. The major checkp​oints in a cell cycle are the
The mitotic cyclins which bind the cyclin​-
Cells of other tissues, lost through cell death or checkpoint G1, just before entry into S-phase
de​pendent kinases during the G2 phase and
damage, are replaced either by mature cell and the checkpoint at G2, just before entry into
regulate entry into mitosis.
division, or differ​ent​iation of stem cells. mitosis.
One of the charac​ter​istics of the cyclins is the
The liver is an example of a tissue subject to When enviro​nmental circum​stances forbid cell
level of cyclins go up and down, i.e., oscillate
slow turnover. Following liver damage, cells division, most cells will stop at G1, as this is the
during the cell cycle.
simply divide to produce daughter cells of the point if the cell does not stop it will initiate S-
same type. In tissues such as the intestinal phase DNA replic​ation. In contrast the levels of the cyclin​-de​pendent
epithe​lium, the hemato​poietic system, or the kinases do not change. The cyclin​-de​pendent
The G1 and G2 checkp​oints can be regulated
skin, which have a very rapid turnover, kinases associate with specific cyclins to trigger
by both specific intrac​ellular proteins and
damaged cells are rapidly replaced by adult various events in the cell cycle. The activity of
extrac​ellular stimuli. In most eukaryotic cells,
stem cell differ​ent​iation. cyclin​-de​pendent kinases is usually terminated
cell cycle checkp​oints at G1 and G2 are times
as a result of degrad​ation of the cyclin.
Stem cells by definition are not terminally in which the cell cycle can be arrested, if the
differ​ent​iated and have the ability to divide previous cell cycle events have not been Specific cyclins act in each phase of the cell

throughout the lifetime of an organism. Pools of completed. cycle, for example, there are S-phase cyclins

stem cells yield some progeny that will and M-phase cyclins, which in turn form
The G1 checkpoint will prevent entry into the S
differ​entiate into more specia​lized cells and complexes with the cyclin​-de​pendent kinases
or synthetic phase, if DNA mutations or errors
others that remain stem cells with the capacity and trigger cell specific cell cycle events.
are detected.
to self renew.

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 2.3.1 Cancer Biology Cheat Sheet
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Regulation by specific Protein Kinases Cell Cycle Control System The Cell Cycle and Cancer (cont)
(cont)
This delay in entry into S-phase allows the cell
In addition to the regulation of cyclin​- time to repair DNA damage, prior to replic​ation
de​pendent kinase activity via complex with the of the DNA in S-phase. Should the function of
cyclins, additional mechanisms exist which p53 be lost, as occurs in many cancers, over
regulate cyclin dependent kinase activity. the long term there will be an accumu​lation of
genetic damage. Mutation of p53 has been
The cyclin​-cy​cli​n-d​epe​ndent kinase complex
can be inhibited by phosph​ory​lation via a detected in more than 50% of all human

protein kinase. cancers.

In contrast dephos​pho​ryl​ation of CDK by The G1 checkpoint is a critical checkpoint

