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Carcinogenesis

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell
somewhat.
Carcinogenesis (the creation of cancer), is the process by which normal cells are
transformed into cancer cells.
Cell division is a physiological process that occurs in almost all tissues and under many
circumstances. Under normal circumstances, the balance between proliferation and
programmed cell death, usually in the form of apoptosis, is maintained by tightly
regulating both processes to ensure the integrity of organs and tissues. Mutations in DNA
that lead to cancer (only certain mutations can lead to cancer and the majority of potential
mutations will have no bearing) disrupt these orderly processes by disrupting the
programming regulating the processes.
Carcinogenesis is caused by this mutation of the genetic material of normal cells, which
upsets the normal balance between proliferation and cell death. This results in
uncontrolled cell division and the evolution of those cells by natural selection in the
body. The uncontrolled and often rapid proliferation of cells can lead to benign tumors;
some types of these may turn into malignant tumors (cancer). 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. Malignant tumors can invade other organs, spread to distant
locations (metastasis) and become life-threatening.
More than one mutation is necessary for carcinogenesis. In fact, a series of several
mutations to certain classes of genes is usually required before a normal cell will
transform into a cancer cell.[1] Only mutations in those certain types of genes which play
vital roles in cell division, apoptosis (cell death), and DNA repair will cause a cell to lose
control of its cell proliferation.
Mechanisms of carcinogenesis
Cancer is a genetic disease: In order for cells to start dividing uncontrollably, genes that
regulate cell growth must be damaged. Proto-oncogenes are genes that promote cell
growth and mitosis, whereas tumor suppressor genes discourage cell growth, or
temporarily halt cell division to carry out DNA repair. Typically, a series of several
mutations to these genes is required before a normal cell transforms into a cancer cell.
This concept is sometimes termed "oncoevolution."

Characteristics of Cancer Cells - Almost all types of


differentiated cells can become neoplastic ,or
cancerous.
The process of cell change in which ,a cell loses its
ability to control its rate of division, and thus
becomes a tumour cell, is called cell transformation.
The cancerous cell generally retains the structural
and functional characteristics of the normal cell
type from, which it is derived.
Thus cancerous cells of the thyroid gland continue
to secrete thyroxin.
Neoplastic cells, however, differ from their normal
counterparts in several respects.

1. Immortalization. Normal cell cultures do not survive indefinitely. For example human cell cultures
die after about 50 generations, and chicken cell cultures have a much shorter life expectancy.
On the other hand transformed cell cultures are immortal and can grow indefinitely.
Cell cultures infected with mouse sarcoma virus can be maintained as long as nutrition is provided and
overcrowding avoided.
2. Loss of contact inhibitions. Normal cells in a culture stop growing when their plasma membranes
come into contact with one another.
When two normal cells come into contact, one or both will stop moving and then begin to move in
another direction. This inhibition of growth after contact is caned contact inhibition.

If mouse cells are grown in a culture medium the


adhesive properties of the cell membranes cause the
cells to stick to the walls of the glass vessel.
As long as the cells are few, they go on dividing
regularly at 24 hour intervals, until they form a
single layer (monolayer).
After this their rate of division slows down.
Apparently contact of the plasma membranes of the
cells inhibits growth and division.
Transformed cells on the other hand usually do not
stop dividing after forming a monolayer.
Division continues until several layers of cells are
formed.
Thus transformed cells are unable to go into a
quiescent stage, and will grow continuously until
they kill themselves.

Transformed cells apparently, undergo a change in the property of their cell membranes which become
less adhesive. This change enables the cells to dissociate from neighboring cells and to infiltrate other
organs, where they form metastatic tumours.
Cancer cells apparently lack proper recognition and communication.