CDC25 increases cyclin​-de​pendent kinase The Cell Cycle and Cancer of no return, cancer cells often abandon the
activity. In addition, the cyclin​-cy​cli​n- controls, which are present in normal cells,
d​epe​ndent kinase complexes can also be The control of G1 progre​ssion into S-phase is
which regulate the G1-S-phase entry.
important because if there is damage to the
regulated by binding of a specific inhibitors
DNA the cell cycle must pause to allow time for Once cells exit G1 and progress into S-phase,
known as CDK inhibitor proteins.
the DNA to be repaired, prior to its duplic​ation the cell cycle is automatic.
These inhibitory proteins act primarily in the
in S-phase.
control of the G1 and S-phase entry. As M-Phase
The control of G1 progre​ssion and the initiation
previously noted, the cyclin​-cy​cli​n-d​epe​ndent
of S-phase is often abnormal in cancer cells. If M-phase, “mitosis” is a phase of nuclear
kinase complexes are regulated by proteo​lysis
the G1 checkpoint is lost this leads to division, which takes approx​imately 1 hour.
of the cyclins at specific stages of the cell cycle.
unrest​rained entry into the cell cycle and
Cyclin destru​ction is mediated by ubiqui​tin​- During this time the chromo​somes are
consequent cell prolif​era​tion.
de​pendent mechan​isms, resulting in segregated and two nuclei form.
proteo​lysis of the cyclin via the proteo​some. Several important tumour suppressor genes,
In cytoki​nesis cytopl​asmic division occurs and
The transfer of ubiquitin onto the cyclin is including the retino​bla​stoma gene product and
the whole cell splits into two. M-phase is
mediated by enzymes known as ubiquitin the tumour suppressor gene p53 function to
charac​terized by progre​ssive compaction of the
ligases. regulate G1 to S-phase progre​ssion. The
chromatin (DNA and bound proteins). The DNA
retino​bla​stoma gene product Rb is an inhibitor
There are 4 specific classes of cyclins, which is replicated not as bare DNA, but as complex
of cell cycle progre​ssion, during G1, Rb binds to
are defined by the stage of the cell cycle at with tightly bound proteins called histones. The
the transc​ription factor E2F and blocks the
which they bind their respective cyclin​- condensed chromo​somes segregate onto the
transc​ription of S-phase genes.
de​pendent kinases. mitotic spindle. During mitosis the nuclear
Cell cycle progre​ssion is also regulated by p53. envelope breaks down, the nucleus condenses
hese are the G1/S cyclins, which work at the
DNA damage leads to activation of the gene to visible chromo​somes and microt​ubules
end of G1 and commit the cell to DNA
regulatory protein known as p53, which condense onto the mitotic spindle.
replic​ation
regulates the transc​ription of many important
the S cyclins, which bind the cyclin​-de​pendent In the middle of mitosis the cell cycle pauses
genes, including the cyclin​-de​pendent kinase
kinases during S-phase, and initiate DNA briefly and the duplicated chromo​somes are
inhibitory protein p21, which regulates the
replic​ation aligned on the spindle ready for segreg​ation.
cyclin​-de​pendent kinases, thereby blocking
This may quite often be seen in highly
the M cyclins, which promote entry into and the entry into S-phase.
prolif​erative and also malignant cells as mitotic
events of mitosis
figures. The mitotic index can be used as a
Many cells also contain a fourth class of cyclin marker of the degree of malignancy of the
known as the G1 cyclins which promote entry tumour.
through the restri​ction point in late G1.

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 2.3.1 Cancer Biology Cheat Sheet
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M-Phase (cont) Apoptosis (cont)

During mitosis, mitotic spindles radiate from a The balance between the level of cell division
body known as the “centr​osome”, which is the and apoptosis is an important determ​inant in
major microt​ubule organising centre in the cell. cancer. Billions of cells die from apoptosis, and
During interphase the centrosome is typically in some cancer cells the level of apoptosis is
located to the side of the nucleus, embedded decreased. For example, billions of cells die in
within the centrosome are the centri​oles. During the bone marrow and intestine every hour, in
mitosis the centriole splits into two and the adult humans. In the healthy adult cell death
daughter centro​somes move to opposite sides exactly balances cell division resulting in no
of the nucleus. Mitosis is organised by the nett change in organ or tissue size. Some novel
microt​ubule asters, which form around each of therap​eutic experi​mental strategies aim to
the two centro​somes. In mitosis the mitotic increase apoptosis in cancer cells.
spindle aligns the chromo​somes, then each
chromosome separates into two daughter
chromo​somes.

Each chromosome is aligned by the spindle to

the opposite spindle pole. Following mitosis
cytoki​nesis occurs during which time the
contra​ctile ring of actin forms beneath the
plasma membrane and as the ring contracts it
pulls the membrane inward to divide the cell into
two.

Apoptosis

Apoptosis is a physio​logical form of cell death

associated with distinct set of bioche​mical and
physical changes involving the cytoplasm,
nucleus and plasma membrane.

Apoptosis is an important inducible form of cell

death involved in the sculpture of structures
during develo​pment ie., digits, killing of viral
infected cells by cytotoxic T cells, the removal
of cells that have unsucc​ess​fully completed
mitosis or have unrepa​irable DNA damage, and
in general the adjustment of cell numbers.

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