3. Reduced cellular adhesio


. When normal cells become cancerous there is a change in the 'stickiness' of their cell membranes.
Normal cells show stickiness or adhesiveness. If grown in a nutrient medium kept in a glass vessel, the
cells stick to the glass rather than float in the medium.
Transformed cells show a decreased adhesiveness, and if grown in solid media stick to each other less
than do normal cells.
However, examples of increased adhesiveness following malignant transformation have also been
reported.
Adhesiveness shows considerable specificity. Thus
liver cells tend to stick to other liver cells but not to
other cell types, E.g, kidney cells,
If the Cells of the liver and the pancreas are
separated by the enzyme trypsin and incubated
together, they aggregate to form small pieces of
liver tissue and kidney tissue.
Thus kidney cells stick to kidney cells and liver
cells to liver cells, Cancerous cells do not show this
property. H malignant skin cancer cells are mixed
with normal kidney cells the aggregates formed
contain both kidney and skin cells mixed together.
This probably explains why malignant cells
caninvade several normal organs

4 Invasiveness. One of the most important characteristics of transformed cells is their


invasiveness, i.e. the ability to invade other tissues.
In contrast to normal cells, transformed cells can penetrate the chorioaallantoic
membrane of the hen's egg. This invasiveness could be the result of changes in the
plasma membrane and or proteases released by the cells
6. Loss of anchorage dependenc
. Most normal cells must be attached to a rigid substratum (i.e, they must be anchored) in
order to grow. Transformed cells can grow even when they are not attached to the
substratum, as for example when they are suspended in a semisolid medium containing
agar or methyl cellulose.
This loss of anchorage is the most striking characteristic of transformed cells which form
malignant tumours.
It is used to select transformed cells from a normal cell population.
6. Lower serum requirements. Growth of normal cel1s in a tissue culture medium
requires a high concentration of serum. Some serum growth factors (somatomedins)
resemble insulin in interacting with external receptors of the cell membrane to regulate
biochemical activities within the cell. Transformed cells can grow in a culture medium
containing much less serum than required by normal cells.
For example normal 3T3 cells (established fibroblasts of the mouse, line commonly used
in tissue culture) grow optimally in 10% foetal calf serum, while cel1s transformed by
SV40 (simian virus number 40) can grow equally well in 1% or 10 % serum. It has been
suggested that the lower serum requirement of transformed cells is because of their lesser
requirement of outside substances to lower their intracellular cAMP (cyclic- AMP) level
to trigger mitosis
7. Selective agglutination by lectins - Lectins are proteins widely distributed in plants,
particularly legumes, but are also found in some animals.
They have the ability to bind to receptors, which are branched chain sugar molecules
(oligosaccharides), on the surface of the cell membrane.
As a result of this binding lectins cause agglutination or clumping of cells. They are
therefore, agglutinins.
In normal cells the receptors or agglutinin binding sites for lectins lie in a diffuse manner
on the cell surface and are immobile.
Lectins make Jew intercellular bridges, and therefore agglutination is not possible. In
transformed cel1s the, receptors are more mobile within the membrane.
Local regions of high binding site concentration are formed. Lectins are thus able to form
enough intercellular bridges to result in agglutination.
8. Molecular changes in cell membrane components. There are several differences
between the surface cell membranes of normal and transformed cells.
The cell membrane consists of four main types of phospholipids, which form the lipid
bilayer, with glycolipids and glyco proteins inserted into this bilayer. Cancerous cells
apparently do not differ from normal cells in their relative amounts of phospholipids
However, gangliosides (glycolipids which contain sialic acids) become reduced in certain
mouse cancer cells. Enzymes involved in their biosynthesis are also reduced. Normal
cells possess four types of gangliosides, GMla, GM1, GM2 and GM3.
Tumours cell predominantly contain the simplest type, GM3. It is however, not certain
whether these changes are primarily responsible for the cancerous condition, since some
transformed mouse cell lines contain normal amount of gangliosides.
Certain changes have been found in the glycoproteins of cancerous cells. The surface
glycoprotein of MW 46,000 disappears early in transformation to the cancerous
condition. There is also a slow disappearance of a major protein, called LETS (large,
external, transforming sensitive) protein (MW -240,0.00).
Probably the most important protein to, disappear after transformation is the One having
MW 200,000.
As mentioned previously, the mobility of the surface proteins increases in transformed
cells, thus permitting easier agglutination of tumour cells by lectins.
9 Disorganisation of the Cytoskeleton - Normal cells have a cytoskeleton (very much
like. muscle fibres) which consists of microtubules and microfilaments.
These fibres have a regular arrangement and bring about coordinated cell movement. In
transformed cancer cells the fibres are much fewer in number and usually much thinner.
It has been suggested that in transformed cells the cytoskeleton undergoes
depolymerization.
The microtubules disaggregate.
The microfilaments (actin) fibres undergo depolymerization and disappear, but diffuse
actin remains. The myosin-like filaments also disappear.
Thus in transformed cells the cytoskeleton proteins become less organised than in normal
cells. It has been suggested that it is this disorganisation of the cytoskeleton, and not the
changed fluidity of lipids, that results in increased mobility of cell membrane proteins.
The disorganisation of the cytoskeleton also affects the cell surface in another way. When
cancer cells touch there is a constant and unco ordinated throwing out and retraction of
blebs, microvilli and ruffles from the cell surface.
Tumour cells have a more ruffled surface than normal cells, with many more surface
processes.
10.Increase in negative surface charge of cell membrane: Comparisons of surface
membrane charge by microlectrophoresis have been made between normal and malignant
cells.
In malignant cells anodic mobility is usually higher, indicating increase in negative
surface charge
11. Increased sugar transport: Tumour cells consume much more glucose than normal
cells because they have to grow and multiply.
There is a great increase in the rate of sugar transport across the surface cell membrane
after transformation. This increases sugar intake by malignant cells
12. Appearance of virus specific transplantation rejection antigens: Plasma membranes of
most transformed cells contain antigens which are not present in normal cells.
Thus in cell transformed by adenoviruses and papovaviruses the T antigen is always
present. Similarly all cells transformed by the Epstein-Barr virus (EB. virus) contain an
antigen called the EB nuclear antigen (EBNA).
Tumour antigens can bring about an immunity response against themselves in.
genetically similar hosts, This is in contrast to normal histocompatibility antigens.
The immunity response brought about by the antigens results in recognition and
destruction of newly formed cancer cells and their descendants.
Such a defence mechanism is called immunological surveillance, and can lead to the
elimination of cancer cells under favorable conditions. It has been suggested that only in
the rare cases when this defense mechanism fails that tumours are formed
13. Defective electrical communication: Electrical connections normally occur between
individual cells. In some cancer cells, however, It has been reported that such connections
are defective
14. Increased secretion of proteolytic enzymes. Large amounts of proteolytic enzymes are
secreted by all types of cancer cells, except those of blood-forming tissues. The cancer
cell secretes a protease called the cell factor (MWI , 40,00O), to form a plasmin, a
proteolytic enzyme (MW 76,000).
It has been suggested that plasmin removes many proteins projecting from the cell
surface by enzymatic digestion and signals the cell into division
If normal cells are treated with proteases they show many of the characteristics of
transformed cells, It has been speculated that viral proteins cause the release of
extracellular protease.
There is no direct evidence for this, however
15. Aldolases: In most mammalian tissues the enzyme aldolase exists in the form of three
isozymes A, Band C. Isozymes A and C predominate in embryonic tissues, while in adult
differentiated tissues the B isozyme is predominant.
In some tumours, especially in poorly differentiated and rapidly growing cancers like
certain hepatomas, isozyme B is replaced by isozyme A, the embryonic form.
16. Increased rate of glycolysis: In the 1920s War burg pointed out the oxidative
(aerobic) respiration is depressed in tumour cells, and that glycolysis (anaerobic
respiration) increases.
This has been demonstrated by an increase in lactic acid production in cells of solid
tumours.
There is a corresponding increase in the uptake of glucose, It has been suggested that
increase in glycolysis is the result of injury to the normal oxidation mechanism of the
cell.
Studies On respiration in tumour cells have, however, yielded conflicting results. Both
oxidation and ATP synthesis have remained unchanged in isolated tumour mitochondria.
On the other hand, increase in these activities has also been observed.
Moreover, it is not clear whether the changes in respiratory metabolism are the causes of
cancer or the results of cancer.
It is possible that the high energy requirements of actively dividing cancer cells may
result in the cell adapting anaerobic glycolysis as a supplement to normal aerobic
respiration

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